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Cancer protection of soy resembles cancer protection during pregnancy
Abstract
It has been established that carrying a pregnancy to full-term at an early age can protect against contracting cancer by up to 50% in later life. The trophoblast theory of cancer states that trophoblast and cancer tissue are very similar. New findings suggest that the loss of fetal cells during pregnancy resemble those cells responsible for causing metastasis in cancer. Fetal cells and spreading cancer cells are highly proliferative. They are similar to stem cells, exhibiting no or low hormone receptor expression, and require a hormone receptor independent mechanism for control. Control of membrane stability during pregnancy is of vital importance for a successful pregnancy and is mediated by androstenediol and 2-methoxyestradiol. 2-Methoxyestradiol has no hormone receptor affinity and elicits strong anticancer effects particularly against cancer stem cells and fetal cells, for which currently no treatment has yet been established. There is a discussion whether pregnancy reduces cancer stem cells in the breast. Soy isoflavones are structurally similar to both hormones, and elicit strong anticancer effects and antiangiogenesis via inhibition of NF-κB, even in hormone receptor independent breast cancers seen in epidemiologic studies. The trophoblast theory of cancer could help to explain why soy baby nutrition formulas have no effect on baby physiology, other than the nutritional aspect, although soy elicits many effects on the adult immune system. To survive the immune system of the mother, the immune system of the fetus has to be separated; otherwise, the reduction of the immune system in the mother, a necessary feature for the blastocyst to grow, would immediately reduce the immunity for the fetus and endanger its survival. Similar to a fetus, newly born babies show immune insensitive to Th1 and Th2 cytokines, which are necessary and crucial for regulating the immune system of the mother, thus raising the risk of the baby of developing allergies and neurodermatitis. Gene expression studies in vitro as well as in circulating tumor cells from patients consuming a fermented soy product support the antiangiogenic as well as antiproliferative effects of soy.
... For example, when fish conquered land for the first time, the only oxygen source was salt water in the ocean and not the surrounding air [17]. Evolution added a steroidal hormone called aldosterone to increase potassium to keep water in [1,2].) the lungs of the fish who had moved on to dry land, thus they recovered oxygen from the water and not from the surrounding air [18]. Stress edema in the lung and legs, in today's severe human immune diseases, in cancer, severe mental diseases and swollen legs in PMS in the female hormone cycle have to be considered unnecessary, as we can retrieve enough oxygen from the surrounding air causing hypertension in humans [18,19]. ...
... It is not clear whether progesterone is a mediator of the stress response reaction and a marker of severe mental disease or is involved in the etiology of severe mental disease. Nevertheless (a) severe PMS, the so-called premenstrual dysphoric disorder (PMDD), is compared to bipolar disorders by clinicians, as similar steroidal hormone alterations exist, and (b) women suffering from schizophrenia and bipolar disorders are very frequently admitted to the hospital during their late luteal phase and suffer also from PMS [55]: 68% of all women suffering from bipolar disorder show a maximum in the premenstrual phase and 67% also show PMS-like symptoms whereas a subfraction show a maximum in the preovulatory phase [2]. It may be more appropriate to explain the premenstrual relationship with bipolar and schizophrenia as an exacerbation: A literature survey showed a clear relationship between the premenstrual phase of young women and schizophrenia, psychosis, menstrual exacerbation [56]. ...
... The innate immunity is a nontoxic method to protect against living cells and diseased cells. Besides being nontoxic, it has been established that carrying a pregnancy to full-term at an early age can protect against contracting cancer by up to 50% in later life, showing that the innate defense can be very powerful [2]. The necessity to develop treatments against severe mental diseases may involve also genomic treatments as was expressed by the Department of Mental Health of the NIH [63]. ...
There are two forms of immune defense, the specific or adaptive immune defense and the unspecific innate immune defense. Vaccination is utilized against specific bacteria via the adaptive immune system. The innate immunity DNA stress defense is a non-toxic mechanism developed in yeasts and conserved in mammals and in plants. Although the steroidal hormone cascade has overtaken the stress response and allows superfast response via non-genomic receptors, the old innate immunity response is still mediated via the steroidal hormones cascade. The classical drug/receptor model has provided for many solutions, however, in antibiotics, cancer, and in severe mental diseases this model reaches to certain limits. The NIH/Department of Mental Health has developed a new model that shows severe mental diseases may be immune diseases that can be treated by replacing old diseased nerve cells by new healthy nerve cells, where the old innate immunity may be exploited. This means that severe mental diseases are physical diseases. A newly developed model, where modifications of the steroidal hormone cascade help to understand bipolarity, schizophrenia, and PTSD in men and women can be transferred to gynecological hormone modifications in women, where innate immunity is mediated via the same steroidal hormone cascade. Treatment via immune response via the DNA cascade should be developed in cancer, infections and severe mental disease, because foreign cells or diseased cells may be removed by the unspecific innate immunity.
... This problem is well known during the treatment of urogenital atrophy, with all forms of local application including pure moisturizers [38]. A high level of medical safety was achieved through the selection of safe herbal drugs [28,[30][31][32]39]. ...
b> Introduction: Urogenital atrophy and its sequelae, particularly genital dryness, urological problems, and pain on genital touching, are common medical problems for menopausal women and women undergoing antihormonal cancer treatment. To meet the requirements for a nonhormonal local treatment, a compounded herbal preparation was developed as a vaginal ovule ( Dioscorea comp. ovulum), and the efficacy and applicability of this herbal treatment were investigated. Methods: This was a retrospective chart review of patients’ records. The study was approved by the Ethics Committee of the Canton of Zurich (project number BASEC 2016-01982). Between 2007 and 2011, patients with urogenital atrophy and related symptoms, who wanted to initiate herbal treatment, were asked for consent to be interviewed (4-point rating scale) and examined gynecologically with photo documentation of their vaginal discharge. A total of 26 patients met the enrollment criteria and consented to the procedure. The first 8 weeks consisted of a daily application of low-dose Dioscorea comp. ovulum followed by high-dose Dioscorea comp. ovule twice weekly for at least 3 months. Result: A total of 23 patients completed the trial. Of the 19 patients in the subgroup with an atrophic vaginal maturation index (VMI), 16 achieved a eutrophic VMI. Four patients began therapy with hypotrophy. There was a 96% decrease in complaints (22/23). The genital dryness score decreased from 1.80 to 0.25 points, urological problems from 2.38 to 0.85 points, and pain on genital touching from 1.70 to 0.60 points. Application, tolerability, and medical safety of the formula were good. Conclusion: The phytotherapeutic compounded preparation Dioscorea comp. ovule ( Dioscorea villosa , Glycine max , Salvia officinalis ) is suitable for the treatment of urogenital atrophy and its sequelae.
... Volume 4| Issue 1 | 3 in cancer cells [11]. Although apoptosis is generally considered to be a form of cell death, according to Uwe Rohr the same processes that initiate apoptosis may also lead to differentiation of stem cells into functional tissue. ...
Symbiont Conversion Theory is a new scientific theory, summarizing and generalizing efforts that have been made by various researchers in the past years; it could even be perceived as a new scientific paradigm. This theory states that microorganisms and cells which are commonly considered to display parasitic behaviour can be "educated" and transformed into symbionts. This is not just a hypothesis but a theory since there is already evidence that proves that this is possible. The primary motivation for developing this theory is the failure of classical approaches to therapy of cancer and infectious diseases that follow the paradigm "destroy and kill". It is common knowledge about medical doctors that chemotherapy and radiation therapy have detrimental side effects on healthy, functional tissue, and also that antibiotics can harm benevolent cells. These negative side effects can possibly be avoided by the new approach of treating parasitic diseases by converting the culprits into symbionts of which the human organism profits. Another motivation for developing this theory is that some researchers have suggested bacteria and other microbes have certain innate rights themselves [Cockell]. Motivation and Goals Symbiont Conversion Theory is the statement that parasites can be converted into symbionts, and it explains by a couple of examples how this can be done. There is both a practical and an ethical motivation for the development of this theory. Some may dismiss the ethical dimension as being unimportant; after all, who empathizes with microorganisms, except perhaps some crazy people? However, even if you dismiss the ethical component, Symbiont Conversion Theory has a practical value: it is just too well-known a matter of fact that chemotherapy, radiation therapy and antibiotics can have harmful side-effects which are better to be avoided. The long-term goal is to create organisms, most of all humanoid organisms, that have an improved immune system. Instead of destroying and killing intruders, the immune system of this post-human species should educate the parasites and convert them into symbionts. This, of course, is only a long-term goal. It requires synthetic biology to reach a level that allows to create artificial immune systems. It also requires artificial life and computational systems biology to be far more developed than now, so that synthetic organisms can be simulated on a computer before the modifications are actually implemented, to avoid mistakes. This may sound more like fiction than science, but it actually is science. Moreover, this is only the long-term goal. The short-term goal is to make new treatments of cancer and infectious diseases possible by means of signalling cascades triggered by hormones and by modification of microorganisms using synthetically engineered bacteriophages that do not kill bacteria but rather alter their behaviour.
... Increased food consumption in the Docetaxel C Iso group compared with the Docetaxel group can also be attributed to the reduction of NF-kBp65 expression. Inflammatory cytokines induced by cancer tumor may cause cachexia in cancer patients (29). ...
Background:
One major concern in the treatment of cancer patients during chemotherapy is drug resistance. Here we investigated the effects of soy isoflavone extracts alone or in combination with Docetaxel on the drug resistance, angiogenesis, apoptosis, and tumor volume in mouse 4T1 breast tumor model.
Methods:
Sixty female BALB/c mice were randomly divided into 4 groups: control, dietary soy isoflavone extract [Iso, 100 mg/kg diet (0.01%)], Docetaxel (10 mg/kg) injection, and the combination of dietary soy isoflavone extract and intravenous Docetaxel injection (Docetaxel + Iso). One week after the third injection, the breast tumors of eight mice from each group were excised to analyze NF-κBp65' vascular endothelial growth factor receptor-2 (VEGFR2) and Pgp gene and protein expressions and the other seven mice were monitored for survival rate analysis until they died.
Results:
NF-κBp65 gene and protein expressions were significantly lower in the Docetaxel + Iso group in comparison with that of the Docetaxel group. VEGFR2 protein expression in the Docetaxel + Iso and Iso groups was significantly lower than that of the Docetaxel group.
Conclusion:
These findings may indicate that the combined use of isoflavone extracts together with chemotherapeutic agents has more efficient anti-carcinogenic effects than their individual use.
... The results are in agreement with those of Rohr et al's 17 who found that daily consumption of fermented soy significantly increased appetite and decreased cytokine TNF-α level in cancer patient sera during chemotherapy compared to placebo group. Reduction of cytokines such as interleukin 6 (IL-6) due to soy isoflavone consumption may be another possible explanation 19 . ...
Emergence of drug resistance has brought major problems in chemotherapy. Using nutrients in combination with chemotherapy could be beneficial for improvement of sensitivity of tumors to drug resistance. Soybean-derived isoflavones have been suggested as chemopreventive agents for certain types of cancer, particularly breast cancer. In this study, the synergistic effects of soy isoflavone extract in combination with docetaxel in murine 4T1 breast tumor model were investigated.
In this study, mice were divided into 4 groups (15 mice per group) of control, the dietary Soy Isoflavone Extract (SIE, 100 mg/kg diet), the Docetaxel (DOCE, 10 mg/kg) injection and the combination of dietary soy isoflavone extract and intravenous docetaxel injection (DOCE+SIE). After 3 injections of docetaxel (once a week), 7 mice were sacrificed to analyze MKI67 gene and protein expressions and the rest were monitored for diet consumption, tumor growth and survival rates.
In DOCE+SIE group, diet consumption was significantly higher than DOCE group. While lifespan showed a trend towards improvement in DOCE+SIE group, no significant difference was observed among the 4 studied groups. Tumor volume was not significantly affected in treated groups. A lower but not significant MKI67 protein expression was detected in western blot in DOCE+SIE group. The mRNA expression was not significantly different among groups.
The results suggest that the combination of soy isoflavone as an adjunct to docetaxel chemotherapy can be effective in improving diet consumption in breast cancer.
Under FSWW08, mental stress and anxiety was reduced, accompanied by a normal sleeping pattern at night and increased energy levels, which caused increased physical activity. Patient reported improved breathing, documented by stable FVW. The patient exhibited a normalization of blood pressure (from pre diagnosed ALS and no consumption of FSWW08, similarly in the off phase, when FSWW08 was not taken) from 170/100 mm HG to 120/80 mm HG under FSWW08 consumption) within seven days, blood lipids were normalized (cholesterol, triglycerides, HDL, LDL). It is reported in the literature that unfavorable blood lipids are related to severity of ALS in Japanese and Western patients. This is the first time stabilization of ALS has been observed accompanied by improvements in blood lipids in patients. This single report corroborates studies conducted with FSWW08 in other diseases including cancer, severe mental diseases (PTSD and Schizophrenia) and severe virus infections. The FDA has granted a general unspecific Health Claim that soy improves blood lipids like cholesterol and triglycerides. This is the first time a fermented soy formulation, FSWW08, has prevent progression of ALS over a two years period and normalized blood lipids. The special fermentation of FSWW08 causes an increase in immunity, cellular stress reduction and blood lipids. Larger clinical trials in ALS patients with FSWW08 are now warranted to investigating whether these results can be confirmed, and whether FSWW08 increases survival, as well as whether blood lipids are a prognostic marker of ALS.
Introduction: It was suggested that specific plants may reduce cancer's resistance to chemotherapy. Resistance inhibits apoptosis, as well as other fundamental anti-cancer protective mechanisms. Soy bean has been found to reduce cellular stress and repair DNA damage caused by drought or parasites, and can transfer this defense mechanism to other plant species as well. The aim of this study is therefore to conduct a systematic comparison of the effect of soy bean formulation (FSWW08) on gene expression in in vitro human breast cancer cell line, and in in vivo in blood circulating tumor cells (CTC), after oral consumption of FSWW08 by patients suffering from breast-, ovarian-, and prostate cancer. Method: In vitro gene expressions studies were conducted with the human breast cancer cell line BT-474 that was exposed to doxorubicin or FSWW08, either alone or in combination. Ovarian-, prostate-, and breast cancer patients received FSWW08 for 30 days. CTC were extracted from their blood according to an established protocol. Gene expression evaluations were conducted before and after treatment. Results: In vitro, the multi-drug resistance (MDR) protein was reduced by FSWW08, but was increased by doxorubicin. The combination of FSWW08 and doxorubicin, however, showed a protective effect against the increase of MDR in physiologic concentrations, increased, however, also in high experimental concentrations of both agents. The expression of several cancer-related protective genes, such as tumor suppressor factors p21, p38 and p53, was improved by FSWW08 in vitro and in vivo, which helped cell differentiation and new tissue formation. Additionally, the BAX/Bcl2 ratio was improved, in vitro, as well as gene expression of estrogen receptor beta, NF-κB, MAP kinase, c-JUN, and matrix metalloproteinase 9, together with an increase of VEGF expression in vivo in CTC.
Many cancer patients do not die due to impaired organ functions, but as a result of reduced general conditions, such as cachexia, sarcopenia, depression, infections, or stress. Reduced general health may be caused by immune modifying cytokines released from the tumor into the body. Improvement of immunity would not only reduce cancer side effects through inhibiting cytokine release from the tumor into the blood, but also, according to a new hypothesis, modify the cancer stem cells (CSC) in the tumor, which are believed to drive cancer growth and metastasis. We reported previously several investigations with a dietary fermented soy formulation (FSWW08) in cancer patients, where we saw a) strong reduction of cancer symptoms, b) broken resistance to chemotherapy, and c) a strong reduction of chemotherapy's toxic side effects, when taken in combination. This publication reports two new findings from a pilot study with postsurgical, treatment resistant patients conducted over four years. First, neither treatment resistance nor side effects were observed. Second, more patients have survived than expected. The improved health and immunity is detected together with increased CSC differentiation, suggesting lower aggressiveness, which was corroborated by increased gene expressions, particularly of steroidal hormones, MAPkinase, NF-κB, and tumor suppressor factor p53, a typical marker of "stemness" or cell differentiation. Although limited by its small, homogenous sample size, the results of this pilot study illustrate the relationship between CSCs differentiation, and the clinical symptoms of immunity, which influence survival outcomes and raise the clinical potential of measuring CSCs in ovarian, prostate, and breast cancers. The improved survival rates are also seen in larger cohort studies, which show similar gene expression profiles, which were induced by FSWW08 in the treatment resistant cancer patients in this study.
Abstract In cancer patients, appetite and immune status are significantly weakened. Two experimental fermented formulations without (group A, named as FSWW08) and with (group B, FSWW08) an extract from yam root were investigated against a placebo formulation with casein (group C) in a clinical study conducted in six cancer hospitals where cancer patients underwent radio or chemotherapy (patients undergoing radiation therapy n=78, patients undergoing chemotherapy n=184, total 262). IgG and IgA were increased by formulation A in patients despite receiving radio- or chemotherapy. Group A experienced statistically significant increases in lymphocyte transformation rates, whereas group B and group C did not. Formulations A and B either inhibited or lessened statistically significant decreases in white blood counts, whereas the placebo group experienced substantial decreases. Hemoglobin and platelet decreases were inhibited in group A, although not statistically significantly. Patients in group A received no blood transfusions, whereas many patients from the placebo group received blood transfusions. Appetite loss was reduced in group A from 57.9% to 13.3% and in group B from 70% to 35.8%. In the placebo group, an increase in appetite loss was detected under chemo and radiation therapy from 41.8% to 70.9%.
A clinical study was conducted to determine steroidal hormone cascade in the blood to relate them to mental performance with the Clinician-Administered PTSD scale (CAPS), serum lipid concentrations, and steroidal hormones, particularly cortisol, testosterone, estradiol, dehydroepiandrosterone (DHEA), and pregnenolone, in treatment-resistant male veterans with combat-related chronic posttraumatic stress disorder (PTSD) before and after consumption of a special fermented soy formulation (FSWW08). Admitted veterans in the study were resistant to conventional psychological and pharmacological therapies.
Ten treatment-resistant soldiers with combat-related PTSD (according to the
FSWW08 increased blood levels of steroids, such as testosterone, estradiol, and particularly the adrenal hormones cortisol and androstenediol. Decreased steroidal hormones from the upper part of the hormone cascade, such as cholesterol, DHEA, and pregnenolone were experienced. The arteriosclerotic risk was reduced (cholesterol, 280±35 to 205±22 mmol/L, p
The transcription factor NF-kappaB has been the focus of intense investigation for nearly two decades. Over this period, considerable progress has been made in determining the function and regulation of NF-kappaB, although there are nuances in this important signaling pathway that still remain to be understood. The challenge now is to reconcile the regulatory complexity in this pathway with the complexity of responses in which NF-kappaB family members play important roles. In this review, we provide an overview of established NF-kappaB signaling pathways with focus on the current state of research into the mechanisms that regulate IKK activation and NF-kappaB transcriptional activity.
Considerable research has focused on the anti-inflammatory and antiproliferative activities exhibited by the soy isoflavone genistein. We previously demonstrated that genistein suppresses TNF-alpha-induced NF-kappaB-dependent IL-6 gene expression in cancer cells by interfering with the mitogen- and stress-activated protein kinase 1 activation pathway. However, effects of isoflavones on immune cells, such as dendritic cells, remain largely unknown. Here we show that genistein markedly reduces IL-6 cytokine production and transcription in LPS-stimulated human monocyte-derived dendritic cells. More particularly, we observe that genistein inhibits IL-6 gene expression by modulating the transcription factor NF-kappaB. Examination of NF-kappaB-related events downstream of TLR4 demonstrates that genistein affects NF-kappaB subcellular localization and DNA binding, although we observe only a minor inhibitory impact of genistein on the classical LPS-induced signaling steps. Interestingly, we find that genistein significantly increases p53 protein levels. We also show that overexpression of p53 in TLR4/MD2 HEK293T cells blocks LPS-induced NF-kappaB-dependent gene transcription, indicating the occurrence of functional cross-talk between p53 and NF-kappaB. Moreover, analysis of IL-6 mRNA levels in bone marrow-derived p53 null vs wild-type dendritic cells confirms a role for p53 in the reduction of NF-kappaB-dependent gene expression, mediated by genistein.
Full-term pregnancies are associated with long-term reductions in maternal risk of breast cancer, but the biological determinants of the protection are unknown. Experimental observations suggest that human chorionic gonadotropin (hCG), a major hormone of pregnancy, could play a role in this association. A case-control study (242 cases and 450 controls) nested within the Northern Sweden Maternity Cohort included women who had donated a blood sample during the first trimester of a first full-term pregnancy. Total hCG was determined on Immulite 2000 analyzer. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through conditional logistic regression. Maternal breast cancer risk decreased with increasing hCG (upper tertile OR, 0.67; CI, 0.46-0.99), especially for pregnancies before age 25 (upper tertile OR, 0.41; CI, 0.21-0.80). The association diverged according to age at diagnosis: risk was reduced after age 40 (upper tertile OR, 0.60; CI, 0.39-0.91) and seemed to increase before age 40 (upper tertile OR, 1.78; CI, 0.72-4.38). Risk was reduced among those diagnosed 10 years or longer after blood draw (upper tertile OR, 0.60; CI, 0.40-0.90), but not so among those diagnosed within 10 years (upper tertile OR, 4.33; CI, 0.86-21.7). These observations suggest that the association between pregnancy hCG and subsequent maternal risk of breast cancer is modified by age at diagnosis. Although the hormone seems to be a determinant of the reduced risk around or after age 50, it might not confer protection against, or it could even increase the risk of, cancers diagnosed in the years immediately following pregnancy.
To examine whether there are any characteristics of women or their initial tumors that might be useful for tailoring surveillance recommendations to optimize outcomes. We followed 17,286 women for up to 5 years after an initial diagnosis of ductal carcinoma in situ (DCIS) or early stage (I/II) invasive breast cancer diagnosed between 1996 and 2006. We calculated rates per 1,000 women years of recurrences and second breast primaries relative to demographics, risk factors, and characteristics of initial diagnosis: stage, treatment, mode of initial diagnosis. Nearly 4% had a second breast cancer event (314 recurrences and 344 second breast primaries). Women who used adjuvant hormonal therapy or were ≥ 80 years had the lowest rates of second events. Factors associated with higher recurrence and second primary rates included: initial DCIS or stage IIB, estrogen/progesterone receptor-negative, younger women (<50 years). Women with a family history or greater breast density had higher second primary rates, and women who received breast conserving surgery without radiation had higher recurrence rates. Roughly one-third of recurrences (37.6%) and second primaries (36.3%) were not screen-detected. Initial mode of diagnosis was a predictor of second events after adjusting for age, stage, primary treatment, and breast density. A recent negative mammogram should not falsely reassure physicians or women with new breast symptoms or changes because one-third of second cancers were interval cancers. This study does not provide any evidence in support of changing surveillance intervals for different subgroups.
The last 15 years has seen an explosion of interest in the cancer stem cell (CSC). Although it was initially believed that only a rare population of stem cells are able to undergo self-renewing divisions and differentiate to form all populations within a malignancy, a recent work has shown that these cells may not be as rare as thought first, at least in some malignancies. Improved experimental models are beginning to uncover a less rigid structure to CSC biology, in which the concepts of functional plasticity and clonal evolution must be incorporated into the traditional models. Slowly the genetic programmes and biological processes underlying stem cell biology are being elucidated, opening the door to the development of drugs targeting the CSC. The aim of ongoing research to understand CSCs is to develop novel stem cell-directed treatments, which will reduce therapy resistance, relapse and the toxicity associated with current, non-selective agents.
An estimated 1 million cases of breast cancer are diagnosed annually worldwide. Of these, more than 170,000 are described as triple-negative. Triple-negative breast cancer (TNBC) is defined by the lack of protein expression of estrogen receptor (ER) and progesterone receptor (PR) and the absence of HER2 protein overexpression. TNBC is a subtype of breast cancer that overlaps with the "basal-like" breast cancer. TNBC has significant clinical implications.
The epidemiology, diagnosis, clinical course, prognosis, and pathology of this subtype of breast cancer are reviewed. The authors compare the "triple-negative" and "basal-like" definitions of breast cancer. A discussion of both standard and experimental treatments for TNBC is included.
The poor prognosis of high-grade TNBC relates to poor disease-free interval in the adjuvant setting, shortened progression-free survival in the metastatic setting, and the lack of targeted therapy. However, not all TNBCs are associated with a poor prognosis.
Although chemotherapy is the main current treatment of this subtype of breast cancer, new agents such as PARP inhibitors, which show promise in the treatment of TNBC, are currently in clinical trials.
Although high soy consumption may be associated with lower breast cancer risk in Asian populations, findings from epidemiological studies have been inconsistent.
We investigated the effects of soy intake on breast cancer risk among Korean women according to their menopausal and hormone receptor status.
We conducted a case-control study with 358 incident breast cancer patients and 360 age-matched controls with no history of malignant neoplasm. Dietary consumption of soy products was examined using a 103-item food frequency questionnaire.
The estimated mean intakes of total soy and isoflavones from this study population were 76.5 g per day and 15.0 mg per day, respectively. Using a multivariate logistic regression model, we found a significant inverse association between soy intake and breast cancer risk, with a dose-response relationship (odds ratios (OR) (95% confidence interval (CI)) for the highest vs the lowest intake quartile: 0.36 (0.20-0.64)). When the data were stratified by menopausal status, the protective effect was observed only among postmenopausal women (OR (95% CI) for the highest vs the lowest intake quartile: 0.08 (0.03-0.22)). The association between soy and breast cancer risk did not differ according to estrogen receptor (ER)/progesterone receptor (PR) status, but the estimated intake of soy isoflavones showed an inverse association only among postmenopausal women with ER+/PR+ tumors.
Our findings suggest that high consumption of soy might be related to lower risk of breast cancer and that the effect of soy intake could vary depending on several factors.
Breast cancer remains a significant public health problem despite advances in the understanding of the molecular and cellular events that underlie the disease. Crucial pathways regulating the cell cycle, proliferation and survival of breast cancer cells have been investigated and aberrant components of these pathways have been exploited as new drug targets. However, the mortality from breast cancer is only slowly declining. Recently, a model has been proposed that might explain the heterogeneous biological features of breast cancer cell populations and their differential response to therapeutic agents, which has interesting implications for further progress in therapy. This model links the emergence of breast cancer cells to stem cells and progenitors, an observation originally made in other cancer entities. It hypothesizes that the tumors originate from a small population of undifferentiated cells. These cells can undergo self-renewal and are able to generate a large number of partially differentiated cells, which constitute the bulk of the tumor. These cancer stem cells resemble adult stem and progenitor cells found in the normal breast, but are deregulated in their patterns of proliferation and differentiation. They could originate from normal stem cells or from more differentiated progenitors and lose their normal growth restraints through a series of oncogenic mutations that deregulate a small number of central signaling pathways. If breast cancer really is a stem and progenitor cell disease, this will have important implications for the understanding of the emergence of cancer cells. A combination of the cell-type of origin, stem cells, early or late progenitors and the particular oncogenic mutations acquired could provide a new classification of the different types of breast cancer. These parameters might determine the mechanisms of cancer progression and the responsiveness of patients to drug treatment. Stem cell-specific features could possibly be exploited as innovative drug targets.
Soy foods are rich in isoflavones, a major group of phytoestrogens that have been hypothesized to reduce the risk of breast cancer. However, the estrogen-like effect of isoflavones and the potential interaction between isoflavones and tamoxifen have led to concern about soy food consumption among breast cancer patients.
To evaluate the association of soy food intake after diagnosis of breast cancer with total mortality and cancer recurrence.
The Shanghai Breast Cancer Survival Study, a large, population-based cohort study of 5042 female breast cancer survivors in China. Women aged 20 to 75 years with diagnoses between March 2002 and April 2006 were recruited and followed up through June 2009. Information on cancer diagnosis and treatment, lifestyle exposures after cancer diagnosis, and disease progression was collected at approximately 6 months after cancer diagnosis and was reassessed at 3 follow-up interviews conducted at 18, 36, and 60 months after diagnosis. Annual record linkage with the Shanghai Vital Statistics Registry database was carried out to obtain survival information for participants who were lost to follow-up. Medical charts were reviewed to verify disease and treatment information.
Total mortality and breast cancer recurrence or breast cancer-related deaths. Cox regression analysis was carried out with adjustment for known clinical predictors and other lifestyle factors. Soy food intake was treated as a time-dependent variable.
During the median follow-up of 3.9 years (range, 0.5-6.2 years), 444 deaths and 534 recurrences or breast cancer-related deaths were documented in 5033 surgically treated breast cancer patients. Soy food intake, as measured by either soy protein or soy isoflavone intake, was inversely associated with mortality and recurrence. The hazard ratio associated with the highest quartile of soy protein intake was 0.71 (95% confidence interval [CI], 0.54-0.92) for total mortality and 0.68 (95% CI, 0.54-0.87) for recurrence compared with the lowest quartile of intake. The multivariate-adjusted 4-year mortality rates were 10.3% and 7.4%, and the 4-year recurrence rates were 11.2% and 8.0%, respectively, for women in the lowest and highest quartiles of soy protein intake. The inverse association was evident among women with either estrogen receptor-positive or -negative breast cancer and was present in both users and nonusers of tamoxifen.
Among women with breast cancer, soy food consumption was significantly associated with decreased risk of death and recurrence.
In Asian and Asian-American women, soy consumption is associated with reduced breast cancer risk, perhaps due to its effects on estrogen production or metabolism. In a sample of Asian-American women, we investigated the associations of usual adult soy intake with the urinary concentrations of 15 estrogens and estrogen metabolites (EM) measured using liquid chromatography-tandem mass spectrometry.
Participants included 430 Chinese-American, Japanese-American, and Filipino-American women, ages 20 to 55 years, and living in San Francisco-Oakland (California), Los Angeles (California), or Oahu (Hawaii). They were postmenopausal (n = 167) or premenopausal in luteal phase (n = 263) when 12-hour urine samples were collected. Robust linear regression was used to assess soy tertiles as predictors of log-transformed EM measures. Individual and grouped EM were considered as concentrations (pmol/mg creatinine) and as percentages of total EM (%EM).
Factor analysis confirmed that EM groups defined by metabolic pathways appropriately captured covariation in EM profiles. Total EM concentrations were not significantly associated with soy in premenopausal or postmenopausal women. Among all women, %2-hydroxylated EM and %4-hydroxylation pathway EM were 16% higher (P(trend) = 0.02) and 19% higher (P(trend) = 0.03) in the highest versus lowest soy tertiles, respectively. In contrast, 16% hydroxylated EM were 11% lower (P(trend) < 0.01). Results were consistent across ethnic and menopausal groups and after adjustment for westernization measured by birthplace (Asia or United States).
Findings suggest that regular soy intake is associated with increased ratios of 2:16-pathway EM and with higher relative levels of 4-hydroxylated EM. The observed variations in estrogen metabolism might modify breast cancer risk.
Angiogenesis, a complex multistep process that comprehends proliferation, migration and anastomosis of endothelial cells (EC), has a major role in the development of pathologic conditions such as inflammatory diseases, tumor growth and metastasis. Brazilian flora, the most diverse in the world, is an interesting spot to prospect for new chemical leads, being an important source of new anticancer drugs. Plant-derived alkaloids have traditionally been of interest due to their pronounced physiological activities. We investigated the anti-angiogenic potential of the naturally occurring guanidine alkaloid pterogynidine (Pt) isolated from the Brazilian plant Alchornea glandulosa. The purpose of this study was to examine which features of the angiogenic process could be disturbed by Pt.
Human umbilical vein endothelial cells (HUVEC) were incubated with 8 muM Pt and cell viability, proliferation, apoptosis, invasion and capillary-like structures formation were addressed. Nuclear factor kappaB (NFkappaB), a transcription factor implicated in these processes, was also evaluated in HUVEC incubated with Pt. Quantifications were expressed as mean +/- SD of five independent experiments and one-way analysis of variance (ANOVA) followed by the Dunnet test was used.
A significant decrease in proliferation and invasion capacity and an effective increase in apoptosis as assessed by bromodeoxyuridine (BrdU), double-chamber and terminal transferase dUTP nick end labeling (TUNEL) assay, respectively, have been found. Pt also led to a drastic reduction in the number of capillary-like structures formation when HUVEC were cultured on growth factor reduced-Matrigel (GFR-Matrigel) coated plates. In addition, incubation of HUVEC with Pt resulted in reduced NFkappaB activity.
These findings emphasize the potential use of Pt against pathological situations where angiogenesis is stimulated as tumor development.
A critical component of disease progression in rheumatoid arthritis (RA) involves neovascularization associated with pannus formation. 2-methoxyestradiol (2ME2) is a naturally occurring molecule with no known physiologic function, although at pharmacologic concentrations it has antiproliferative and antiangiogenic activities. We investigated the impact of orally administered 2ME2 on the initiation and development of proliferative synovitis using the anti-collagen monoclonal antibodies (CAIA) model.
Severe polyarticular arthritis was induced in Balb/c female mice by administration of 2 mg of a monoclonal antibody cocktail intravenously into the tail vein of mice. Twenty-four hours following monoclonal antibody administration, mice were injected with 25 microg of LPS (E. coli strain 0111:B4) via the intraperitoneal route. Treatment with 2ME2 (100, 75, 50, 25, 10, 1 mg/kg, p.o., daily), or vehicle control began 24 hrs following LPS challenge and continued to day 21. Hind limbs were harvested, sectioned and evaluated for DMARD activity and general histopathology by histomorphometric analysis and immunohistochemistry (vWF staining). In a separate study, different dosing regimens of 2ME2 (100 mg/kg; q.d. vs q.w. vs q.w. x 2) were evaluated. The effect of treatment with 2ME2 on gene expression of inflammatory cytokines and angiogenic growth factors in the joint space was evaluated 5 and 14 days after the induction of arthritis.
Mice treated with 2ME2 beginning 24 hours post anti-collagen monoclonal antibody injection, showed a dose-dependent inhibition in mean arthritic scores. At study termination (day 21), blinded histomorphometric assessments of sectioned hind limbs demonstrated decreases in synovial inflammation, articular cartilage degradation, pannus formation, osteoclast activity and bone resorption. At the maximal efficacious dosing regimen (100 mg/kg/day), administration of 2ME2 resulted in total inhibition of the study parameters and prevented neovascularization into the joint. Examination of gene expression on dissected hind limbs from mice treated for 5 or 14 days with 2ME2 showed inhibition of inflammatory cytokine message for IL-1beta, TNF-alpha, IL-6 and IL-17, as well as the angiogenic cytokines, VEGF and FGF-2.
These data demonstrate that in the CAIA mouse model of RA, 2ME2 has disease modifying activity that is at least partially attributable to the inhibition of neovascular development. Further, the data suggests new mechanistic points of intervention for 2ME2 in RA, specifically inhibition of inflammatory mediators and osteoclast activity.
Soy isoflavones, structurally similar to endogenous estrogens, may affect breast cancer through both hormonally mediated and non-hormonally related mechanisms. Although the effects of soy are not well understood, some breast cancer survivors increase their soy intake post-diagnosis in attempt to improve their prognosis. Therefore, we examined the role of soy isoflavone intake and the risk of breast cancer recurrence by hormone receptor status, menopausal status, and tamoxifen therapy. A cohort of 1,954 female breast cancer survivors, diagnosed during 1997-2000, was prospectively followed for 6.31 years and 282 breast cancer recurrences were ascertained. Isoflavone intake was assessed by mailing modified Block and supplemental soy food frequency questionnaires to participants, on average 23 months post-diagnosis. Risk of breast cancer recurrence, measured by hazard ratios (HR) and 95% confidence intervals (CI), was estimated using multivariable delayed entry Cox proportional hazards models. Suggestive trends for a reduced risk of cancer recurrence were observed with increasing quintiles of daidzein and glycetin intake compared to no intake among postmenopausal women (P for trend: P = 0.08 for daidzein, P = 0.06 for glycetin) and among tamoxifen users (P = 0.10 for daidzein, P = 0.05 for glycetin). Among postmenopausal women treated with tamoxifen, there was an approximately 60% reduction in breast cancer recurrence comparing the highest to the lowest daidzein intakes (>1,453 vs. <7.7 microg/day; HR, 0.48; 95% CI, 0.21-0.79, P = 0.008). Soy isoflavones consumed at levels comparable to those in Asian populations may reduce the risk of cancer recurrence in women receiving tamoxifen therapy and moreover, appears not to interfere with tamoxifen efficacy. Further confirmation is required in other large prospective studies before recommendations regarding soy intake can be issued to breast cancer survivors.
This report illustrates that the beta-androstenes are indeed able to upregulate the host immune response to a level that enables the host to resist lethal infection by viruses or bacteria. These agents consist of a subgroup of steroids, which also mediates a rapid recovery of hematopoietic precursor cells after whole-body lethal radiation injury. In vivo, the androstenes increase the levels of the Th1 cytokines such as IL-2, IL-3, and IFN. Similar to hydrocortisone, they suppress inflammation, but without immune suppression, and have a role in the maintenance of the Th1/Th2 balance and immune homeostasis.
Inflammation is a process by which tissues respond to various insults. It is characterized by upregulation of chemokines, cytokines, and pattern recognition receptors that sense microbes and tissue breakdown products. During pregnancy, the balance of Th1 (cell-mediated immunity) and Th2 (humoral immunity) cytokines is characterized by an initial prevalence of Th2 cytokines, followed by a progressive shift toward Th1 predominance late in gestation, that when is abnormal, may initiate and intensify the cascade of inflammatory cytokine production involved in adverse pregnancy outcomes. Maternal and placental hormones may affect the inflammatory pathway. Hypoxia and the innate immune response are 2 adaptive mechanisms by which organisms respond to perturbation in organ function, playing a major role in spontaneous abortion, intrauterine growth restriction, preeclampsia, and preterm delivery. The interaction between tissue remodeling factors, like matrix metalloproteinases, and vasoactive/hemostatic factors, like prostaglandin and coagulation factors, mediates this adaptive response.
The trophoblastic theory of cancer, proposed in the early 1900s by Dr John Beard, may not initially seem relevant to current cancer models and treatments. However, the underpinnings of this theory are remarkably similar to those of the cancer stem cell (CSC) theory. Beard noticed that a significant fraction of germ cells never reach their final destination as they migrate during embryonic development from the hindgut to the germinal ridge. In certain situations, upon aberrant stimulation, these vagrant germ cells are able to generate tumors. Simplistically, the CSC theory surmises that a small population of tumorigenic cells exists, which initiate and maintain tumors, and these cells have a likely origin in normal stem cells. Both these theories are based on the potential of a single primitive cell to form a tumor. This has a major implication for cancer therapy, in that only a small percentage of cells need to be targeted to ablate a tumor.
The British developmental biologist John Beard, DSc (1858-1924) is little remembered today. Yet, he made outstanding contributions to the life sciences. Beard deserves to be included among the leading biologists of the late 19th and early 20th century. He has been hailed as a forerunner of the present-day theory of the cancer stem cell (CSC). He was the first to point to the parallels between cancer and the trophoblastic cells that envelop and nourish the embryo, characterizing cancer as "irresponsible trophoblast." He pointed out that the initiation of fetal pancreatic function coincided with a reduction in the invasiveness of trophoblast, which otherwise might progress to clinical cancer (ie, choriocarcinoma). Based on the above propositions, he recommended the therapeutic use of pancreatic enzymes in treating cancer and other diseases. This therapy created a worldwide controversy, and although rejected in his day, persists in the world of complementary and alternative medicine (CAM) today.
Disseminated malignancy is the major cause of prostate cancer-related mortality. Circulating tumor cells (CTCs) are essential for the establishment of metastasis. Various contemporary and molecular methods using prostate-specific biomarkers have been applied to detect extraprostatic disease that is undetectable by conventional imaging techniques, assessing the risk for disease recurrence after therapy of curative intent. However, the clinical relevance of CTC detection is still controversial. We review current literature regarding molecular methods used for the detection of CTCs in the peripheral blood and bone marrow biopsies of patients with prostate cancer, and we discuss the methodological pitfalls that influence the clinical significance of molecular staging.
Tumours contain immune cells and a network of pro- and anti-inflammatory cytokines, which collaborate in the development and progression of cancer. Cytokine profiles might prove to be prognostic. The systemic effects of pro-inflammatory cytokines are associated with fatigue, depression and cognitive impairment, and can affect quality of life before, during and after treatment. In people with advanced cancer, pro-inflammatory cytokines are additionally associated with anorexia and cachexia, pain, toxicity of treatment and resistance to treatment. However, physical activity might modify cytokine levels and decrease fatigue in patients with cancer, and might also improve their prognosis.
A completed pregnancy at a young age reduces a woman's lifetime risk of breast cancer by up to 50%. A similar protective effect of an early pregnancy has been observed in rodent models using chemical carcinogens. However, the mechanisms responsible for this protective effect remain unclear. Stem cells have been proposed to be the cells of origin for breast cancer. We hypothesized that an early pregnancy reduces adult levels of either mammary stem cells or mammary multipotent progenitor cells. Unsorted mammary cells from adult mice that had undergone an early parity had the same mammosphere formation efficiency as cells from age-matched virgin mice. However, when we transplanted adult mammary cells in limiting dilutions into cleared fat pads of syngeneic mice, we found a significant reduction in the outgrowth potential of the cells from early parous mice compared with age-matched virgin mice. The extent of fat pad filling in successful outgrowths did not change, suggesting that although mammary stem cells in parous mice retained their functional competence, the number of mammary stem cells was reduced. Our results provide the first direct evidence that an early pregnancy has an effect on mammary stem cells.
Disclosure of potential conflicts of interest is found at the end of this article.
We analyzed circulating tumor cells (CTC) in blood of metastatic breast cancer patients (n = 42) and determined the ability of this method to predict therapy response.
CTC from blood were analyzed before and during therapy for EpCAM, MUC1 and HER2 transcripts with the AdnaTest BreastCancer. The estrogen (ER) and progesterone (PR) receptor expression was assessed by RT-PCR.
The overall detection rate for CTC was 52% (thereof 86% EpCAM; 86% MUC1; 32% HER2; 35% ER; 12% PR). CTC were ER, PR and HER2 negative in 45% (ER), 78% (PR) and 60% (HER-2) of patients with steroid receptor-positive tumors. 29% of patients with HER2-negative tumors had HER2-positive CTC. The test predicted therapy response in 78% of all cases. Persistence of CTC significantly correlated with shorter overall survival (P = 0.005).
Molecular profiling of CTC may offer superior prognostic information with regard to risk assessment for recurrence and predictive judgement of therapeutical regimens.
Cachexia causes weight loss and increased mortality. It affects more than 5 million persons in the United States. Other causes of weight loss include anorexia, sarcopenia, and dehydration. The pathophysiology of cachexia is reviewed in this article. The major cause appears to be cytokine excess. Other potential mediators include testosterone and insulin-like growth factor I deficiency, excess myostatin, and excess glucocorticoids. Numerous diseases can result in cachexia, each by a slightly different mechanism. Both nutritional support and orexigenic agents play a role in the management of cachexia.
Methoxyestradiol (2ME), an endogenous metabolite of 17β-estradiol, has been reported to play an active role in the induction of apoptosis in both proliferating endothelial and cancer cells. Since it has been indicated that an increased ratio of pro-apoptotic Bax protein to anti-apoptotic Bcl-2 protein expression can be associated with apoptosis, and since the exact action mechanism of 2ME is still not clearly defined and appears to vary according to cell type, the influence of 1 μM 2ME was investigated on Bax and Bcl-2 expression levels in squamous esophageal carcinoma cells. 2ME exposure led to statistically significant decreases (0.69 over DMSO controls) in Bcl-2 expression levels. In contrast, no statistically significant effects were observed on Bax expression levels after exposure to 2ME. The Bax/Bcl-2 ratio for 2ME-exposed cells was 1.45, normalised against Bcl-2 levels. Although the exact mechanisms of apoptosis induction in squamous esopha- geal cancer cells require further investigation, the present study suggests that this altered ratio in favor of Bax could lead to the induction of apoptosis in these cells.
The role of reactive oxygen intermediates (ROIs) in nuclear factor-kappaB (NF-κB) activation remains a matter of controversy. We have studied whether ROIs played any role in NF-κB induction by interleukin-1β (IL-1β) in different cell types. Our studies indicated three different pathways. IL-1β stimulation of lymphoid cells generates ROIs, which are required for IκB-α degradation and NF-κB activation. The source of these ROIs is the 5-lipoxygenase (5-LOX) enzyme. In monocytic cells, ROIs are also produced in response to IL-1β and necessary for NF-κB induction, but their source appears to be the NADPH oxidase complex. Finally, epithelial cells do not generate ROIs after IL-1β stimulation, but do rapidly activate NF-κB. Interestingly, transfection of epithelial cells with the 5-LOX and 5-LOX activating protein expression vectors restored ROI production and ROI-dependent NF-κB activation in response to IL-1β. Our data thus indicate that ROIs are cell type-specific second messengers for NF-κB induction by IL-1β.
In this work we present Giant Magneto-Impedance measurements of a NiFe-Au multilayer film at frequencies up to 3 GHz, using RF techniques, complemented with a derivative of the microwave absorption spectrum at 9.4 GHz. The curves allow to identify two different type of peaks: ones at low fields, associated to transverse permeability and others at fields increasing with frequency, caused by the ferromagnetic resonance. Usual data reduction consists on subtracting the impedance of the elements of the measuring circuit. If more accurate calculations are made, we can also eliminate the contributions to the impedance due to the interaction between the sample itself and the circuit. The results obtained using this technique display extraordinary sensitivities and Magneto-Impedance ratios. Besides, the derivative of the microwave absorption spectrum proves the existence of a low field contribution even at higher frequencies.
To test whether accelerated sarcopenia in older persons with high interleukin (IL)-6 serum levels plays a role in the prospective association between inflammation and disability found in many studies.
Cohort study of older women with moderate to severe disability.
Six hundred twenty older women from the Women's Health and Aging Study in whom information on baseline IL-6 serum level was available.
Self-report of functional status, objective measures of walking performance, and knee extensor strength were assessed at baseline and over six semiannual follow-up visits. Potential confounders were baseline age, race, body mass index, smoking, depression, and medical conditions.
At baseline, women with high IL-6 were more often disabled and had lower walking speed. After adjusting for confounders, women in the highest IL-6 tertile (IL-6>3.10 pg/mL) were at higher risk of developing incident mobility disability (risk ratio (RR) = 1.50, 95% confidence interval (CI) = 1.01-2.27), disability in activities of daily living (RR = 1.41, 95% CI = 1.01-1.98), and severe limitation in walking (RR = 1.61, 95% CI = 1.09-2.38) and experienced steeper declines in walking speed (P <.001) than women in the lowest IL-6 tertile (IL-6 < or =1.78 pg/mL). Decline in knee extensor strength was also steeper, but differences across IL-6 tertiles were not significant. After adjusting for change over time in knee extensor strength, the association between high IL-6 and accelerated decline of physical function was no longer statistically significant.
Older women with high IL-6 serum levels have a higher risk of developing physical disability and experience a steeper decline in walking ability than those with lower levels, which are partially explained by a parallel decline in muscle strength.
Loss of neurofibromin, the protein product of the tumor suppressor gene neurofibromatosis type 1 (NF1), is associated with neurofibromas, composed largely of Schwann cells. The number and size of neurofibromas in NF1 patients have been shown to increase during pregnancy. A mouse embryonic stem cell (mESC) model was used, in which mESCs with varying levels of neurofibromin were differentiated into Schwann-like cells. NF1 cell lines derived from a malignant and a benign human tumor were used to study proliferation in response to hormones. Estrogen and androgen receptors were not expressed or expressed at very low levels in the NF1+/+ cells, at low levels in NF1+/−cells, and robust levels in NF1−/−cells. A 17β-estradiol (E2) metabolite, 2-methoxy estradiol (2ME2) is cytotoxic to the NF1−/− malignant tumor cell line, and inhibits proliferation in the other cell lines. 2ME2 or its derivatives could provide new treatment avenues for NF1 hormone-sensitive tumors at times of greatet hormonal influence. Developmental Dynamics 237:513–524, 2008. © 2008 Wiley-Liss, Inc.
Background
Cancer cachexia is a debilitating, wasting condition that affects many cancer patients, including those with head and neck cancer. The overall incidence of cancer cachexia is quite high for some types of cancer, and cachexia will be the main cause of death for more than 20% of all cancer patients. This syndrome uniquely challenges patients with head and neck cancer. This article outlines the diagnosis of cancer cachexia, reviews its impact on patient quality of life (QOL) and survival, and updates the reader on potential therapies that may suppress it.MethodsA comprehensive literature search was performed using PubMed of the National Library of Medicine, which includes more than 15 million citations back to the 1950s. The Cochrane Library and Google search engine were used as well.ResultsThis syndrome differs significantly from starvation, and thus accurate and timely diagnosis is essential. Nutritional therapy alone is insufficient. Current management strategies include corticosteroids and megesterol acetate, in conjunction with nutritional therapy. Future strategies may include nutraceuticals, omega-3 fatty acids, inflammatory antagonists, and other targeted treatments.Conclusions
Because cancer cachexia differs significantly from starvation, nutritional supplementation must be used in conjunction with other anti-cachexia agents to reverse the chronic systemic inflammatory state and the effects of circulating tumor-derived factors seen in cachexia. Careful identification of patients at risk and those suffering from this syndrome will lead to better outcomes and treatments. Ultimately, more research is needed to better treat this devastating condition. © 2007 Wiley Periodicals, Inc. Head Neck, 2007
The prognosis of prostate cancer is mainly determined by thepresence or absence of metastases. Nevertheless, the metastasic pathways in prostate cancer are not entirely understood. Among 19,316 routine autopsies performed from 1967 to 1995 on men older than 40 years of age, the reports from those 1,589 (8.2%) with prostate cancer were analyzed. Hematogeneous metastases were present in 35% of 1,589 patients with prostate cancer, with most frequent involvement being bone (90%), lung (46%), liver (25%), pleura (21%), and adrenals (13%). Several lines of evidence suggested the existence of a backward metastasic pathway through veins from the prostate to the spine in addition to classical hematogeneous tumor spread via the vena cava. First, there was an inverse relationship between spine and lung metastases, suggesting that metastasis to the spine is independent of lung metastasis. Second, the maximum frequency of spine involvement occurred in smaller tumors (4 to 6 cm) as compared with the maximum spread to lung (6 to 8 cm) and liver (> 8 cm), suggesting that spine metastases precede lung and liver metastases in many prostate cancers. Third, there was a gradual decrease in spine involvement from the lumbar to the cervical level (97% v 38%), which is consistent with a subsequent upward metastasic spread along spinal veins after initial lumbar metastasis. The results of this study show that bone, lung, and liver are the most frequent sites of distant prostate cancer metastases. Besides the cava-type of metastasis through lung passage, there are strong arguments for the existence and clinical significance of a backward venous spread to the spine, which is likely to occur early in the metastatic process.
The precise cell types that give rise to tumors and mechanisms that underpin tumor heterogeneity are poorly understood. There is increasing evidence to suggest that diverse solid tumors are hierarchically organized and may be sustained by a distinct subpopulation of cancer stem cells (CSCs). The CSC hypothesis provides an attractive cellular mechanism that can account for the therapeutic refractoriness and dormant behavior exhibited by many tumor types. Breast cancer was the first solid malignancy from which CSCs were identified and isolated. Direct evidence for the CSC hypothesis has also recently emerged from mouse models of mammary tumorigenesis, although alternative models to explain heterogeneity also seem to apply. Our group has found that the luminal epithelial progenitor marker CD61/beta3 integrin identified a CSC population in mammary tumors from MMTV-wnt-1 mice. However, no CSCs could be identified in the more homogeneous MMTV-neu/erbB2 model, suggesting an alternate (clonal evolution or stochastic) model of tumorigenesis. It seems likely that both paradigms of tumor propagation exist in human cancer. From a clinical perspective, the CSC concept has significant implications. Quiescent CSCs are thought to be more resistant to chemotherapy and targeted therapy. Enrichment of putative CSCs has been noted in studies of chemotherapy-treated patients, lending support to the CSC hypothesis and their potential role in chemoresistance. Although many unresolved questions on CSCs remain, ongoing efforts to identify and characterize CSCs continue to be an important area of investigation, with the potential to identify novel tumor targeting strategies.
There is increasing evidence that many cancers, including breast cancer, contain populations of cells that display stem-cell properties. These breast cancer stem cells, by virtue of their relative resistance to radiation and cytotoxic chemotherapy, may contribute to treatment resistance and relapse. The elucidation of pathways that regulate these cells has led to the identification of potential therapeutic targets. A number of agents capable of targeting breast cancer stem cells in preclinical models are currently entering clinical trials. Assessment of the efficacy of the agents will require development of innovative clinical trial designs with appropriate biologic and clinical end points. The effective targeting of breast cancer stem cells has the potential to significantly improve outcome for women with both early-stage and advanced breast cancer.
Although all cells within a colon cancer may harbour adenomatous polyposis coli (APC) or beta-catenin mutations, activation of Wnt signalling is limited to a subpopulation of cells that display cancer stem cell properties. This activation requires a co-stimulatory signal mediated by hepatocyte growth factor, which is produced by tumour-associated myofibroblasts.
There is a large variation in breast cancer incidence and mortality rates worldwide. Migration studies have indicated that this variation is primarily the result of lifestyle influences. Although there has been much research conducted, definitively identifying dietary factors that impact breast cancer risk has proven difficult. In part this may be because most clinical and epidemiologic studies have focused on adult dietary exposure. However, evidence suggests that childhood and/or adolescence is the period of life when the breast is most sensitive to dietary influences. Further, the available epidemiologic and animal data suggest that early soy intake reduces breast cancer risk. Soy foods are unique dietary sources of isoflavones, diphenolic compounds that exert estrogen-like effects under certain experimental conditions. The protection effects of soy may result from the soybean isoflavones stimulating differentiation of the breast in much the same way that the elevated estrogen levels do during pregnancy. More specifically, in rats, the primary isoflavone genistein reduces mammary tumorigenesis and increases mammary tissue differentiation by leading to a reduction in the number of terminal end buds (TEB) and an increase in the number of differentiated lobules. There is need and justification for continued investigation of the early soy intake hypothesis, particularly to determine the cellular targets of soy action and to identify the signaling pathways mediating the effects on mammary gland morphology and susceptibility to breast cancer.
Melanoma is an uncommon tumour in childhood. Only isolated cases in pregnant patients younger than 18 years old have been previously described, therefore the biological behaviour of cutaneous melanoma in this group of age remains largely unknown. We report a single-institution experience with three patients who developed cutaneous melanoma before the age of 18 years and became pregnant concomitantly or during the course of the disease. High tumour thickness was attributed to later diagnosis and could be responsible for the aggressive biological behaviour in these patients. This delay was in part due to patients considering changes in nevi to be normal during pregnancy. The effect of pregnancy on the prognosis of patients with melanoma, particularly the role of hormonal and immunological factors on clinical outcome, survival and risk of developing metastases, as well as the differences between adolescent and adult populations are still controversial. Since there are no specific treatment strategies for this group of patients, treatment recommendations should be established according to adult experience.
2-methoxyestradiol (2ME2) is a potent antiangiogenic molecule that inhibits the expression of hypoxia-inducible factor (HIF)-1alpha and, consequently, of VEGF and other HIF-1alpha target genes. Although 2ME2 is elevated during pregnancy in maternal serum, its presence in fetal fluids and its impact in neonatal health are unknown. In this study, we 1) described normal levels of 2ME2 in maternal blood, cord blood, breast milk, and amniotic fluid, and 2) compared a composite measure of perinatal outcome between infants born with high and low levels of 2ME2. We found that 2ME2 was significantly decreased in all fluids compared with prepartum maternal serum. After stratifying babies by 2ME2 exposure levels, we observed no differences in the vulnerability to impaired lung development or to complications involving aberrant angiogenesis or vascular leak, such as necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), posthemorrhagic hydrocephalus (PHH), and retinopathy of prematurity (ROP). In summary, fetal 2ME2 concentrations do not appear to affect neonatal outcome.
The soybean-derived serine protease inhibitor, Bowman-Birk inhibitor (BBI), has been reported as a potent chemoprevention agent against several types of tumors. The present study was undertaken to evaluate the effects of BBI on androgen-sensitive/dependent prostate cancers using a human prostate cancer cell (LNCaP) and the transgenic rats developing adenocarcinoma of the prostate (TRAP) model. Treatment of LNCaP prostate cancer cells with 500 microg/mL BBI resulted in inhibition of viability measured on WST-1 assays, with induction of connexin 43 (Cx43) and cleaved caspase-3 protein expression. Feeding of 3% roughly prepared BBI (BBIC) to TRAP from the age 3 weeks to 13 weeks resulted in significant reduction of the relative epithelial areas within the acinus and multiplicity of the adenocarcinomas in the lateral prostate lobes. Cx43- and terminal deoxynucleotidyl transferase mediated dUTP-biotin end labeling of fragmented DNA (TUNEL)-positive apoptotic cancer cells were more frequently observed in the lateral prostates treated with BBIC than in the controls. These in vivo and in vitro results suggest that BBI possesses chemopreventive activity associated with induction of Cx43 expression and apoptosis.
The association between soy food consumption and breast cancer risk has been inconsistent. A hospital-based case-control study was conducted to assess the relationship between soy food intake and breast cancer risk according to the estrogen receptor (ER) and/or progesterone receptor (PR) status of breast cancer in Chinese women residing in Guangdong province from June 2007 to August 2008. A total of 438 consecutively recruited cases with primary breast cancer were frequency matched to 438 controls by age (5-year interval) and residence (rural/urban). Dietary intake was assessed by face-to-face interviews using a validated food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were obtained by using multiple unconditional logistic regression adjusted for the potential confounders. We observed a statistically significant inverse association between soy isoflavone and soy protein intake with breast cancer risk. The multivariate ORs (95% CIs) of breast cancer risk for the highest quartile compared with the lowest quartile were 0.54 (0.34-0.84) for soy isoflavone and 0.62 (0.40-0.96) for soy protein, respectively. A preventive effect of soy food was found for all subtypes of ER and/or PR status of breast cancer. The inverse association was more evident among premenopausal women. This study suggests that consumption of soy food, soy isoflavone, is inversely associated with the risk of breast cancer. The protective effects of soy did not seem to differ by ER and PR breast cancer status.
Metastases do not result from random survival of cells released from the primary tumour but from the selective growth of specialised subpopulations of highly metastatic cells endowed with specific properties that befit them to complete each step of the metastatic process.
To study the clinical effects of Prescription Zhuyun-III (ZYIII) on early pregnant women diagnosed as threatened abortion, and its mechanism in immunity and endocrine by determining serum Th1- and Th2-type cytokines, progesterone, and beta-human chorionic gonadotropin (beta-HCG).
The treatment group comprised 30 early pregnant women diagnosed as threatened abortion of deficiency syndrome of Pi, Shen, or both. The control group consisted of 20 normal early pregnant women of similar gestational age. Patients in the treatment group were administered with ZYIII for 4 weeks. Peripheral blood samples were collected pre- and post-treatment from both the treatment and the control groups. Serum Th1-type cytokine [interleukin-2 (IL-2)] and Th2-type cytokine [interleukin-10 (IL-10)] were determined by flow cytometry, and serum progesterone and beta-HCG were determined by ELISA.
(1) The treatment was effective in 26 and ineffective in 4 patients of the treatment group. Therefore, the cure percentage was 86.67%. (2) In the treatment group before the treatment, IL-2 was significantly higher, IL-10 tended to be less, and the Th1/Th2 balance shifted toward Th1 compared with those in the control group. (3) After the treatment, IL-2 was decreased, IL-10 was increased, and IL-2/IL-10 was decreased. Both progesterone and beta-HCG were increased. Changes of progesterone were positively correlated with changes of IL-10, whereas changes of beta-HCG were negatively correlated with changes of IL-2.
Our study suggests that ZYIII has an evident function of protecting the fetus, and one of its mechanisms is inhibiting the secretion of Th1 cytokines, promoting the secretion of Th2 cytokines, and recovering the pathological shift of the Th1/Th2 balance. The other possible mechanism is increasing serum progesterone and beta-HCG concentrations. Moreover, there are some correlations between the above two effects.
The neonate is born with a distinct immune system that is biased against the production of T-helper cell 1 (Th1) cytokines. Birth imposes a great challenge on the neonatal immune system, which is confronted with an outside world rich in foreign antigens. Exposure to these antigens shapes the developing neonatal immune system. Inducing Th-1 or Th-2 polarized responses that may extend beyond the neonatal age and counteract or promote allergic sensitization. This review describes how engagement of the innate immune system might contribute to the development of allergy in children.
The exact role of innate immune stimulation in the development of allergies is a controversial area. Epidemiological literature suggests that microbial exposure in early childhood protects against the development of allergies, whereas a large amount of experimental data demonstrates that innate immune stimulation enhances Th2 responses upon primary and secondary antigen exposure.
Dose, site and timing of allergen exposure are likely to modulate the innate immune response, polarizing the maturing neonatal immune system towards Th1 or Th2-type responses, thereby protecting from or predisposing to asthma and allergies. Modulation of neonatal innate immune responses may be a novel approach to prevent asthma and allergies.
The use of herbal preparations (HEP) to alleviate climacteric disorders is expected to increase as women seek alternatives to menopausal hormone therapy to avoid the associated breast cancer risk. Data are sparse on the long-term effects of HEP containing phytoestrogens and black cohosh on breast cancer risk.
Within a German case-control study, associations between patterns of HEP use and incident breast cancer were investigated in 10,121 postmenopausal women (3,464 cases, 6,657 controls). Information on HEP use was collected in face-to-face interviews supported by a list of brand names. Multivariate logistic and polytomous regression analyses were done.
Ever use of HEP (9.9%) was inversely associated with invasive breast cancer [odds ratio (OR), 0.74; 95% confidence interval (CI), 0.63-0.87] in a dose-dependent manner (OR, 0.96 per year of use; P = 0.03). Classes of HEP did not differ significantly (P(heterogeneity) = 0.81). Risks for invasive ductal (OR, 0.72; 95% CI, 0.60-0.87) and combined lobular/mixed/tubular tumors (OR, 0.76; 95% CI, 0.58-1.01) were similarly reduced by any HEP use but not for in situ carcinomas (1.34; 95% CI, 0.86-2.09). There were no substantial differences in associations of HEP use by estrogen receptor status (ER(+) OR, 0.74; 95% CI, 0.62-0.89; ER- OR, 0.68, 95% CI, 0.50-0.93) and progesterone receptor status of the tumor.
Our findings support the hypothesis that HEP use protects from invasive breast cancer in postmenopausal women. Among conceivable modes of action, those independent of estrogen receptor-mediated pathways seem to be involved (i.e., cytotoxicity, apoptosis).
2-Methoxyestradiol (Panzem, 2ME2) is an endogenous metabolite of estradiol that destabilizes microtubules and exerts anti-angiogenic properties. This study was conducted to determine the activity and safety of 2ME2 administered as a NanoCrystal dispersion (NCD) formulation in patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC).
Eligible patients had relapsed, platinum-resistant or refractory EOC with measurable or detectable disease. There was no limit on the number of prior treatment regimens. 2ME2 NCD 1000 mg orally four times daily (q.i.d.) was administered continuously during 4 week cycles. The primary endpoint was objective response rate (ORR). Secondary endpoints were assessment of toxicity, rate of clinical benefit defined as the number of patients experiencing an objective response, a CA125 response or stable disease (SD) >3 months, mean change in CA-125, progression-free survival (PFS), and pharmacokinetic analyses of 2ME2.
Eighteen patients were enrolled. Median age was 65.5 (range 40-73). Patients had received a median of five prior treatments. The most common adverse events were fatigue (78%), nausea (78%), diarrhea (39%), neuropathy (50%), edema (39%), and dyspnea (44%), the majority being grade 1-2. There were no objective responses, but seven patients had SD as best response. Of those, two patients had SD for greater than 12 months. The rate of clinical benefit was 31.3%. Fairly stable plasma levels of 2ME2 ranging within the predicted therapeutic window were observed.
The NCD formulation of 2ME2 is well tolerated in patients with heavily pretreated EOC. Few of these heavily pretreated patients had sustained stable disease.
Endometriosis affects 5-15% of women in the general population and 40% of women seeking infertility evaluation. Its etiology and pathogenesis is controversial. Abnormalities of genes involved in the regulation of apoptosis have been thought to play a role in origin. Hence, we investigated the expression of pro-apoptotic and anti-apoptotic genes in eutopic endometrium from women with endometriosis and healthy controls in relation to disease occurrence and severity.
A prospective study in women undergoing laparoscopic surgery for pelvic pain was conducted. In total, 45 women (30 healthy controls and 15 patients) matched inclusion criteria. The mRNA expression of apoptotic genes (p53, Bcl-x(L,S) and Bax) from eutopic endometrium was detected by RT-PCR.
A significant increase in expression of mRNA p53 (1.42 versus 1.02; p<0.05), and Bcl-x(S) (0.41 versus 0.19; p=0.0006) was found in women with endometriosis compared to healthy controls. Insignificantly increased expression was found for Bax (1.22 versus 1.15). The expression of anti-apoptotic Bcl-x(L) was unchanged (1.08 versus 1.07). The Bcl-x(L)/Bcl-x(S) ratio was twofold higher (5.63 versus 2.63) in controls. By stratifying patients by disease stage we have revealed an increased mRNA expression of apoptotic genes in patients with grades III-IV endometriosis compared to those with grades I-II. However, the difference was significant only for Bcl-x(S) expression (p<0.05).
Results suggest that an increased transcription of pro-apoptotic genes (p53 and Bcl-x(S)) in eutopic endometrium is significantly associated with endometriosis, which indicates dysregulation of apoptotic gene transcription associated with disease.
Nuclear factor kappaB (NF-kappaB) transcription factors have a key role in many physiological processes such as innate and adaptive immune responses, cell proliferation, cell death, and inflammation. It has become clear that aberrant regulation of NF-kappaB and the signalling pathways that control its activity are involved in cancer development and progression, as well as in resistance to chemotherapy and radiotherapy. This article discusses recent evidence from cancer genetics and cancer genome studies that support the involvement of NF-kappaB in human cancer, particularly in multiple myeloma. The therapeutic potential and benefit of targeting NF-kappaB in cancer, and the possible complications and pitfalls of such an approach, are explored.
Breast cancer is a major health problem and concern of women religious in the USA. Although they have been identified as a high-risk population, only a limited number of breast health studies have been conducted. The purpose of this study was to explore breast-related health practices (breast self-examination [BSE], clinical breast examination [CBE], and mammography) of women religious residing in the United States. A survey design was used to collect a national sample. The probability sample consisted of 1,615 women religious between the ages of 24 and 99 (mean age = 64.5). Nearly 71% of the respondents reported performing BSE; 22.7% monthly. Sixty-nine percent of participants reported having a mammogram within the past year. Nearly 70% of the respondents reported having had a CBE within the past year. Several factors for not performing BSE or having mammogram are described by this population. Findings suggest a need for increase engagement by women religious in breast-related health practices.
During the physiological process of adrenarche, the adrenal glands of healthy children secrete increasing amounts of weak androgenic steroids partly metabolized to potent sex steroids.
The aim of the study was to examine whether adrenal androgen metabolite excretion rates before the onset of puberty may be prospectively associated with late-pubertal diaphyseal bone strength.
We conducted the study in an auxological and metabolic child nutrition research facility. STUDY POPULATION AND DESIGN: The sample included 45 healthy adolescents who underwent proximal forearm bone and muscle area measurements by peripheral quantitative computed tomography at the age of 16 yr (SD 1.5) and who had collected a 24-h urine sample 8 yr earlier, allowing to quantify the prepubertal urine metabolome. Prepubertal hormonal predictors quantified by gas chromatography-mass spectrometry were: dehydroepiandrosterone, its 16-hydroxylated downstream metabolites, 5-androstene-3beta,17beta-diol (androstenediol), sums of total androgen and glucocorticoid metabolites, cortisol, and 6beta-hydroxycortisol.
Proximal forearm radius was measured.
Of all prepubertal hormones analyzed, only sex- and age-specific androstenediol levels significantly predicted pubertal stage-, height-, and muscularity-adjusted diaphyseal bone modeling (periosteal circumference, beta = 0.67, P = 0.002; cortical area, beta = 2.15, P = 0.02), bone mineral content (beta = 2.2; P = 0.04), and polar strength strain index (beta = 12.2; P = 0.002). Androstenediol explained 5-10% of the late-pubertal diaphyseal radius variability.
Our prospective profiling of urinary steroid metabolites in 24-h urine samples collected before puberty suggests that androstenediol is an early predictor of the diaphyseal bone strength in late puberty. This predominantly peripheral conversion product of adrenarchal dehydroepiandrosterone by 17beta-hydroxysteroid dehydrogenase may hence be involved in a sustained improvement of radial bone accretion during growth.
Genistein is an isoflavone with oestrogenic activity that is present in a variety of soy products as a constituent of complex mixtures of bioactive compounds, whose matrix profiles play an important role in determining the overall oestrogenic bioactivity of genistein. We review data on how the profile of soy bioactive compounds can modulate genistein-stimulated oestrogen-dependent tumour growth. Our research has focused on the effects of dietary genistein on the growth of oestrogen (E)-dependent mammary tumours both in vitro and in vivo. Genistein enhances the proliferation of E-dependent human breast cancer tumour growth. In a similar manner, dietary genistein stimulates tumour growth in the chemically-induced (NMU) mammary cancer rodent model. Genistin, the glycoside of genistein, simulates growth similar to that of genistein and withdrawal of either genistein or genistin results in tumour regression. The extent of soy processing modulates the effects of dietary genistein in vivo as soy protein isolate, a highly purified and widely used source of protein that is processed to contain low, medium, and high amounts of isoflavones, stimulate the growth of the E-dependent mammary tumours in a dose dependent manner. In contrast to the more purified diets, studies with soy flour of equivalent genistein levels did not stimulate the growth of E-dependent breast cancer tumours in vivo. However, the size of these tumours also did not regress as is observed in control groups in which oestrogen and genistein have been withdrawn. The expression of the oestrogen-target genes of pS2, progesterone receptor, and cyclin D1 correlates with the growth of E-dependent tumours and has been consistently observed to be induced in response to treatment with dietary genistein. To evaluate whether dietary genistein interacts with current anti-oestrogen breast cancer therapies such as tamoxifen (TAM), we implanted E-dependent tumours into ovariectomized athymic mice and administered oestradiol, oestradiol plus TAM, or oestradiol, TAM, and dietary genistein. In these studies dietary genistein was able to negate the inhibitory effect of TAM on E-stimulated tumour growth. In summary, genistein can act as an oestrogen agonist resulting in proliferation of E-dependent human breast cancer tumours in vivo and its activity can be modulated by the presence of other bioactive components in complex soy foods. Additionally, dietary genistein can negate the inhibitory effects of TAM on E-stimulated growth of MCF-7 cell tumours implanted into ovariectomized athymic mice.
Specific receptor binding of estradiol (E-2) and dihydrotestosterone (DHT) was studied in human myometrial tissue and in human mammary cancer tissue. The inhibition of binding for E-2 and DHT by E-2, testosterone (T), DHT, dehydroepiandosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), androstendione (A) and 5-androstene-3beta, 17beta-diol (Adiol) was tested with the use of dextran-coated charcoal separation of bound and free E-2, respectively, and DHT. The percentage of binding inhibition was calculated with reference to the inhibition obtained with nafoxidine in a molar concentration ratio of 1,000 for E-2 binding, respectively, with cyproterone acetate in a molar concentration ratio of 10,000 for DHT binding. In 15 samples of myometrium tested, receptors were found for both E-2 and DHT. From 19 samples of mammary carcinoma tissue one showed no binding activity, three samples did bind E-2 only, five samples DHT only, and ten samples showed binding of both steroids. A 50% inhibition of E-2 binding, in myometrial as well as in tumor tissue, required a molar concentration ratio of 40 for Adiol, of more than 2,000 for DHEA. No significant inhibiting activity could be found for A up to a molar concentration ratio of 10,000 and for DHEA-S up to 40,000. With regard to DHT binding, Adiol is more active than E-2 and less active than T. Of the substances tested Adiol is therefore the only one which exerts a significant inhibiting influence at a molar ratio not far beyond the physiological range. This signifies that Adiol might interfere at the receptor level in the estrogenic stimulation of mammary cancer cells.
Various numbers of spleen cells from specifically immunized mice were mixed with constant numbers of target tumor cells, and were inoculated subcutaneously into thymectomized, x-irradiated recipients. Small numbers of admixed immune spleen cells produced a statistically significant, and reproducible, acceleration of tumor growth in the inoculum as compared with controls of either nonimmune spleen cells or spleen cells from animals immune to a different, non-cross-reacting, tumor. Larger. numbers of specifically immune spleen cells, however, produced inhibition of tumor growth. These data imply that the normal immune reaction may have a dual function in relation to neoplasia: (i) stimulation of tumor growth, early in the course of the disease, or whenever the immune reaction is minimal; (ii) inhibition of tumor growth at other times.