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ABSTRACT: The circadian clock controls many cellular processes, some of which are key to tumor suppression, including cell proliferation
and apoptosis, DNA repair, metabolism, hormone signaling, and immune function. The association between altered circadian clock
function and increased risk of colorectal cancer is increasingly evident from epidemiologic, preclinical, and clinical studies.
In this review, we discuss several distinct mechanisms by which altered components of the circadian clock might promote intestinal
tumorigenesis. We also review the progress in identifying circadian and clock-based molecular processes that might be targeted
to promote the prevention and control of colorectal cancer.
KeywordsCircadian clock-Colorectal cancer-Period-Melatonin
Current Colorectal Cancer Reports 04/2012; 6(2):74-82.
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ABSTRACT: Hypothesis. Among premenopausal women, both post-resection metastatic potential and tumor growth rate are influenced by the menstrual cycle. There is strong support for the former in large retrospective studies of surgical resection timing within the menstrual cycle and the following experiments were conducted to critically evaluate the latter. Methods. We studied a transplantable breast cancer of C3HeB/FeJ mice (3 studies), and a transplantable methylcholantherene A induced sarcoma of CD2F1 mice (2 studies). We concurrently measured local cancer size and estrous cycle stage up to twice and at least once each day. There is a natural individual variability in the average length of normal estrus (3-1/2 to 7 days) cycle in mice. We assessed the effect of the cycle stage and cycle duration on tumor size. Results. We found identical estrous cycle stage coordination of cancer size, and identical effects of cycling frequency across all studies in each of these two tumors, both of which express both estrogen receptor alpha and progesterone receptor. Little or no change in cancer size occurs during proestrus (preovulatory phase) and estrus (periovulatory phase); tumor size increases several fold during diestrus (post-ovulatory phase); and the tumor shrinks partially as the next proestrus phase is approached. Across both mouse strains and tumor types, mice whose average cycle length is briefer (faster cyclers), have slower average tumor growth rate than those with longer cycles (slower cyclers) who have faster tumor growth rates. Conclusion. The virtually identical modulation of tumor size and cancer growth rate, in each of two very different transplantable cancers (one, classically sex-hormone-dependent, and the other, never previously recognized as hormone dependent) growing in two unrelated inbred mouse strains, indicates that the fertility cycle related host factors affect cancer size and growth rate. These experimental findings suggest that cancer cell proliferation of both breast and non-breast cancers in premenopausal women may be meaningfully coordinated by the menstrual cycle. If this proves to be the case, then any therapeutic strategy targeting proliferating cancer cells should be most effective against cancer of cycling women when given during the follicular phase of their menstrual cycles.
Breast Cancer Research and Treatment 04/2012; 91(1):95-102. · 4.43 Impact Factor
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James F Grutsch,
Carol Ferrans, Patricia A Wood,
Jovelyn Du-Quiton,
Dinah Faith T Quiton,
Justin L Reynolds,
Christine M Ansell,
Eun Young Oh,
Mary Ann Daehler,
Robert D Levin,
Donald P Braun,
Digant Gupta,
Christopher G Lis,
William J M Hrushesky
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ABSTRACT: Cancer patients routinely develop symptoms consistent with profound circadian disruption, which causes circadian disruption diminished quality of life. This study was initiated to determine the relationship between the severity of potentially remediable cancer-associated circadian disruption and quality of life among patients with advanced lung cancer.
We concurrently investigated the relationship between the circadian rhythms of 84 advanced lung cancer patients and their quality of life outcomes as measured by the EORTC QLQ C30 and Ferrans and Powers QLI. The robustness and stability of activity/sleep circadian daily rhythms were measured by actigraphy. Fifty three of the patients in the study were starting their definitive therapy following diagnosis and thirty one patients were beginning second-line therapy. Among the patients who failed prior therapy, the median time between completing definitive therapy and baseline actigraphy was 4.3 months, (interquartile range 2.1 to 9.8 months).
We found that circadian disruption is universal and severe among these patients compared to non-cancer-bearing individuals. We found that each of these patient's EORTC QLQ C30 domain scores revealed a compromised capacity to perform the routine activities of daily life. The severity of several, but not all, EORTC QLQ C30 symptom items correlate strongly with the degree of individual circadian disruption. In addition, the scores of all four Ferrans/Powers QLI domains correlate strongly with the degree of circadian disruption. Although Ferrans/Powers QLI domain scores show that cancer and its treatment spared these patients' emotional and psychological health, the QLI Health/Function domain score revealed high levels of patients' dissatisfaction with their health which is much worse when circadian disruption is severe. Circadian disruption selectively affects specific Quality of Life domains, such as the Ferrans/Powers Health/Function domain, and not others, such as EORTC QLQ C30 Physical Domain.
These data suggest the testable possibility that behavioral, hormonal and/or light-based strategies to improve circadian organization may help patients suffering from advanced lung cancer to feel and function better.
BMC Cancer 01/2011; 11:193. · 3.01 Impact Factor
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ABSTRACT: Many cancer patients report poor sleep quality, despite having adequate time and opportunity for sleep. Satisfying sleep is dependent on a healthy circadian time structure and the circadian patterns among cancer patients are quite abnormal. Wrist actigraphy has been validated with concurrent polysomnography as a reliable tool to objectively measure many standard sleep parameters, as well as daily activity. Actigraphic and subjective sleep data are in agreement when determining activity-sleep patterns and sleep quality/quantity, each of which are severely affected in cancer patients. We investigated the relationship between actigraphic measurement of circadian organization and self-reported subjective sleep quality among patients with advanced lung cancer.
This cross-sectional and case control study was conducted in 84 patients with advanced non-small cell lung cancer in a hospital setting for the patients at Midwestern Regional Medical Center (MRMC), Zion, IL, USA and home setting for the patients at WJB Dorn Veterans Affairs Medical Center (VAMC), Columbia, SC, USA. Prior to chemotherapy treatment, each patient's sleep-activity cycle was measured by actigraphy over a 4-7 day period and sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) questionnaire.
The mean age of our patients was 62 years. 65 patients were males while 19 were females. 31 patients had failed prior treatment while 52 were newly diagnosed. Actigraphy and PSQI scores showed significantly disturbed daily sleep-activity cycles and poorer sleep quality in lung cancer patients compared to healthy controls. Nearly all actigraphic parameters strongly correlated with PSQI self-reported sleep quality of inpatients and outpatients.
The correlation of daily activity/sleep time with PSQI-documented sleep indicates that actigraphy can be used as an objective tool and/or to complement subjective assessments of sleep quality in patients with advanced lung cancer. These results suggest that improvements to circadian function may also improve sleep quality.
Journal of Circadian Rhythms 01/2011; 9:4.
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ABSTRACT: Human breast cancer incidence has seasonal patterns that seem to vary among global populations. The aggregate monthly frequency of breast cancer diagnosis was collected and examined for 2,921,714 breast cancer cases diagnosed across 64 global regions over spans from 2 to 53 years. Breast cancer is consistently diagnosed more often in spring and fall, both in the Northern and Southern Hemispheres, regardless of presumable menopausal status (<or=50, >50). This seasonality is increasingly more prominent as population distance from the equator increases and this latitude dependence is most pronounced among women living in rural areas. Moreover, the overall annual incidence (2005-2006), per 100,000 population, of breast cancer increased as the latitude of population residence increased. These data make it clear that human breast cancer discovery occurs non-randomly throughout each year with peaks near both equinoxes and valleys near both solstices. This stable global breast cancer seasonality has implications for better prevention, more accurate screening, earlier diagnosis, and more effective treatment. This complex latitude-dependent breast cancer seasonality is clearly related to predictable local day/night length changes which occur seasonally. Its mechanism may depend upon seasonal sunlight mediation of vitamin D and seasonal mediation of nocturnal melatonin peak level and duration.
Breast Cancer Research and Treatment 08/2010; 123(1):233-43. · 4.43 Impact Factor
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ABSTRACT: The regeneration of the 11-cis-retinyl imine chromophore of rhodopsin during the visual cycle and mechanisms that control this process are central questions in the field of vision research. The retinal pigment epithelium (RPE)-specific protein RPE65 is centrally involved in the isomerization and hydrolysis of all-trans-retinyl esters. In this study, we investigated RPE65 cleavage and potential regulatory mechanisms under oxidative stress conditions. The D407 RPE cell cultures were exposed to H(2)O(2) (100-1000 microM). Changes in the levels of RPE65 and proteins related to apoptosis were investigated using gel electrophoresis and western blotting. Mass spectrometry was used to confirm the identity of RPE65. C57BL/6J (M450) and C3HeB/FeJ (L450) mice were used for in vivo experiments. We found that a novel 45kDa truncated fragment of the RPE65 protein, designated RPE45, appears in RPE cells upon light exposure or oxidative stress. RPE45 is generated in vitro by recombinant caspases via an ubiquitination-dependent mechanism. Collectively, our results indicate that oxidative stress during the visual cycle results in cleavage of RPE65.
International journal of biological macromolecules 08/2010; 47(2):104-8. · 2.37 Impact Factor
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ABSTRACT: Melatonin, a small organic molecule synthesized by the pineal gland and the retina, has a variety of physiologic functions such as circadian clock pacemaker and antioxidant. Retinal melatonin is down-regulated by light and is barely detectable during the day. The absence of melatonin in the retina during prolonged light exposure may contribute to light-induced retinal degeneration. We sought to investigate the impact of melatonin in the light-exposed retina using proteomic approaches. We exposed mice to either light (250-300lux) for 12h followed by 12h of darkness or the same intensity of continuous light for 7 days. In half of the animals exposed to continuous light, melatonin was injected each night. Proteomic analysis of the retina from these three groups of animals showed that five proteins prominently up-regulated by constant light were down-regulated by melatonin treatment. These five proteins were identified as vimentin, serine/threonine-protein phosphatase 2A, Rab GDP dissociation inhibitor alpha, guanine nucleotide-binding protein G(o) alpha, and retinaldehyde-binding protein. These five proteins are known to be involved in several cellular processes that may contribute to light-induced retinal degeneration. Identification of melatonin target proteins in our study provides a basis for future studies on melatonin's potential in preventing or treating light-induced retinal degeneration.
International journal of biological macromolecules 04/2010; 47(2):255-60. · 2.37 Impact Factor
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ABSTRACT: Period genes ( Per2, Per1) are essential circadian clock genes. They also function as negative growth regulators. Per2 mutant mice show de novo and radiation-induced epithelial hyperplasia, tumors, and an abnormal DNA damage response. Human tumors show Period gene mutations or decreased expression. Other murine clock gene mutations are not associated with a tumor prone phenotype. Shift work and nocturnal light exposure are associated with circadian clock disruption and with increased cancer risk. The mechanisms responsible for the connection between the circadian clock and cancer are not well defined. We propose that circadian disruption per se is not uniformly tumor promoting and the mechanisms for tumor promotion by specific circadian clock disturbances will differ dependent upon the genes and pathways involved. We propose that Period clock gene mutations promote tumorigenesis by unique molecular pathways. Per2 and Per1 modulate beta-catenin and cell proliferation in colon and non-colon cancer cells. Per2 mutation increases intestinal beta-catenin levels and colon polyp formation. Per2 mutation also increases Apc(Min/+)-mediated intestinal and colonic polyp formation. Intestinal tumorigenesis per se may also alter clock function as a result of increased beta-catenin destabilizing PER2 protein. Levels and circadian rhythm of PER2 in Apc(Min/+) mouse intestine are markedly decreased, and selective abnormalities in intestinal clock gene and clock-controlled gene expression are seen. We propose that tumor promotion by loss of PERIOD clock proteins is unique to these clock genes as a result of altered beta-catenin signaling and DNA damage response. PERIOD proteins may offer new targets for cancer prevention and control.
Integrative Cancer Therapies 12/2009; 8(4):303-8. · 2.14 Impact Factor
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ABSTRACT: Cell cycle progression is tightly regulated. The expressions of cell cycle regulators, the products of which either promote or inhibit cell proliferation, oscillate during each cell cycle. Cellular proliferation and the expression of cell cycle regulators are also controlled by the circadian clock. Disruption of the circadian clock may thereby lead to deregulated cell proliferation. Mammalian Per2 is a core clock gene, the product of which suppresses cancer cell proliferation and tumor growth in vivo and in vitro. Because Per1, another key clock gene, is mutated in human breast cancers, and because its clock functions are similar and complementary to those of Per2, we have studied its role in modulating breast cancer cell proliferation and tumor growth. We find that breast cancer growth rate is gated by the circadian clock with two daily peaks and troughs, and that they are coupled to the daily expression patterns of clock-controlled genes that regulate cell proliferation. Down-regulation of the expression of tumor Per1 increases cancer cell growth in vitro and tumor growth in vivo by enhancing the circadian amplitude of the two daily tumor growth peaks. The data of the study suggest Per1 has tumor-suppressor function that diminishes cancer proliferation and tumor growth, but only at specific times of day.
Chronobiology International 10/2009; 26(7):1323-39. · 4.03 Impact Factor
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ABSTRACT: Purpose Per2, a core circadian clock gene, has tumor suppressor properties and is mutated or down regulated in human breast cancers. We have manipulated the expression of this gene in vitro and in vivo to more fully understand how the Per2 clock gene product affects cancer growth. Methods We used siRNA and shRNA to down regulate Per2 expression in vitro and in vivo and measured cancer cell proliferation, tumor growth rate and several molecular pathways relevant to cancer growth and their circadian organizations. All statistical tests were two-sided. Results Down regulation of functional Per2 gene expression increases Cyclin D and Cyclin E levels and doubles in vitro breast cancer cell proliferation (P < 0.05). Down regulation of Per2 also accelerates in vivo tumor growth and doubles the daily amplitude of the tumor growth rhythm (P < 0.05). Conclusions The clock gene Per2 exerts its tumor suppressor function in a circadian time dependent manner. Therefore, Per2 and perhaps other clock genes represent a new class of potential therapeutic targets whose manipulation will modulate cancer growth and cancer cell proliferation.
Breast Cancer Research and Treatment 09/2009; 117(2):423-31. · 4.43 Impact Factor
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ABSTRACT: Erythropoietin (EPO) stimulates red blood cell production, in part by inhibiting apoptosis of the red blood cell precursors. The erythropoietic effects of EPO are circadian stage dependent. Retinal injury due to light occurs through oxidative mechanisms and is manifest by retinal and retinal pigment epithelium (RPE) cells apoptosis. The visual cycle might be circadian coordinated as a means of effectively protecting the retina from the detrimental effects of light-induced, oxygen-dependent, free radical-mediated damage, especially at the times of day when light is more intense. We show that the retinal expression of EPO and its receptor (EPOR), as well as subsequent Janus kinase 2 (Jak2) phosphorylations, are each tightly linked to a specific time after oxidative stress and in anticipation of daily light onset. This is consistent with physiological protection against daily light-induced, oxidatively mediated retinal apoptosis. In vitro, we verify that EPO protects RPE cells from light, hyperoxia, and hydrogen peroxide-induced retinal cell apoptosis, and that these stimuli increase EPO and EPOR expression in cultured RPE cells. Together, these data support the premise that EPO and its EPOR interactions represent an important retinal shield from physiologic and pathologic light-induced oxidative injury.
Journal of Neuroscience Research 04/2009; 87(10):2365-74. · 2.74 Impact Factor
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Jovelyn Du-Quiton, Patricia A Wood,
James B Burch,
James F Grutsch,
Digant Gupta,
Kevin Tyer,
Christopher G Lis,
Robert D Levin,
Dinah Faith T Quiton,
Justin L Reynolds,
William J M Hrushesky
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ABSTRACT: We measured subjectively evaluated depression and anxiety, and objectively measured daily sleep-activity patterns in inpatients and outpatients with advanced non-small cell lung cancer (NSCLC) and determined whether cancer-associated depression and anxiety are accompanied by characteristic circadian rhythm abnormalities.
Equal numbers of inpatients (n=42) and outpatients (n=42) with advanced NSCLC were studied. Baseline depression and anxiety, assessed by the Hospital Anxiety and Depression Scale (HADS), and actigraphy were recorded before chemotherapy initiation. The effects of the presence and severity of chronic obstructive pulmonary disease (COPD) on depression, anxiety, and actigraphy were assessed only among the 42 outpatients.
Anxiety occurred in 40% and depression in 25% of these lung cancer patients, equally among inpatients and outpatients. All patients suffer extremely disturbed daily sleep-activity cycles but each patient also maintains some degree of circadian organization. Outpatients maintain more robust daily activity patterns and longer, more consolidated nighttime sleep compared with inpatients. The more disrupted the daily sleep-activity rhythm, the worse the depression and/or anxiety scores for outpatients. These relationships are obscured among inpatients. COPD has no independent measurable effects on the daily organization of sleep-activity, depression, or anxiety.
Lung cancer patients whose diurnal activity is disturbed by prolonged and frequent sedentary episodes and whose sleep is disturbed by frequent and prolonged waking are most anxious and depressed. These findings and relationships are masked by hospitalization. Since diurnal exercise improves both sleep and mood, it is reasonable to test whether enhancing daytime activity and nighttime sleep can diminish cancer-associated depression.
Psycho-Oncology 02/2009; 19(2):180-9. · 3.34 Impact Factor
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ABSTRACT: Circadian clocks gate cellular proliferation and, thereby, therapeutically target availability within proliferative pathways. This temporal coordination occurs within both cancerous and noncancerous proliferating tissues. The timing within the circadian cycle of the administration of drugs targeting proliferative pathways necessarily impacts the amount of damage done to proliferating tissues and cancers. Concurrently measuring target levels and associated key pathway components in normal and malignant tissues around the circadian clock provides a path toward a fuller understanding of the temporal relationships among the physiologic processes governing the therapeutic index of antiproliferative anticancer therapies. The temporal ordering among these relationships, paramount to determining causation, is less well understood using two- or three-dimensional representations. We have created multidimensional multimedia depictions of the temporal unfolding of putatively causative and the resultant therapeutic effects of a drug that specifically targets these ordered processes at specific times of the day. The systems and methods used to create these depictions are provided, as well as three example supplementary movies.
International Journal of Biomedical Imaging 02/2009; 2009:231539.
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ABSTRACT: Proliferation of intestinal epithelial cells is rhythmic throughout the day. This temporal organization occurs through the interaction between the endogenous peripheral circadian clock and pathways controlling cell cycle progression. Per2, a core clock gene with tumour suppresser function, is critical to clock function and to the regulation of cellular proliferation. Circadian disruption, which increases colon cancer incidence, may do so by deregulating clock controlled epithelial cell proliferation. Increased expression of beta-catenin is a contributing cause of most familial and spontaneous human colon cancer and the cause of multiple intestinal neoplasia of the Apc(Min/+) mouse. Here we report that increased beta-catenin destabilizes PER2 clock protein by inducing beta-TrCP, an F-box protein of SCF ubiquitin E3 ligase. In the intestinal mucosa of the Apc(Min/)(+) mouse, the decrease in PER2 protein levels is associated with altered circadian rhythms of clock genes, Per1 and Per2, and clock controlled genes, Dbp and Wee1. These findings suggest that disruption of the peripheral intestinal circadian clock may be intimately involved in beta-catenin induced intestinal epithelial neoplastic transformation in both mouse and man.
Journal of biochemistry 01/2009; 145(3):289-97. · 1.95 Impact Factor
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Patricia A Wood,
Xiaoming Yang,
Andrew Taber,
Eun-Young Oh,
Christine Ansell,
Stacy E Ayers,
Ziad Al-Assaad,
Kevin Carnevale,
Franklin G Berger,
Maria Marjorette O Peña,
William J M Hrushesky
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ABSTRACT: Colorectal cancer risk is increased in shift workers with presumed circadian disruption. Intestinal epithelial cell proliferation is gated throughout each day by the circadian clock. Period 2 (Per2) is a key circadian clock gene. Per2 mutant (Per2(m/m)) mice show an increase in lymphomas and deregulated expression of cyclin D and c-Myc genes that are key to proliferation control. We asked whether Per2 clock gene inactivation would accelerate intestinal and colonic tumorigenesis. The effects of PER2 on cell proliferation and beta-catenin were studied in colon cancer cell lines by its down-regulation following RNA interference. The effects of Per2 inactivation in vivo on beta-catenin and on intestinal and colonic polyp formation were studied in mice with Per2 mutation alone and in combination with an Apc mutation using polyp-prone Apc(Min/+) mice. Down-regulation of PER2 in colon cell lines (HCT116 and SW480) increases beta-catenin, cyclin D, and cell proliferation. Down-regulation of beta-catenin along with Per2 blocks the increase in cyclin D and cell proliferation. Per2(m/m) mice develop colonic polyps and show an increase in small intestinal mucosa beta-catenin and cyclin D protein levels compared with wild-type mice. Apc(Min/+)Per2(m/m) mice develop twice the number of small intestinal and colonic polyps, with more severe anemia and splenomegaly, compared with Apc(Min/+) mice. These data suggest that Per2 gene product suppresses tumorigenesis in the small intestine and colon by down-regulation of beta-catenin and beta-catenin target genes, and this circadian core clock gene may represent a novel target for colorectal cancer prevention and control.
Molecular Cancer Research 12/2008; 6(11):1786-93. · 4.29 Impact Factor
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ABSTRACT: Dysregulated cellular proliferation is a characteristic property of cancer. We show that, despite this fact, cancers maintain high amplitude, circadian rhythms in their growth, DNA synthesis, and mitosis. These patterns are accompanied by the daily traverse of BMAL-1 protein between the cytoplasm, where it is produced, and nucleus, where it influences timing of cancer cell proliferation. This core clock gene product gates cancer cell proliferation by coordinating clock-controlled proteins, thymidylate synthase [thymidylate synthase activity (TSA) cell DNA replication], WEE-1 (cell mitosis), and vascular endothelial growth factor (growth). 5-Fluorouracil (5-FU)-induced host bone marrow and gut toxicity and tumor shrinkage following administration at six equispaced times of day allowed determination of circadian relationships among tumor growth, relevant clock, and clock-controlled proteins and dependence of 5-FU target availability (TSA) in normal and cancer tissues and resultant 5-FU toxic-therapeutic index. The time of day (hours after lights on) of low TSA in each tissue and tumor is respectively associated with greatest toxicity to that tissue and greatest tumor shrinkage. 5-FU treatment near daily awakening results in least damage to bone marrow and gut, greatest antitumor effect, and best survival. This time of day is associated with maximum tumor nuclear BMAL-1 and total cell WEE-1 protein. The described chain of events, for the first time, links cancer cell clock proteins, cancer cell DNA synthesis, proliferation, TSA, and 5-FU toxic-therapeutic index, explaining the dependence of cancer outcome on circadian timing of 5-FU.
Molecular Cancer Therapeutics 09/2006; 5(8):2023-33. · 5.23 Impact Factor
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Shaojin You,
Masami Ohmori,
Maria Marjorette O Peña,
Basel Nassri,
Jovelyn Quiton,
Ziad A Al-Assad,
Lucy Liu, Patricia A Wood,
Sondra H Berger,
Zhijian Liu,
Michael D Wyatt,
Robert L Price,
Franklin G Berger,
William J M Hrushesky
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ABSTRACT: Germ-line mutation of the Apc gene has been linked to familial adenomatous polyposis (FAP) that predisposes to colon cancer. Apc(Min/+) mice, heterozygous for the Apc gene mutation, progressively develop small intestinal tumours in a manner that is analogous to that observed in the colon of patients with FAP (Su et al. 1992; Fodde et al. 1994; Moser et al. 1995). We have studied the effects of Apc gene mutation on murine intestinal and extra-intestinal, proliferatively active tissues. We have contrasted the histology to that of the age- and sex-matched wild-type C57BL/6 mice. Histological assessment of the normal appearing intestinal mucosa demonstrates minimal change in size of crypts. In contrast, villi are longer in the ileum of Apc(Min/+) mice relative to C57BL/6 mice at 12 and 15 weeks of age. Vigorous splenic haematopoiesis in Apc(Min/+) mice was seen at 12 and 15 weeks of age, as reflected by marked splenomegaly, increased splenic haematopoietic cells and megakaryocytes. Peripheral blood counts, however, did not differ between C57BL/6 and Apc(Min/+) mice at 15 weeks of age. Lymphoid depletion in Apc(Min/+) mice was characterized by diminished numbers of splenic lymphoid follicles and small intestinal Peyer's patches. The ovaries of 12- and 15-week-old Apc(Min/+) mice exhibited increased numbers of atretic follicles, and estrous cycling by serial vaginal smears showed tendency of elongation in the mutant mice during these age ranges. The testicles of 10-week-old Apc(Min/+) mice showed increased numbers of underdeveloped seminiferous tubules. Collectively, these data suggest that, in addition to its obvious effects upon intestinal adenoma formation, Apc gene mutation causes impairment of developmental and apparent differentiation blockade in proliferative tissues, including those of the haematopoietic system, lymphoid and reproductive tract.
International Journal of Experimental Pathology 07/2006; 87(3):227-36. · 2.57 Impact Factor
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ABSTRACT: The frequency of breast cancer metastatic spread is affected by the menstrual cycle phase of its resection. Breast cancer growth, post-resection spread, and cure frequency are each modulated by the estrous cycle in C(3)HeB/FeJ mice. Tumor metastases are 2- to 3-fold more frequent when the resection is done during diestrus as compared with estrus. Tumor angiogenesis is essential for both cancer growth and lethal metastatic cancer spread. The balance between vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) modulates new blood vessel formation and blood vessel permeability. Sex hormones modulate the expression of these key angiogenesis regulators in the endometrium and uterus. We, therefore, asked whether the estrous cycle modulates the density of CD31-positive vessels within the tumor, the permeability of tumor blood vessels, levels of VEGF and bFGF immunoreactive protein in normal breast and breast cancer, and whether expression of these genes are modulated by the estrous cycle stage in C(3)HeB/FeJ mice. We find that tumor blood vessel density and blood volume do not vary throughout the cycle; however, tumor capillary permeability is regulated by the estrous cycle being highest in diestrus, the cycle stage associated with the highest cancer growth rate and the highest frequency of post-resection cancer metastasis. VEGF protein levels in breast cancer are >100-fold higher than in normal breast. VEGF protein in this mammary tumor varies with the estrus cycle with highest levels in proestrus. In a non-breast tumor, methylcholantrenene A sarcoma, from CD(2)F(1) mice, tumor VEGF protein also varies with the estrus cycle with highest levels in proestrus and diestrus. VEGF gene expression in the mammary tumor does not change significantly across the cycle, but is modulated by the cycle in normal breast tissue. bFGF protein concentration is 6-fold higher in normal breast than in breast cancer. bFGF protein pattern in both tumor and breast are similar, opposite to VEGF, and affected by oophorectomy. bFGF message is modulated by the cycle in both breast cancer and normal breast. The changes in breast cancer capillary permeability, VEGF, and bFGF that occur during each fertility cycle, in breast tissue and breast cancer, putatively in response to cyclical changes in sex hormones, might contribute, at least in part, to both the modulation of cancer growth and post-resection breast cancer spread by the fertility cycle. These fertility cycle-induced effects on tumor biology also seem to extend to non-breast cancer biology.
Molecular Cancer Therapeutics 07/2005; 4(7):1065-75. · 5.23 Impact Factor
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ABSTRACT: Circadian coordination in mammals is accomplished, in part, by coordinate, rhythmic expression of a series of circadian clock genes in the central clock within the suprachiasmatic nuclei (SCN) of the hypothalamus. These same genes are also rhythmically expressed each day within each peripheral tissue.
We measured tumor size, tumor cell cyclin E protein, tumor cell mitotic index, and circadian clock gene expression in liver and tumor cells at six equispaced times of day in individual mice of a 12-h light, 12-h dark schedule.
We demonstrate that C3HFeJ/HeB mice with transplanted syngeneic mammary tumor maintain largely normal circadian sleep/activity patterns, and that the rate of tumor growth is highly rhythmic during each day. Two daily 2.5-fold peaks in cancer cell cyclin E protein, a marker of DNA synthesis, are followed by two daily up-to-3-fold peaks in cancer cell mitosis (one minor, and one major peak). These peaks are, in turn, followed by two prominent daily peaks in tumor growth rate occurring during mid-sleep and the second, during mid-activity. These data indicate that all therapeutic targets relevant to tumor growth and tumor cell proliferation are ordered in tumor cells within each day. The daily expression patterns of the circadian clock genes Bmal1, mPer1, and mPer2, remain normally circadian coordinated in the livers of these tumor bearing mice. Bmal1 gene expression remains circadian rhythmic in cancer cells, although damped in amplitude, with a similar circadian pattern to that in normal hepatocytes. However, tumor cell mPer1 and mPer2 gene expression patterns fail to maintain statistically significant daily rhythms.
We conclude that, if core circadian clock gene expression is essential to gate tumor cell proliferation within each day, then there may be substantial redundancy in this timing system. Alternatively, the daily ordering of tumor cell clock gene expression may not be essential to the daily gating of cancer cell DNA synthesis, mitosis and growth. This would indicate that host central SCN-mediated neuro-humoro-behavioral controls and/or daily light-induced changes in melatonin or peripherally-induced rhythms such as those resulting from feeding, may be adequate for the daily coordination of cancer cell expression of proliferation related therapeutic targets.
Breast Cancer Research and Treatment 06/2005; 91(1):47-60. · 4.43 Impact Factor
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ABSTRACT: Among premenopausal women, both post-resection metastatic potential and tumor growth rate are influenced by the menstrual cycle. There is strong support for the former in large retrospective studies of surgical resection timing within the menstrual cycle and the following experiments were conducted to critically evaluate the latter.
We studied a transplantable breast cancer of C3HeB/FeJ mice (3 studies), and a transplantable methylcholantherene A induced sarcoma of CD2F1 mice (2 studies). We concurrently measured local cancer size and estrous cycle stage up to twice and at least once each day. There is a natural individual variability in the average length of normal estrus (3-1/2 to 7 days) cycle in mice. We assessed the effect of the cycle stage and cycle duration on tumor size.
We found identical estrous cycle stage coordination of cancer size, and identical effects of cycling frequency across all studies in each of these two tumors, both of which express both estrogen receptor alpha and progesterone receptor. Little or no change in cancer size occurs during proestrus (preovulatory phase) and estrus (periovulatory phase); tumor size increases several fold during diestrus (post-ovulatory phase); and the tumor shrinks partially as the next proestrus phase is approached. Across both mouse strains and tumor types, mice whose average cycle length is briefer (faster cyclers), have slower average tumor growth rate than those with longer cycles (slower cyclers) who have faster tumor growth rates.
The virtually identical modulation of tumor size and cancer growth rate, in each of two very different transplantable cancers (one, classically sex-hormone-dependent, and the other, never previously recognized as hormone dependent) growing in two unrelated inbred mouse strains, indicates that the fertility cycle related host factors affect cancer size and growth rate. These experimental findings suggest that cancer cell proliferation of both breast and non-breast cancers in premenopausal women may be meaningfully coordinated by the menstrual cycle. If this proves to be the case, then any therapeutic strategy targeting proliferating cancer cells should be most effective against cancer of cycling women when given during the follicular phase of their menstrual cycles.
Breast Cancer Research and Treatment 06/2005; 91(1):95-102. · 4.43 Impact Factor
