[show abstract][hide abstract] ABSTRACT: Background: Infections of teeth are highly prevalent, often leading to tooth extractions. Missing teeth can thus be considered as proxy for chronic dental infections, caries or periodontitis. We followed-up a cohort for 24 years investigating the association between missing teeth and the incidence of cancer with the hypothesis that dental chronic inflammation links to cancer. Methods: WHO ICD-7-9-10 malignant diagnoses were recorded from the Swedish Cancer Registry from 1985 to 2009 in 1 390 individuals who had underwent clinical oral examination in 1985. The subjects appeared periodontally healthy and thus the probable reason for tooth extractions was deep caries. Using Fisher's exact t-test and multiple logistic regression analysis the results were analysed for the association between cancer incidence and baseline oral health parameters and a number of other explanatory factors. Results: Of the 1 390 subjects 71 had got cancer by year 2009. The results of the multiple regression analysis showed that between any type of cancer as a dependent variable, and several independent explanatory variables, missing second molar in the right mandible and age appeared as the principle independent predictors significantly associating with cancer, with an odds ratio (95% confidence interval) of 2.62 (1.18-5.78) and 1.91 (1.06-3.43), respectively. Conclusions: In periodontally healthy subjects extracted molars, proxy for past dental infections, seemed to predict cancer risk in the studied age group - hence supporting a role of chronic dental infection/inflammation in carcinogenesis.
[show abstract][hide abstract] ABSTRACT: We investigated statistical association between long-term periodontal disease and cancer in a group of patients followed-up for 24 years with the hypothesis that chronic infection affects carcinogenesis. We made a prospective study of 1676 30-40-year old subjects in Stockholm, clinically examined in 1985. The data were combined with Swedish Cancer Registry in 2009. All cancer types were registered according to WHO International Classification of Diseases. Associations between cancer and dental parameters were studied using multiple logistic regression analysis with background variables and known risk factors for cancer. Age, gender, dental visits, education, income, socioeconomic status, working history, smoking, dental plaque, calculus, gingival bleeding, periodontal disease indicated by extracted or extruded molars were the independent variables. 286 subjects had periodontal disease in 1985. Of these, 18 subjects (6.3%) got cancer by 2009. In women breast cancer dominated (50%) while in men the types of malignancies were scattered. Logistic regression analysis showed that if a subject had periodontitis with extruded/extracted first molar tooth (d. 46) of the mandible in 1985, the risk of cancer increased with odds ratio (OR) 8.43, if the second molar (d. 47) was missing, OR for cancer was 6.11. To conclude chronic periodontal disease indicated by extracted or extruded molars associated statistically with elevated incidence of cancer.
International Journal of Cancer Research 04/2013; 47:2051-784.
[show abstract][hide abstract] ABSTRACT: Bacillus cereus, aseptically isolated from potato tubers, were screened for cereulide production and for toxicity on human and other mammalian cells. The cereulide producing isolates grew slowly, the colonies remained small (∼1 mm), tested negative for starch hydrolysis, and varied in productivity from 1 to 100 ng of cereulide mg(-1) wet wt (∼ 0.01 to 1 ng per 10(5) CFU). By DNA-fingerprint analysis the isolates matched B. cereus F5881/94, connected to human foodborne illness, but were distinct from cereulide producing endophytes of spruce tree (Picea abies). Exposure to cell extracts (1 to 10 μg bacterial biomass ml(-1)) and to purified cereulide ( 0.4 to 7 ng ml(-1)) from the potato isolates caused mitochondrial depolarization (loss of ΔΨm) in human peripheral blood mononuclear cells (PBMC) and keratinocytes (HaCaT), porcine spermatozoa and kidney tubular epithelial cells (PK-15), murine fibroblasts (L-929) and pancreatic insulin producing cells (MIN-6). Cereulide (10 - 20 ng ml(-1)) exposed pancreatic islets (MIN-6) disintegrated into small pyknotic cells followed by necrotic death. Necrotic death in other test cells was observed only after 2 logs higher exposure. Exposure to 30 - 60 ng ml(-1) of cereulide induced K(+) translocation in intact, live PBMC, keratinocytes and sperm cells within seconds of exposure, depleting 2 to 10% of the cellular K(+) stores in 10 minutes. The ability of cereulide to transfer K(+) ions across biological membranes may benefit the producer bacterium in K(+) deficient environments such as extracellular spaces inside plant tissue, but is a pathogenic trait when in contact with mammalian cells.
Applied and environmental microbiology 03/2013; · 3.69 Impact Factor
[show abstract][hide abstract] ABSTRACT: Reg IV is a 17kD secreted C-type lectin physiologically found in selected enteroendocrine cells (EEC). It is thought be involved in the regulation of normal and pathological intestinal and/or neuroendocrine differentiation and proliferation but its ultimate functional role(s) is still unclear. We used immunostaining and compared the cellular expression of Reg IV with a panel of neuroendocrine markers in human GI-tract tissue samples. Reg IV showed cellular co-distribution with serotonin and chromogranin A in all parts of GI-tract. Co-localization of Reg IV with somatostatin was seen in colon and with substance P in ileum. Subpopulations of cells expressing Reg IV overlapped with EECs containing GLP-1, GLP-2, secretin, PYY, and ghrelin, depending on the anatomical localization of the samples. The results further underscore the high degree of diversity among EECs and suggest that Reg IV may be involved in the finetuning of functions exerted by the neuroendocrine cells in the GI-tract.
[show abstract][hide abstract] ABSTRACT: Breast cancer can recur even decades after the primary therapy. Markers are needed to predict cancer progression and the risk of late recurrence. The estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2), proliferation marker Ki-67, and cytokeratin CK5 were studied to find out whether their expression or occurrence in subgroups of breast cancers correlated with the time of recurrence. The expression of HER2, ER, PR, Ki-67, and CK5 was studied by IHC in 72 primary breast cancers and their corresponding recurrent/metastatic lesions. The patients were divided into three groups according to the time of the recurrence/metastasis: before two years, after 5 years, and after 10 years. Based on their IHC profiles, the tumors were divided into surrogates of the genetically defined subgroups of breast cancers and the subtype definitions were as follows: luminal A (ER or PR+HER2-), luminal B (ER or PR+HER2+), HER2 overexpressing (ER-PR-HER2+), triple-negative (ER-PR-HER2-), basal-like (ER-PR-HER2-CK5+), non-classified (ER-PR-HER2-CK5-) and luminobasal (ER or PR+CK5+). In multivariate analysis, tumor size and HER2 positivity were a significant risk of early cancer relapse. The metastases showed a significantly lower CK5 expression. CK5 positivity distinguished triple negative tumors into rapidly and slowly recurring cancers. The IHC subtype ER or PR+HER2- luminal A presented a significantly lower risk of early tumor recurrence. Ki-67 expression denoted early-relapsing tumors and correlated linearly with tumor progression, since Ki-67 positivity declined gradually from early-relapsing toward late-recurring cancers.
[show abstract][hide abstract] ABSTRACT: Stanniocalcin 1 (STC1), originally described as an antihypercalcemic hormone in fish, is highly expressed in differentiated mammalian neurons. Mild hypoxic treatment and focal cerebral ischemia induce upregulation of STC1 in the brain. These findings prompted us to investigate whether STC1 contributes to neuroprotection after ischemia and whether STC1 is required for development of ischemic tolerance. We induced 60 minutes of temporary middle cerebral artery occlusion in wild type (WT) and STC1-deficient mice (STC1(-/-)) with or without prior hypoxic preconditioning (HPC, 8% oxygen for 6 hours followed by reoxygenation for 24 hours). Infarct sizes, neurological scores, and Stc1, Stc2, and Il-6 mRNA brain levels were measured 24 hours after ischemia. Additionally, we examined blood-brain barrier (BBB) integrity (Evans Blue fluorescence) under normal conditions and 0 and 24 hours after hypoxia. STC1(-/-) and WT mice developed brain infarcts of similar size. In both strains, HPC triggered ischemic tolerance with similar reduction in infarct size. However, STC1(-/-) mice had worse neurological scores in both scenarios. HPC induced upregulation of STC1 and STC2 in WT mice and of STC2 in STC1(-/-) mice. Ischemic STC1(-/-) mice showed significantly lower Il-6 mRNA expression than ischemic WT mice. Evans Blue fluorescence levels showed no difference in between WT and STC1(-/-) mice under evaluated conditions, thus BBB integrity is preserved despite STC1 deficiency. STC1 was not crucial for the development of ischemic tolerance triggered by HPC or for preserving BBB integrity but may be involved in functional recovery after stroke.
[show abstract][hide abstract] ABSTRACT: Bmx (Bone marrow kinase in chromosome X), also known as Etk, is a member of the Tec family of nonreceptor tyrosine kinases. Bmx is expressed mainly in arterial endothelia and in myeloid hematopoietic cells. Bmx regulates ischemia-mediated arteriogenesis and lymphangiogenesis, but its role in tumor angiogenesis is not known. In this study, we characterized the function of Bmx in tumor growth using both Bmx knockout and transgenic mice. Isogenic colon, lung, and melanoma tumor xenotransplants showed reductions in growth and tumor angiogenesis in Bmx gene-deleted ((-/-)) mice, whereas developmental angiogenesis was not affected. In addition, growth of transgenic pancreatic islet carcinomas and intestinal adenomas was also slower in Bmx(-/-) mice. Knockout mice showed high levels of Bmx expression in endothelial cells of tumor-associated and peritumoral arteries. Moreover, endothelial cells lacking Bmx showed impaired phosphorylation of extracellular signal-regulated kinase (Erk) upon VEGF stimulation, indicating that Bmx contributes to the transduction of vascular endothelial growth factor signals. In transgenic mice overexpressing Bmx in epidermal keratinocytes, tumors induced by a two-stage chemical skin carcinogenesis treatment showed increased growth and angiogenesis. Our findings therefore indicate that Bmx activity contributes to tumor angiogenesis and growth.
Cancer Research 05/2012; 72(14):3512-21. · 8.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Stanniocalcin 2 (STC2) is a homolog of stanniocalcin 1, a 56kD glycoprotein hormone that originally was found to confer calcitonin-like activity in fish. Human STC2 is expressed in various tissues such as kidney, spleen, heart, and pancreas. STC2 has been demonstrated to be induced by different kinds of stress and display cytoprotective activity, but the molecular mechanism is poorly understood. Heme oxygenase 1 (HO1) degrades heme to biliverdin, carbon monoxide and free iron, and is a stress-responsive protein. Using yeast two-hybrid screening we identified HO1 as a binding partner of STC2. The interaction was validated by in vivo co-immunoprecipitation and immunofluorescence. The binding site for HO1 was located to amino acids 181-200 of STC2. We also found that STC2 binds hemin via a consensus heme regulatory motif. Moreover, STC2 expression was induced by heat shock in HEK293 cells. Taken together, our findings point to three novel functions of STC2, and suggest that STC2 interacts with HO1 to form a eukaryotic 'stressosome' involved in the degradation of heme.
Biochemical and Biophysical Research Communications 04/2012; 421(2):274-9. · 2.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: To study whether the amount of dental plaque, which indicates poor oral hygiene and is potential source of oral infections, associates with premature death from cancer.
Prospective cohort study.
1390 randomly selected healthy young Swedes followed up from 1985 to 2009. All subjects underwent oral clinical examination and answered a questionnaire assessing background variables such as socioeconomic status and smoking.
Causes of death were recorded from national statistics and classified according to the WHO International Classification of Diseases. Unpaired t test, χ(2) tests and multiple logistic regressions were used.
Of the 1390 participants, 4.2% had died during the follow-up. Women had died at a mean age of 61.0 (±2.6 SD) years and men at the age of 60.2 (±2.9 SD) years. The amount of dental plaque between those who had died versus survived was statistically significant (p<0.001). In multiple logistic regression analysis, dental plaque appeared to be a significant independent predictor associated with 1.79 times the OR of death (p<0.05). Age increased the risk with an OR of 1.98 (p<0.05) and gender (men) with an OR of 1.91 (p<0.05). The malignancies were more widely scattered in men, while breast cancer was the most frequent cause of death in women.
This study hypothesis was confirmed by showing that poor oral hygiene, as reflected in the amount of dental plaque, was associated with increased cancer mortality.
[show abstract][hide abstract] ABSTRACT: Prostate and seminal vesicle are two similar hormone responsive human organs that differ dramatically in their cancer incidence. DNA damage response (DDR) is required for maintenance of genomic integrity.
In this study we investigated the DDR and cell cycle checkpoint activation of these organs using orthotopic cultures of human surgery-derived tissues and primary cultures of isolated prostate and seminal vesicle cells.
We find that the activation of ATM signaling pathway by ionizing radiation (IR) was comparable in both tissues. Previously, we have shown that the prostate secretory cells express low levels of histone variant H2AX and phosphorylated H2AX (γH2AX) after IR. Here we demonstrate that H2AX levels are low also in the secretory seminal vesicle cells suggesting that this is a common phenotype of postmitotic cells. We consequently established primary epithelial cell cultures from both organs to compare their DDR. Interestingly, contrary to human prostate epithelial cells (HPEC), primary seminal vesicle epithelial cells (HSVEC) displayed effective cell cycle checkpoints after IR and expressed higher levels of Wee1A checkpoint kinase. Furthermore, HSVEC but not HPEC cells were able to activate p53 and to induce p21 cell cycle inhibitor.
Our results show that during replication, the checkpoint enforcement is more proficient in the seminal vesicle than in the prostate epithelium cells. This indicates a more stringent enforcement of DDR in replicating seminal vesicle epithelial cells, and suggests that epithelial regeneration combined with sub-optimal checkpoint responses may contribute to high frequency of genetic lesions in the prostate epithelium.
The Prostate 11/2011; 72(10):1060-70. · 3.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: PROX1 is a specific target of the β-catenin/TCF pathway in the intestinal epithelium. It acts as a regulator of progression from a benign to a highly dysplastic phenotype in colorectal tumours. However, the clinical significance of PROX1 expression is not known.
We studied the prognostic value of immunohistochemical expression of PROX1 in a series of 517 patients with colorectal cancer (CRC).
The majority of the tumour samples expressed PROX1 (91%, 471 out of 517). High PROX1 expression was associated with a poor grade of tumour differentiation (P<0.0001). In the subgroup of patients with colon cancer, high PROX1 expression was associated with unfavourable colorectal cancer-specific survival (CCSS) as compared with low PROX1 expression (CCSS 47% vs 62%; P=0.045; RR 1.47). The association between high PROX1 and poor outcome was further strengthened in female colon cancer patients (CCSS 38% vs 63%; P=0.007; RR 2.02). Nonetheless, in multivariate survival analysis PROX1 expression was not retained as an independent prognostic factor.
High PROX1 expression is associated with a poor grade of tumour differentiation, and, in colon cancer patients, also with less favourable patient outcome. Our results strengthen the previous preclinical observations that PROX1 has a role in tumour progression in CRC.
British Journal of Cancer 10/2011; 105(9):1346-51. · 5.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: Transcription factor GATA-4 is expressed in early fetal liver and essential for organogenesis. It is also implicated in carcinogenesis in several endoderm-derived organs. Hepatoblastoma (HB), the most common malignant pediatric liver tumor, has features of fetal liver including extramedullary hematopoiesis. We investigated the expression of GATA-4 and its purported target gene erythropoietin (Epo) in liver tumors and the role of GATA-4 in HB pathogenesis.
Immunohistochemistry, Western blotting, and reverse transcription-polymerase chain reaction were used for liver samples from patients with HB or hepatocellular carcinoma. To further investigate the role of GATA-4 in pediatric liver tumors, we used adenoviral transfections of wild-type or dominant negative GATA-4 constructs in the human HB cell line, HUH6.
We found abundant GATA-4 expression in both types of liver tumors in children, whereas it was absent in adult hepatocellular carcinoma. A close family member GATA-6 was expressed in a minority of childhood but not adult liver tumors. Epo, present in the fetal liver, was also expressed in childhood liver tumors. Moreover, cell line HUH6 was GATA-4 positive and produced Epo. We found that altering the amount of functional GATA-4 in HUH6 cells did not significantly affect either proliferation or apoptosis.
GATA-4 is abundant in pediatric liver tumors, but unraveling its exact role in these neoplasms requires further investigation.
Journal of pediatric gastroenterology and nutrition 07/2011; 54(1):101-8. · 2.18 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hemin (iron protoporphyrin IX) is a necessary component of many proteins, functioning either as a cofactor or an intracellular messenger. Hemoproteins have diverse functions, such as transportation of gases, gas detection, chemical catalysis and electron transfer. Stanniocalcin 1 (STC1) is a protein involved in respiratory responses of the cell but whose mechanism of action is still undetermined. We examined the ability of STC1 to bind hemin in both its reduced and oxidized states and located Cys(114) as the axial ligand of the central iron atom of hemin. The amino acid sequence differs from the established (Cys-Pro) heme regulatory motif (HRM) and therefore presents a novel heme binding motif (Cys-Ser). A STC1 peptide containing the heme binding sequence was able to inhibit both spontaneous and H(2)O(2) induced decay of hemin. Binding of hemin does not affect the mitochondrial localization of STC1.
Biochemical and Biophysical Research Communications 06/2011; 409(2):266-9. · 2.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: Breast cancer is known for its propensity to recur decades after treatment. The biology behind the phenomenon of tumor dormancy is still poorly understood. Bmi-1, c-myc, and Snail are transcription factors that have prognostic roles in several malignancies. In order to reveal whether any of these markers has impact on late relapses, we used immunohistochemistry to study the expression of Bmi-1, c-myc, Snail, and estrogen receptor in 73 primary breast cancers and in their metastatic relapses detected within 2 years, or 5 or 10 years after primary surgery. The expression of Bmi-1 was higher in the metastases than in their corresponding primary tumors in both early and late relapses. The highest expression of Bmi-1 was seen in the very late relapsing tumors (first tumor relapse after 10 years). Previously, Bmi-1 has been reported to function as a marker of tumor stem cells in breast cancer. Our results indicate that metastases, when compared to primary tumors, arise from tumor cells that have retained stem cell properties. We also analyzed the relationship between the expression of these markers and clinical parameters. A significant association between the expression of Bmi-1 and estrogen receptor was found. Nuclear expression of c-myc in primary tumors correlated with an increased risk for axillary lymph node metastasis.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 06/2011; 459(1):31-9. · 2.68 Impact Factor
[show abstract][hide abstract] ABSTRACT: The dissemination of tumor cells to sites far from the primary tumor (metastasis) is the principal cause of death in cancer patients. Tumor-associated lymphatic vessels are a key conduit for metastatic tumor cells, which typically first colonize the lymph nodes. Although the primary tumor and affected lymph nodes can be removed during surgery, tumor cells inside lymphatic vessels are left behind. Here, we show that in-transit tumor cells inside lymphatic vessels in mice bearing mouse melanomas or human lung tumors give rise to metastases. Using photodynamic therapy with the benzoporphyrin derivative verteporfin, we selectively destroyed lymphatic vessels in mice and pigs. Destruction of tumor-associated lymphatic vessels also eradicated intralymphatic tumor cells and prevented metastasis of mouse melanoma cells and subsequent relapse. Photodynamic therapy, when combined with anti-lymphangiogenic therapy, prevented further tumor invasion of lymphatic vessels. These findings highlight the potential of targeting in-transit tumor cells in patients.
Science translational medicine 02/2011; 3(69):69ra11. · 10.76 Impact Factor
[show abstract][hide abstract] ABSTRACT: Twinfilins are evolutionarily conserved regulators of cytoskeletal dynamics. They inhibit actin polymerization by binding both actin monomers and filament barbed ends. Inactivation of the single twinfilin gene from budding yeast and fruit fly results in defects in endocytosis, cell migration, and organization of the cortical actin filament structures. Mammals express three twinfilin isoforms, of which twinfilin-1 and twinfilin-2a display largely overlapping expression patterns in non-muscle tissues of developing and adult mice. The expression of twinfilin-2b, which is generated through alternative promoter usage of the twinfilin-2 gene, is restricted to heart and skeletal muscles. However, the physiological functions of mammalian twinfilins have not been reported. As a first step towards understanding the function of twinfilin in vertebrates, we generated twinfilin-2a deficient mice by deleting exon 1 of the twinfilin-2 gene. Twinfilin-2a knockout mice developed normally to adulthood, were fertile, and did not display obvious morphological or behavioural abnormalities. Tissue anatomy and morphology in twinfilin-2a deficient mice was similar to that of wild-type littermates. These data suggest that twinfilin-2a plays a redundant role in cytoskeletal dynamics with the biochemically similar twinfilin-1, which is typically co-expressed in same tissues with twinfilin-2a.
PLoS ONE 01/2011; 6(8):e22894. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: In addition to circulation, where it transfers phospholipids between lipoprotein particles, phospholipid transfer protein (PLTP) was also identified as a component of normal tear fluid. The purpose of this study was to clarify the secretion route of tear fluid PLTP and elucidate possible interactions between PLTP and other tear fluid proteins. Human lacrimal gland samples were stained with monoclonal antibodies against PLTP. Heparin-Sepharose (H-S) affinity chromatography was used for specific PLTP binding, and coeluted proteins were identified with MALDI-TOF mass spectrometry or Western blot analysis. Immunoprecipitation assay and blotting with specific antibodies helped to identify and characterize PLTP-mucin interaction in tear fluid. Human tear fluid PLTP is secreted from the lacrimal gland. MALDI-TOF analysis of H-S fractions identified several candidate proteins, but protein-protein interaction assays revealed only ocular mucins as PLTP interaction partners. We suggest a dual role for PLTP in human tear fluid: (1) to scavenge lipophilic substances from ocular mucins and (2) to maintain the stability of the anterior tear lipid film. PLTP may also play a role in the development of ocular surface disease.
The Journal of Lipid Research 11/2010; 51(11):3126-34. · 4.39 Impact Factor
[show abstract][hide abstract] ABSTRACT: Detection of recurrent somatic rearrangements routinely allows monitoring of residual disease burden in leukemias, but is not used for most solid tumors. However, next-generation sequencing now allows rapid identification of patient-specific rearrangements in solid tumors. We mapped genomic rearrangements in three cancers and showed that PCR assays for rearrangements could detect a single copy of the tumor genome in plasma without false positives. Disease status, drug responsiveness, and incipient relapse could be serially assessed. In future, this strategy could be readily established in diagnostic laboratories, with major impact on monitoring of disease status and personalizing treatment of solid tumors.
Genes Chromosomes and Cancer 11/2010; 49(11):1062-9. · 3.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: Vascular endothelial growth factor-B (VEGF-B) binds to VEGF receptor-1 and neuropilin-1 and is abundantly expressed in the heart, skeletal muscle, and brown fat. The biological function of VEGF-B is incompletely understood.
Unlike placenta growth factor, which binds to the same receptors, adeno-associated viral delivery of VEGF-B to mouse skeletal or heart muscle induced very little angiogenesis, vascular permeability, or inflammation. As previously reported for the VEGF-B(167) isoform, transgenic mice and rats expressing both isoforms of VEGF-B in the myocardium developed cardiac hypertrophy yet maintained systolic function. Deletion of the VEGF receptor-1 tyrosine kinase domain or the arterial endothelial Bmx tyrosine kinase inhibited hypertrophy, whereas loss of VEGF-B interaction with neuropilin-1 had no effect. Surprisingly, in rats, the heart-specific VEGF-B transgene induced impressive growth of the epicardial coronary vessels and their branches, with large arteries also seen deep inside the subendocardial myocardium. However, VEGF-B, unlike other VEGF family members, did not induce significant capillary angiogenesis, increased permeability, or inflammatory cell recruitment.
VEGF-B appears to be a coronary growth factor in rats but not in mice. The signals for the VEGF-B-induced cardiac hypertrophy are mediated at least in part via the endothelium. Because cardiomyocyte damage in myocardial ischemia begins in the subendocardial myocardium, the VEGF-B-induced increased arterial supply to this area could have therapeutic potential in ischemic heart disease.