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Demetrius Albanes - One of the best experts on this subject based on the ideXlab platform.
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Vitamin d binding Protein and risk of renal cell carcinoma in the cancer prevention study ii cohort
Cancer Epidemiology Biomarkers & Prevention, 2018Co-Authors: Alison M. Mondul, Stephanie J. Weinstein, Dominick Parisi, Marjorie L Mccullough, Demetrius AlbanesAbstract:Background: Kidney cancer has several well-established risk factors, including smoking, obesity, and hypertension. These factors do not, however, completely account for its etiology. One previous study of Vitamin D–binding Protein (DBP) and risk of renal cell carcinoma found a striking inverse association that warranted replication. Methods: We conducted a nested case–control study in the American Cancer Society Cancer Prevention Study-II Nutrition Cohort to prospectively examine circulating DBP concentration and renal cell carcinoma risk. Cases (n = 87) were matched 1:1 to controls on gender, race, age (±5 years), and date of blood collection (±30 days). ORs and 95% confidence intervals (CIs) were estimated for quartiles of DBP using conditional logistic regression. Results: There was a statistically significant inverse trend across quartiles of DBP such that participants with higher DBP had a markedly decreased risk of renal cell carcinoma (vs. Q1: Q2 OR, 0.93; 95% CI, 0.41–2.11; Q3 OR, 0.42; 95% CI, 0.15–1.15; Q4 OR, 0.33; 95% CI, 0.10–1.06; Ptrend = 0.03). Conclusions: Our findings demonstrate a strong inverse association between circulating DBP and risk of renal cell carcinoma, supporting the findings from previous research. Impact: This is only the second study to examine DBP and risk of kidney cancer, and one of only a handful of studies to examine circulating DBP and risk of cancer at any site. Our findings support emerging evidence for an etiologic role of DBP in cancer and may provide insights into the etiology of kidney and other cancers. Cancer Epidemiol Biomarkers Prev; 27(10); 1203–7. ©2018 AACR.
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serum 25 hydroxyVitamin d Vitamin d binding Protein and prostate cancer risk in black men
Cancer, 2017Co-Authors: Tracy M Layne, Stephanie J. Weinstein, Barry I Graubard, Susan T Mayne, Demetrius AlbanesAbstract:BACKGROUND Few studies have prospectively examined the relationship between Vitamin D status and prostate cancer risk in black men, a group at high risk for both low Vitamin D status and prostate cancer. METHODS Among black men in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we identified 226 prostate cancer cases and 452 controls matched on age at randomization (±5 years), date of blood draw (±30 days), calendar year of cohort entry, and time since baseline prostate cancer screening (±1 year). Conditional logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between serum 25-hydroxyVitamin D [25(OH)D], Vitamin D binding Protein (DBP), the 25(OH)D:DBP molar ratio, and prostate cancer risk. RESULTS Serum 25(OH)D was not associated with overall prostate cancer (Q4 vs Q1: OR, 0.73; 95% CI, 0.40-1.33; P for trend = .25), although there were apparent inverse associations for nonaggressive disease (global P = .03, clinical stage I/II, and Gleason score <7) and among men ≥62 years old (P for interaction = .04) that were restricted to Q3. Interestingly, serum DBP was significantly inversely associated with prostate cancer risk (Q4 vs Q1: OR, 0.45; 95% CI, 0.20-1.00; P for trend = .03), whereas the 25(OH)D:DBP molar ratio was not. Results were similar when we mutually adjusted for 25(OH)D and DBP, and we found no evidence of interaction between the two. CONCLUSION Our study suggests higher (versus lower) circulating DBP may be independently associated with a decreased prostate cancer risk in black men independent of 25(OH)D status. Cancer 2017;123:2698-704. © 2017 American Cancer Society.
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Serum Vitamin D, Vitamin D binding Protein, and lung cancer survival
Lung cancer (Amsterdam Netherlands), 2014Co-Authors: Gabriella M. Anic, Stephanie J. Weinstein, Alison M. Mondul, Satu Männistö, Demetrius AlbanesAbstract:Objectives Vitamin D may prolong cancer survival by inhibiting tumor progression and metastasis, however, there are limited epidemiologic studies regarding the association between circulating 25-hydroxyVitamin D (25(OH)D) and lung cancer survival. The aim of this study was to examine the relationship between serum 25(OH)D and lung cancer specific survival and to evaluate whether Vitamin D binding Protein (DBP) concentration modified this association.
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serum Vitamin d Vitamin d binding Protein and risk of colorectal cancer
WOS, 2014Co-Authors: Gabriella M. Anic, Stephanie J. Weinstein, Alison M. Mondul, Satu Männistö, Demetrius AlbanesAbstract:Background We previously reported a positive association between serum 25-hydroxyVitamin D (25(OH)D) and colorectal cancer risk. To further elucidate this association, we examined the molar ratio of 25(OH)D to Vitamin D binding Protein (DBP), the primary 25(OH)D transport Protein, and whether DBP modified the association between 25(OH)D and colorectal cancer risk. Methods In a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, controls were 1∶1 matched to 416 colorectal cancer cases based on age and date of blood collection. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for quartiles of 25(OH)D, DBP, and the molar ratio of 25(OH)D:DBP, a proxy for free, unbound circulating 25(OH)D. Results Comparing highest to lowest quartiles, DBP was not associated with colorectal cancer risk (OR = 0.91; 95% CI: 0.58, 1.42, p for trend = 0.58); however, a positive risk association was observed for the molar ratio of 25(OH)D:DBP (OR = 1.44; 95% CI: 0.92, 2.26, p for trend = 0.04). In stratified analyses, the positive association between 25(OH)D and colorectal cancer was stronger among men with DBP levels above the median (OR = 1.89; 95% CI: 1.07, 3.36, p for trend = 0.01) than below the median (OR = 1.20; 95% CI: 0.68, 2.12, p for trend = 0.87), although the interaction was not statistically significant (p for interaction = 0.24). Conclusion Circulating DBP may influence the association between 25(OH)D and colorectal cancer in male smokers, with the suggestion of a stronger positive association in men with higher DBP concentrations. This finding should be examined in other populations, especially those that include women and non-smokers.
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genome wide association study of circulating Vitamin d binding Protein
The American Journal of Clinical Nutrition, 2014Co-Authors: Kristin A Moy, Stephanie J. Weinstein, Alison M. Mondul, Satu Männistö, Han Zhang, William Wheeler, Charles C Chung, Stephen J Chanock, Demetrius AlbanesAbstract:Background: Vitamin D status may influence a spectrum of health outcomes, including osteoporosis, arthritis, cardiovascular disease, and cancer. Vitamin D–binding Protein (DBP) is the primary carrier of Vitamin D in the circulation and regulates the bioavailability of 25-hydroxyVitamin D. Epidemiologic studies have shown direct DBP-risk relations and modification by DBP of Vitamin D–disease associations. Objective: We aimed to characterize common genetic variants that influence the DBP biochemical phenotype. Design: We conducted a genome-wide association study (GWAS) of 1380 men through linear regression of single-nucleotide polymorphisms (SNPs) in the Illumina HumanHap500/550/610 array on fasting serum DBP, assuming an additive genetic model, with adjustment for age at blood collection. Results: We identified 2 independent SNPs located in the gene encoding DBP, GC, that were highly associated with serum DBP: rs7041 (P = 1.42 × 10−246) and rs705117 (P = 4.7 × 10−91). For both SNPs, mean serum DBP decreased with increasing copies of the minor allele: mean DBP concentrations (nmol/L) were 7335, 5149, and 3152 for 0, 1, and 2 copies of rs7041 (T), respectively, and 6339, 4280, and 2341, respectively, for rs705117 (G). DBP was also associated with rs12144344 (P = 5.9 × 10−7) in ST6GALNAC3. Conclusions: In this GWAS analysis, to our knowledge the first to examine this biochemical phenotype, 2 variants in GC—one exonic and one intronic—were associated with serum DBP concentrations at the genome-wide level of significance. Understanding the genetic contributions to circulating DBP may provide greater insights into the Vitamin D binding, transport, and other functions of DBP and the effect of Vitamin D status on health outcomes. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention clinical trial was registered at clinicaltrials.gov as {"type":"clinical-trial","attrs":{"text":"NCT00342992","term_id":"NCT00342992"}}NCT00342992.
Edward Giovannucci - One of the best experts on this subject based on the ideXlab platform.
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circulating 25 hydroxyVitamin d Vitamin d binding Protein and risk of advanced and lethal prostate cancer
International Journal of Cancer, 2019Co-Authors: Chen Yuan, Irene M Shui, Kathryn M Wilson, Meir J Stampfer, Lorelei A Mucci, Edward GiovannucciAbstract:We previously found that higher total 25-hydroxyVitamin D [25(OH)D] levels were associated with lower risk of lethal prostate cancer. However, the relationships of bioavailable 25(OH)D and Vitamin D binding Protein (VDBP) with risk of advanced and lethal prostate cancer are unclear. In a prospective case-control study of 156 pairs of advanced prostate cancer cases and controls, we directly measured prediagnostic circulating 25(OH)D and VDBP and calculated bioavailable 25(OH)D using a validated formula. We examined the association of bioavailable 25(OH)D and VDBP levels with risk of advanced and lethal prostate cancer and whether total 25(OH)D levels interacted with VDBP levels to affect the risk. Conditional logistic models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Compared to total 25(OH)D (ptrend = 0.02), bioavailable 25(OH)D levels were not more strongly associated with risk of advanced prostate cancer (ptrend = 0.14). Although VDBP levels were not associated with risk of advanced prostate cancer (ptrend = 0.16), we observed an interaction between total 25(OH)D levels and VDBP levels in relation to risk of advanced prostate cancer (pinteraction = 0.03). Compared to those with total 25(OH)D levels below the median and VDBP levels above the median (at highest risk), men with both levels above the median had a multivariable-adjusted OR of 0.31 (95% CI, 0.15-0.65) for advanced prostate cancer. We observed similar results when we restricted the analyses to 116 lethal prostate cancer cases and their controls. Our data suggest that VDBP levels may modify the association between total 25(OH)D levels and risk of advanced and lethal prostate cancer.
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abstract b62 circulating Vitamin d binding Protein 25 hydroxyVitamin d and advanced and lethal prostate cancer risk
Cancer Prevention Research, 2013Co-Authors: Irene M Shui, Kathryn M Wilson, Meir J Stampfer, Lorelei A Mucci, Edward GiovannucciAbstract:Introduction: Circulating 25-hydroxyVitamin D (25(OH)D) is the most commonly accepted blood biomarker for Vitamin D status in epidemiologic studies. We have previously shown that higher circulating 25(OH)D was related to a reduced risk of advanced and lethal prostate cancer (PCa). However, 85-90% of circulating 25(OH)D is bound to Vitamin D-Binding Protein (DBP) and current laboratory assays do not differentiate between bound and unbound forms of 25(OH)D. The role of DBP on PCa remains unclear. DBP extends the half-life of circulating 25(OH)D, but it is not known whether DBP-bound Vitamin D activity on prostate cells is less than in the unbound form. DBP circulates at much higher levels than 25(OH)D and may also have independent effects on prostate carcinogenesis. Using prospectively measured circulating DBP and 25(OH)D, we assessed whether DBP was related to advanced/lethal PCa and whether the relationship between 25(OH)D and advanced/lethal PCa was modified by DBP levels. Methods: We included 164 men diagnosed with advanced (Stage T3b or higher) and lethal (distant metastases or PCa specific cause of death) PCa and 164 matched controls nested in the Health Professionals Follow-up Study. We used unconditional logistic regression, adjusted for matching factors, to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between DBP, 25(OH)D, and advanced/lethal PCa. We assessed effect modification by high and low 25(OH)D or DBP levels using the median value as the cut point. Results: Circulating DBP and 25(OH)D were modestly correlated in controls (Spearman correlation=0.17; p=0.04). Consistent with our previous study, higher plasma 25(OH)D was associated with a reduced risk of advanced/lethal PCa (OR (95% CI) for highest vs. lowest quartile of 25(OH)D: 0.28 (0.14-0.57); p-trend Conclusions: Adjusting for circulating DBP did not influence the association between 25(OH)D and advanced/lethal PCa in our study. However, the role of DBP in prostate carcinogenesis warrants future investigation. Citation Format: Irene Shui, Kathryn Wilson, Meir Stampfer, Lorelei Mucci, Ed Giovannucci. Circulating Vitamin D binding Protein, 25-hydroxyVitamin D, and advanced and lethal prostate cancer risk. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr B62.
Ishir Bhan - One of the best experts on this subject based on the ideXlab platform.
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Vitamin d binding Protein in health and chronic kidney disease
Seminars in Dialysis, 2015Co-Authors: Michelle R Denburg, Ishir BhanAbstract:Vitamin D-Binding Protein (DBP) is a multifunctional Protein that has attracted increasing interest in recent years, largely because of its potential role in modulating the activity of Vitamin D. Nearly all circulating Vitamin D (~85-90%) circulates bound to DBP, with a smaller proportion bound to albumin, leaving <5% circulating freely. DBP may also play roles beyond Vitamin D binding, with potential roles in the immune system and elsewhere. Numerous polymorphisms of DBP exist around the world, and recent studies have identified relevance of different DBP phenotypes in determining DBP concentration and Vitamin D affinity. This review focuses on the known roles of DBP in health and kidney disease, and current views on the relevance of DBP polymorphisms.
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Vitamin d binding Protein and bone health
International Journal of Endocrinology, 2014Co-Authors: Ishir BhanAbstract:Vitamin D binding Protein (DBP) is the major carrier Protein of 25-hydroxyVitamin D (25(OH) D) in the circulation, where it may serve roles in maintaining stable levels during times of decreased 25(OH) availability and in regulating delivery of 25(OH) D to target tissues. Several genetic polymorphisms of DBP have been described that lead to phenotypic changes in the Protein that may affect affinity, activity, and concentration. These polymorphisms have been linked with alterations in bone density in several populations. One of the mechanisms by which DBP may alter bone health involves regulating Vitamin D bioavailability. DBP-bound Vitamin is thought to be relatively unavailable to target tissues, and thus alterations in DBP levels or affinity could lead to changes in Vitamin D bioactivity. As a result, functional Vitamin D status may differ greatly between individuals with similar total 25(OH) D levels. Additionally, DBP may have independent roles on macrophage and osteoclast activation. This review will summarize recent findings about DBP with respect to measures of bone density and health.
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Vitamin d binding Protein and Vitamin d status of black americans and white americans
The New England Journal of Medicine, 2013Co-Authors: Camille E Powe, Michele K Evans, Julia Wenger, Alan B Zonderman, Anders H Berg, Michael A Nalls, Hector Tamez, Dongsheng Zhang, Ishir BhanAbstract:METHODS In the Healthy Aging in Neighborhoods of Diversity across the Life Span cohort of blacks and whites (2085 participants), we measured levels of total 25-hydroxyVitamin D, Vitamin D–binding Protein, and parathyroid hormone as well as bone mineral density (BMD). We genotyped study participants for two common polymorphisms in the Vitamin D–binding Protein gene (rs7041 and rs4588). We estimated levels of bioavailable 25-hydroxyVitamin D in homozygous participants. RESULTS Mean (±SE) levels of both total 25-hydroxyVitamin D and Vitamin D–binding Protein were lower in blacks than in whites (total 25-hydroxyVitamin D, 15.6±0.2 ng per milliliter vs. 25.8±0.4 ng per milliliter, P<0.001; Vitamin D–binding Protein, 168±3 µg per milliliter vs. 337±5 µg per milliliter, P<0.001). Genetic polymorphisms independently appeared to explain 79.4% and 9.9% of the variation in levels of Vitamin D–binding Protein and total 25-hydroxyVitamin D, respectively. BMD was higher in blacks than in whites (1.05±0.01 g per square centimeter vs. 0.94±0.01 g per square centimeter, P<0.001). Levels of parathyroid hormone increased with decreasing levels of total or bioavailable 25-hydroxyVitamin D (P<0.001 for both relationships), yet within each quintile of parathyroid hormone concentration, blacks had significantly lower levels of total 25-hydroxyVitamin D than whites. Among homozygous participants, blacks and whites had similar levels of bioavailable 25-hydroxy Vitamin D overall (2.9±0.1 ng per milliliter and 3.1±0.1 ng per milliliter, respectively; P = 0.71) and within quintiles of parathyroid hormone concentration. CONCLUSIONS Community-dwelling black Americans, as compared with whites, had low levels of total 25-hydroxyVitamin D and Vitamin D–binding Protein, resulting in similar concentrations of estimated bioavailable 25-hydroxyVitamin D. Racial differences in the prevalence of common genetic polymorphisms provide a likely explanation for this observation. (Funded by the National Institute on Aging and others.)
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Vitamin d binding Protein modifies the Vitamin d bone mineral density relationship
Journal of Bone and Mineral Research, 2011Co-Authors: Camille E Powe, Julia Wenger, Anders H Berg, Ananth S Karumanchi, Ravi Thadhani, Catherine Ricciardi, Delger Erdenesanaa, Gina Collerone, Elizabeth Ankers, Ishir BhanAbstract:Studies examining the relationship between total circulating 25-hydroxyVitamin D [25(OH)D] levels and bone mineral density (BMD) have yielded mixed results. Vitamin D–binding Protein (DBP), the major carrier Protein for 25(OH)D, may alter the biologic activity of circulating Vitamin D. We hypothesized that free and bioavailable 25(OH)D, calculated from total 25(OH)D, DBP, and serum albumin levels, would be more strongly associated with BMD than levels of total 25(OH)D. We measured total 25(OH)D, DBP, and serum albumin levels in 49 healthy young adults enrolled in the Metabolic Abnormalities in College-Aged Students (MACS) study. Lumbar spine BMD was measured in all subjects using dual-energy X-ray absorptiometry. Clinical, diet, and laboratory information also was gathered at this time. We determined free and bioavailable (free + albumin-bound) 25(OH)D using previously validated formulas and examined their associations with BMD. BMD was not associated with total 25(OH)D levels (r = 0.172, p = .236). In contrast, free and bioavailable 25(OH)D levels were positively correlated with BMD (r = 0.413, p = .003 for free, r = 0.441, p = .002 for bioavailable). Bioavailable 25(OH)D levels remained independently associated with BMD in multivariate regression models adjusting for age, sex, body mass index, and race (p = .03). It is concluded that free and bioavailable 25(OH)D are more strongly correlated with BMD than total 25(OH)D. These findings have important implications for Vitamin D supplementation in Vitamin D–deficient states. Future studies should continue to explore the relationship between free and bioavailable 25(OH)D and health outcomes. © 2011 American Society for Bone and Mineral Research.
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Vitamin d binding Protein modifies the Vitamin d bone mineral density relationship
Journal of Bone and Mineral Research, 2011Co-Authors: Camille E Powe, Julia Wenger, Anders H Berg, Ananth S Karumanchi, Ravi Thadhani, Catherine Ricciardi, Delger Erdenesanaa, Gina Collerone, Elizabeth Ankers, Ishir BhanAbstract:Studies examining the relationship between total circulating 25-hydroxyVitamin D [25(OH)D] levels and bone mineral density (BMD) have yielded mixed results. Vitamin D-Binding Protein (DBP), the major carrier Protein for 25(OH)D, may alter the biologic activity of circulating Vitamin D. We hypothesized that free and bioavailable 25(OH)D, calculated from total 25(OH)D, DBP, and serum albumin levels, would be more strongly associated with BMD than levels of total 25(OH)D. We measured total 25(OH)D, DBP, and serum albumin levels in 49 healthy young adults enrolled in the Metabolic Abnormalities in College-Aged Students (MACS) study. Lumbar spine BMD was measured in all subjects using dual-energy X-ray absorptiometry. Clinical, diet, and laboratory information also was gathered at this time. We determined free and bioavailable (free + albumin-bound) 25(OH)D using previously validated formulas and examined their associations with BMD. BMD was not associated with total 25(OH)D levels (r = 0.172, p = .236). In contrast, free and bioavailable 25(OH)D levels were positively correlated with BMD (r = 0.413, p = .003 for free, r = 0.441, p = .002 for bioavailable). Bioavailable 25(OH)D levels remained independently associated with BMD in multivariate regression models adjusting for age, sex, body mass index, and race (p = .03). It is concluded that free and bioavailable 25(OH)D are more strongly correlated with BMD than total 25(OH)D. These findings have important implications for Vitamin D supplementation in Vitamin D-deficient states. Future studies should continue to explore the relationship between free and bioavailable 25(OH)D and health outcomes.
Michael Fannon - One of the best experts on this subject based on the ideXlab platform.
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Vitamin d binding Protein macrophage activating factor directly inhibits proliferation migration and upar expression of prostate cancer cells
PLOS ONE, 2010Co-Authors: Kalvin J Gregory, Bing Zhao, Diane R Bielenberg, Sami Dridi, Weihua Jiang, Bin Huang, Steven Pirieshepherd, Michael FannonAbstract:Background: Vitamin D binding Protein-macrophage activating factor (DBP-maf) is a potent inhibitor of tumor growth. Its activity, however, has been attributed to indirect mechanisms such as boosting the immune response by activating macrophages and inhibiting the blood vessel growth necessary for the growth of tumors. Methods and Findings: In this study we show for the first time that DBP-maf exhibits a direct and potent effect on prostate tumor cells in the absence of macrophages. DBP-maf demonstrated inhibitory activity in proliferation studies of both LNCaP and PC3 prostate cancer cell lines as well as metastatic clones of these cells. Flow cytometry studies with annexin V and propidium iodide showed that this inhibitory activity is not due to apoptosis or cell death. DBP-maf also had the ability to inhibit migration of prostate cancer cells in vitro. Finally, DBP-maf was shown to cause a reduction in urokinase plasminogen activator receptor (uPAR) expression in prostate tumor cells. There is evidence that activation of this receptor correlates with tumor metastasis. Conclusions: These studies show strong inhibitory activity of DBP-maf on prostate tumor cells independent of its macrophage activation.
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Vitamin d binding Protein macrophage activating factor dbp maf inhibits angiogenesis and tumor growth in mice
Neoplasia, 2003Co-Authors: Oliver Kisker, Shinya Onizuka, Michael Fannon, Christian M Becker, Evelyn Flynn, Robert J Damato, Bruce R ZetterAbstract:We have isolated a selectively deglycosylated form of Vitamin D binding Protein (DBP-maf) generated from systemically available DBP by a human pancreatic cancer cell line. DBP-maf is antiproliferative for endothelial cells and antiangiogenic in the chorioallantoic membrane assay. DBP-maf administered daily was able to potently inhibit the growth of human pancreatic cancer in immune compromised mice (T/C=0.09). At higher doses, DBP-maf caused tumor regression. Histological examination revealed that treated tumors had a higher number of infiltrating macrophages as well as reduced microvessel density, and increased levels of apoptosis relative to untreated tumors. Taken together, these data suggest that DBP-maf is an antiangiogenic molecule that can act directly on endothelium as well as stimulate macrophages to attack both the endothelial and tumor cell compartment of a growing malignancy.
Bruce R Zetter - One of the best experts on this subject based on the ideXlab platform.
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Vitamin d binding Protein macrophage activating factor dbp maf inhibits angiogenesis and tumor growth in mice
Neoplasia, 2003Co-Authors: Oliver Kisker, Shinya Onizuka, Michael Fannon, Christian M Becker, Evelyn Flynn, Robert J Damato, Bruce R ZetterAbstract:We have isolated a selectively deglycosylated form of Vitamin D binding Protein (DBP-maf) generated from systemically available DBP by a human pancreatic cancer cell line. DBP-maf is antiproliferative for endothelial cells and antiangiogenic in the chorioallantoic membrane assay. DBP-maf administered daily was able to potently inhibit the growth of human pancreatic cancer in immune compromised mice (T/C=0.09). At higher doses, DBP-maf caused tumor regression. Histological examination revealed that treated tumors had a higher number of infiltrating macrophages as well as reduced microvessel density, and increased levels of apoptosis relative to untreated tumors. Taken together, these data suggest that DBP-maf is an antiangiogenic molecule that can act directly on endothelium as well as stimulate macrophages to attack both the endothelial and tumor cell compartment of a growing malignancy.
