Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor-associated macrophages mediate the link between inflammation and cancer progression. Here, we showed that macrophage-derived soluble factors induce canonical Wnt signaling in colon cancer cells and promote their growth. Tumor cells induced the release of interleukin (IL)-1beta from macrophages, which induced phosphorylation of GSK3beta, stabilized beta-catenin, enhanced T-cell factor (TCF)-dependent gene activation and induced the expression of Wnt target genes in tumor cells. Neutralization experiments using anti-IL-1beta-specific antibodies, or silencing of IL-1beta in THP1 macrophages, showed that IL-1beta was required for macrophages to induce Wnt signaling and to support the growth of tumor cells. Constitutive activation of signal transducer and activator of transcription (STAT)1 in THP1 macrophages was essential for the induction of IL-1beta and thus for the activation of beta-catenin signaling in tumor cells. Vitamin D3, an effective chemopreventive agent, interrupted this crosstalk by blocking the constitutive activation of STAT1 and the production of IL-1beta in macrophages, and therefore-in a vitamin D receptor-dependent manner-inhibited the ability of macrophages to activate Wnt signaling in colon carcinoma cells. Our data therefore established that vitamin D3 exerts its chemopreventive activity by interrupting a crosstalk between tumor epithelial cells and the tumor microenvironment.
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PMID:Macrophage-derived IL-1beta stimulates Wnt signaling and growth of colon cancer cells: a crosstalk interrupted by vitamin D3. 1970 Dec 45

Since the 1970s, it has been well known that long-standing ulcerative colitis (UC) disposes to the development of colorectal adenocarcinoma (CRC). To date, CRC associated with UC is thought to arise along a pathway of dysplasia, however, primary factors for developing of UC-related dysplasia and cancer are unclear. Vitamin D, which works through binding the vitamin D receptor (VDR) has an important role in cancer progression and immune response. In this study, we investigated the impact of VDR expression on UC as well as colon cancer. We examined retrospectively the expression of VDR in extraction specimens of UC (n=124) patients by immunohistochemistry. We counted VDR positive cells in at least 10 fields in each case to evaluate the frequency of VDR positive cells in ductal epithelium. In addition, effect of VDR expression on inflammation was analyzed. On a normal mucosa, the expression of VDR was recognized in 58.8% of ductal cells. In UC patient, the expression of VDR was considerably decreased compared to normal mucosa, VDR positive rate was only 3.4+/-9.0%. Importantly, dysplasia and UC-CRC patients showed lower rate of VDR expression compared to non-colon cancer patients, whose expression rates were 0.6+/-1.3% and 3.8+/-10%, respectively. Moreover, long-term UC patients (more than ten years) who were at high-risk of developing CRC showed significantly lower VDR expression than short-term patients. We did not detect direct association of VDR expression with inflammation and clinical stage of UC. These findings suggested that correlation seems to exist between the level of VDR expression and carcinogenesis in UC. VDR could be a possible marker to detect dysplasia and cancer in ulcerative colitis.
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PMID:Vitamin D receptor expression is associated with colon cancer in ulcerative colitis. 1978 15

The Kaposi sarcoma-associated herpes virus-G protein-coupled receptor is a key molecule in the pathogenesis of Kaposi sarcoma, playing a central role in promoting vascular endothelial growth factor-driven angiogenesis and spindle cell proliferation. We studied the effects of 1 alpha,25-dihydroxyvitamin D(3) [1 alpha,25(OH)(2)D(3)] and the analog TX527 on the proliferation of endothelial cells (SVECs) and SVECs transformed by the viral G protein-coupled receptor (SVEC-vGPCR). 1 alpha,25(OH)(2)D(3) and TX527 decreased SVEC-vGPCR and SVEC numbers, the response being time dependent and similar in both cell lines. Vitamin D receptor (VDR) levels increased on treatment with 10 nm 1 alpha,25(OH)(2)D(3) or 1 nm TX527 in a time-dependent manner (1.5-24 h) in SVECs and SVEC-vGPCR. Basal VDR levels were increased in SVEC-vGPCR. The antiproliferative effects were accompanied by reduction in cyclin D1 and accumulation of p27 in SVECs but not SVEC-vGPCR. Induction of VDR was blocked by transfection of short hairpin RNA against VDR in SVEC-vGPCR and the antiproliferative effects of 1 alpha,25(OH)(2)D(3) and TX527 were decreased, involving the VDR genomic pathway in the hormone and analog mechanism of action. In vivo experiments showed that 1 alpha,25(OH)(2)D(3) and TX527 decreased SVEC-vGPCR tumor progression when the tumor cells were implanted in nude mice. In conclusion, we have demonstrated that 1 alpha,25(OH)(2)D(3) and its TX527 analog have antiproliferative effects on the growth of endothelial cells transformed by the vGPCR in vitro and in vivo, the vitamin D receptor being part of the inhibitory mechanism of action.
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PMID:1 Alpha,25-dihydroxyvitamin D3 and its TX527 analog inhibit the growth of endothelial cells transformed by Kaposi sarcoma-associated herpes virus G protein-coupled receptor in vitro and in vivo. 1991 63

The p53 gene is mutated in many human tumors. Cells of such tumors often contain abundant mutant p53 (mutp53) protein, which may contribute actively to tumor progression via a gain-of-function mechanism. We applied ChIP-on-chip analysis and identified the vitamin D receptor (VDR) response element as overrepresented in promoter sequences bound by mutp53. We report that mutp53 can interact functionally and physically with VDR. Mutp53 is recruited to VDR-regulated genes and modulates their expression, augmenting the transactivation of some genes and relieving the repression of others. Furthermore, mutp53 increases the nuclear accumulation of VDR. Importantly, mutp53 converts vitamin D into an antiapoptotic agent. Thus, p53 status can determine the biological impact of vitamin D on tumor cells.
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PMID:Modulation of the vitamin D3 response by cancer-associated mutant p53. 2022 41

1,25-dihydroxyvitamin D3 affects proliferation, differentiation, and apoptosis and protects DNA against oxidative damage with a net tumorostatic and anticarcinogenic effect. It acts through a specific nuclear receptor that is widely distributed through the body. Although a beneficial role of vitamin D in melanoma patients has been suggested, there is lack of information on the changes in the expression pattern of vitamin D receptor during progression of pigmented lesions. Using immunohistochemistry, we analyzed the expression of vitamin D receptor in 140 samples obtained form 82 patients, including 25 benign nevi, 70 primary cutaneous melanomas, 35 metastases, 5 re-excisions, and 5 normal skin biopsies. The strongest expression was observed in normal skin that significantly decreased in melanocytic proliferations with the following order of expression: normal skin > melanocytic nevi > melanomas = metastases. The vitamin D receptor expression in skin surrounding nevi and melanoma was also significantly reduced as compared to normal skin. Tumor-infiltrating and lymph node lymphocytes retained high levels of vitamin D receptor. There was negative correlation between tumor progression and vitamin D receptor expression with a remarkable decrease of the immunoreactivity in nuclei of melanoma cells at vertical versus radial growth phases and with metastatic melanomas showing the lowest cytoplasmic receptor staining. Furthermore, lack of the receptor expression in primary melanomas and metastases was related to shorter overall patients' survival. In addition, the receptor expression decreased in melanized melanoma cells in comparison to amelanotic or poorly pigmented cells. Therefore, we propose that reduction or absence of vitamin D receptor is linked to progression of melanocytic lesions, that its lack affects survival of melanoma patients, and that melanogenesis can attenuate receptor expression. In conclusion, changes in vitamin D receptor expression pattern can serve as important variables for diagnosis, predicting clinical outcome of the disease, and/or as a guidance for novel therapy of melanomas based on use of vitamin D or its derivatives.
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PMID:Expression of vitamin D receptor decreases during progression of pigmented skin lesions. 2129 98

Epidemiologic data suggest that the incidence and severity of many types of cancer inversely correlates with indices of vitamin D status. The vitamin D receptor (VDR) is highly expressed in epithelial cells at risk for carcinogenesis including those resident in skin, breast, prostate and colon, providing a direct molecular link by which vitamin D status impacts on carcinogenesis. Consistent with this concept, activation of VDR by its ligand 1,25-dihydroxyvitamin D (1,25D) triggers comprehensive genomic changes in epithelial cells that contribute to maintenance of the differentiated phenotype, resistance to cellular stresses and protection of the genome. Many epithelial cells also express the vitamin D metabolizing enzyme CYP27B1 which enables autocrine generation of 1,25D from the circulating vitamin D metabolite 25-hydroxyvitamin D (25D), critically linking overall vitamin D status with cellular anti-tumor actions. Furthermore, pre-clinical studies in animal models has demonstrated that dietary supplementation with vitamin D or chronic treatment with VDR agonists decreases tumor development in skin, colon, prostate and breast. Conversely, deletion of the VDR gene in mice alters the balance between proliferation and apoptosis, increases oxidative DNA damage, and enhances susceptibility to carcinogenesis in these tissues. Because VDR expression is retained in many human tumors, vitamin D status may be an important modulator of cancer progression in persons living with cancer. Collectively, these observations have reinforced the need to further define the molecular actions of the VDR and the human requirement for vitamin D in relation to cancer development and progression.
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PMID:Cellular and molecular effects of vitamin D on carcinogenesis. 2208 99

Unlike prostate and breast cancers, urothelial carcinoma of the urinary bladder is not yet considered as an endocrine-related neoplasm, and hormonal therapy for bladder cancer remains experimental. Nonetheless, there is increasing evidence indicating that nuclear hormone receptor signals are implicated in the development and progression of bladder cancer. Androgen-mediated androgen receptor (AR) signals have been convincingly shown to induce bladder tumorigenesis. Androgens also promote the growth of AR-positive bladder cancer cells, although it is controversial whether AR plays a dominant role in bladder cancer progression. Both stimulatory and inhibitory functions of estrogen receptor signals in bladder cancer have been reported. Various studies have also demonstrated the involvement of other nuclear receptors, including progesterone receptor, glucocorticoid receptor, vitamin D receptor, and retinoid receptors, as well as some orphan receptors, in bladder cancer. This review summarizes and discusses available data suggesting the modulation of bladder carcinogenesis and cancer progression via nuclear hormone receptor signaling pathways. These pathways have the potential to be an extremely important area of bladder cancer research, leading to the development of effective chemopreventive/therapeutic approaches, using hormonal manipulation. Considerable uncertainty remains regarding the selection of patients who are likely to benefit from hormonal therapy and optimal options for the treatment.
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PMID:Nuclear hormone receptor signals as new therapeutic targets for urothelial carcinoma. 2211 35

Epidemiologic data suggest that the incidence and severity of many types of cancer inversely correlates with indices of vitamin D status. The vitamin D receptor (VDR) is highly expressed in epithelial cells at risk for carcinogenesis including those resident in skin, breast, prostate and colon, providing a direct molecular link by which vitamin D status impacts on carcinogenesis. Consistent with this concept, activation of VDR by its ligand 1,25-dihydroxyvitamin D (1,25(OH)(2)D) triggers comprehensive genomic changes in epithelial cells that contribute to maintenance of the differentiated phenotype, resistance to cellular stresses and protection of the genome. Many epithelial cells also express the vitamin D metabolizing enzyme CYP27B1 which enables autocrine generation of 1,25(OH)(2)D from the circulating vitamin D metabolite 25-hydroxyvitamin D (25(OH)D), critically linking overall vitamin D status with cellular anti-tumor actions. Furthermore, pre-clinical studies in animal models have demonstrated that dietary supplementation with vitamin D or chronic treatment with VDR agonists decreases tumor development in skin, colon, prostate and breast. Conversely, deletion of the VDR gene in mice alters the balance between proliferation and apoptosis, increases oxidative DNA damage, and enhances susceptibility to carcinogenesis in these tissues. Because VDR expression is retained in many human tumors, vitamin D status may be an important modulator of cancer progression in persons living with cancer. Collectively, these observations reinforce the need to further define the molecular actions of the VDR and the human requirement for vitamin D in relation to cancer development and progression.
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PMID:Vitamin D and cancer: integration of cellular biology, molecular mechanisms and animal models. 2253 70

Previous studies from our laboratory have shown that testosterone (T) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) co-operate to inhibit cell proliferation and induce significant changes in gene expression and differentiation in LNCaP cells. The data presented here demonstrate that the two agents alter fatty acid metabolism, and accumulation of neutral lipid. Concurrent genome wide analysis of mRNA and miRNA in LNCaP cells reveals an extensive transcription regulatory network modulated by T and 1,25(OH)2D3. This involves not only androgen receptor (AR)- and vitamin D receptor (VDR)-mediated transcription, but also transcription factors E2F1- and c-Myc-dependent transcription. Changes in the activities of these transcription factors alter the steady state levels of several miRNAs, including the miR-17/92 cluster. These changes correlate with the up-regulation of the mRNA encoding peroxisome proliferator-activated receptor alpha (PPARA) and its downstream targets, leading to increased lipogenesis. These data suggest that the coordinated effect of T and 1,25(OH)2D3 in prostate cancer cells increases lipogenesis, diverting energy away from Warburg-based tumor energy metabolism, which slows or halts cell growth and tumor progression. This article is part of a Special Issue entitled 'Vitamin D Workshop'.
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PMID:1,25-Dihydroxyvitamin D3 modulates lipid metabolism in prostate cancer cells through miRNA mediated regulation of PPARA. 2305 73

Carcinoma-associated fibroblasts (CAFs) contribute to both tumor growth and cancer progression. In this report, we applied an emerging transcription factor (TF) activity array to fibroblasts to capture the activity of the intracellular signaling network and to define a signature that distinguishes mammary CAFs from normal mammary fibroblasts. Normal fibroblasts that restrained cancer cell invasion developed into an invasion-promoting CAF phenotype through exposure to conditioned medium from MDA-MB-231 breast cancer cells. A myofibroblast-like CAF cell line expressing high levels of smooth muscle actin was compared to normal mammary fibroblasts before and after induction. Comparison of TF activity profiles for all three fibroblast types identified a TF activity signature common to CAFs which included activation of reporters for TFs ELK1, GATA1, retinoic acid receptor (RAR), serum response factor (SRF), and vitamin D receptor (VDR). Additionally, CAFs resembling myofibroblasts, relative to normal fibroblasts, had elevated activation corresponding to NF-kappaB, RUNX2, and YY1, and distinct activity patterns for several differentiation-related TF reporters. Induction of CAFs by exposure of normal fibroblasts to conditioned medium from MDA-MB-231 cells resulted in increased activation of reporters for HIF1, several STAT TFs, and proliferation-related TFs such as AP1. Myofibroblast-like CAFs and induced normal mammary fibroblasts promoted invasion of breast cancer cells by distinct mechanisms, consistent with their distinct patterns of TF activation. The TF activity profiles of CAF subtypes provide an overview of intracellular signaling associated with the induction of a pro-invasive stroma, and provide a mechanistic link between the microenvironmental stimuli and phenotypic response.
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PMID:Transcription factor networks in invasion-promoting breast carcinoma-associated fibroblasts. 2309 Jan 54


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