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

The vitamin D receptor (VDR) is a member of the steroid/retinoid receptor superfamily of nuclear receptors that controls mineral ion homeostatis and has potential tumor-suppressive functions for various cancer types, specifically prostate cancer. A VDR ablated transgenic animal model (VDDRII, vitamin D-dependent rickets type II) has been developed and the animals typically have various diseases including, hypocalcemia, hyperparathyroidism, rickets, osteomalacia, and alopecia. This transgenic mouse system provides us with a model to decipher the influences of the VDR on prostatic growth and function. VDRs are abundant both in prostatic epithelial and stromal cells, and vitamin D signaling can be studied in this model. Although, there were no gross differences between the prostate tissue of the experimental and control groups, VDR null mice showed fat necrosis and individual cell apoptosis in the periprostatic adipose tissue. This indicates a possible role of VDR in the signaling pathways resulting the prostate. This may be particularly attractive for VDR targets for the inhibition of cancer progression using VD(3) and its analogs as potential chemo-preventive agents.
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PMID:Increased apoptosis of periprostatic adipose tissue in VDR null mice. 1535 70

Although originally discovered as the peptide responsible for humoral hypercalcemia of malignancy (HHM), parathyroid hormone-related protein (PTHrP) has been shown to play a major role in fetal development. In the adult, it is widely distributed in normal and various cancer tissues. In spite of the rarity of HHM in prostate cancer, PTHrP is widely distributed in prostate cancer cells. PTHrP is a precursor molecule with generation of various fragments with distinct biological activities. More recent studies have shown that there is intranuclear localization of PTHrP and that intracrine effects of the peptide are involved in promoting processes that result in tumor progression (nall proliferation, apoptosis, cell attachment and angiogenesis) in prostate cancer. PTHrP expression is controlled by three distinct promoters, with P3 being used most often in cancer cells. The factors that control PTHrP production via interaction with the promoters are growth factors, androgens, vitamin D analogs, and adenoviral proteins. TGF-beta and its effector Smad3 activate the P3 promoter through an AGAC box and an Ets binding site involving Ets1 and to some extent Ets2 proteins. In addition, TGF-beta stimulates P3 promoter activity via Smad-independent pathways that involve the p38 MAP kinase. Although the addition of PTHrP or transfection with the PTHrP gene in prostate cells results in effects that promote tumor development, studies that employ inhibition of PTHrP activity in vitro and in vivo are needed to establish a definitive role of this peptide in the pathogenesis of prostate cancer.
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PMID:Parathyroid hormone-related protein in prostate cancer. 1583 Oct 76

Vitamin D receptor (VDR) and 25-hydroxyvitamin D3 1-alpha-hydroxylase expression have recently been shown to be upregulated in several tumors and thought to represent an important endogenous response to tumor progression. Little is known about the expression of these proteins in thyroid carcinoma, although previous reports have documented evidence of the biological effect of vitamin D in thyroid cells. Using paraffin-embedded and frozen sections of papillary thyroid carcinoma, we utilized real-time quantitative RT-PCR and immunohistochemistry to characterize the expression of VDR and 1-alpha-hydroxylase in thyroid follicular cells, with special emphasis on papillary thyroid carcinoma (PTC). VDR and 1-alpha-hydroxylase expression were increased in PTC compared with normal thyroid tissue and especially high in areas of lymphocyte infiltration. Expression of VDR and 1-alpha-hydroxylase in PTC may be compatible with an overall favorable prognosis for this tumor type and may constitute important prerequisites for using vitamin D and/or vitamin D analogs in the treatment of PTC.
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PMID:25-hydroxyvitamin D3 1alpha-hydroxylase and vitamin D receptor expression in papillary thyroid carcinoma. 1631 44

Although numerous studies have implicated vitamin D in preventing prostate cancer, the underlying mechanism(s) remains unclear. Using normal human prostatic epithelial cells, we examined the role of mitogen-activated protein kinase phosphatase 5 (MKP5) in mediating cancer preventive activities of vitamin D. Up-regulation of MKP5 mRNA by 1,25-dihydroxyvitamin-D3 (1,25D) was dependent on the vitamin D receptor. We also identified a putative positive vitamin D response element within the MKP5 promoter that associated with the vitamin D receptor following 1,25D treatment. MKP5 dephosphorylates/inactivates the stress-activated protein kinase p38. Treatment of prostate cells with 1,25D inhibited p38 phosphorylation, and MKP5 small interfering RNA blocked this effect. Activation of p38 and downstream production of interleukin 6 (IL-6) are proinflammatory. Inflammation and IL-6 overexpression have been implicated in the initiation and progression of prostate cancer. 1,25D pretreatment inhibited both UV- and tumor necrosis factor alpha-stimulated IL-6 production in normal cells via p38 inhibition. Consistent with inhibition of p38, 1,25D decreased UV-stimulated IL-6 mRNA stabilization. The ability of 1,25D to up-regulate MKP5 was maintained in primary prostatic adenocarcinoma cells but was absent in metastases-derived prostate cancer cell lines. The inability of 1,25D to regulate MKP5 in the metastasis-derived cancer cells suggests there may be selective pressure to eliminate key tumor suppressor functions of vitamin D during cancer progression. These studies reveal MKP5 as a mediator of p38 inactivation and decreased IL-6 expression by 1,25D in primary prostatic cultures of normal and adenocarcinoma cells, implicating decreased prostatic inflammation as a potential mechanism for prostate cancer prevention by 1,25D.
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PMID:Inhibition of p38 by vitamin D reduces interleukin-6 production in normal prostate cells via mitogen-activated protein kinase phosphatase 5: implications for prostate cancer prevention by vitamin D. 1661 80

Angiogenesis is an essential step in initial tumor development and metastasis. Consequently, compounds that inhibit angiogenesis would be useful in treating cancer. A variety of antitumor effects mediated by 1alpha, 25-dihydroxyvitamin D3 (1,25-VD) have been reported, one of which is anti-angiogenesis; however, detailed mechanisms remain unclear. We have demonstrated that 1,25-VD inhibits prostate cancer (PCa) cell-induced human umbilical vein endothelial cell migration and tube formation, two critical steps involved in the angiogenesis. An angiogenesis factor, interleukin-8 (IL-8), secreted from PCa cell was suppressed by 1,25-VD at both mRNA and protein levels. Mechanistic dissection found that 1,25-VD inhibits NF-kappaB signal, one of the most important IL-8 upstream regulators. The 1,25-VD-mediated NF-kappaB signal reduction was shown to result from the blocking of nuclear translocation of p65, a subunit of the NF-kappaB complex, and was followed by attenuation of the NF-kappaB complex binding to DNA. The role of IL-8 in PCa progression was further examined by PCa tissue microarray analyses. We found that IL-8 expression was elevated during PCa progression, which suggests that IL-8 may play a role in tumor progression mediated through its stimulation on angiogenesis. These findings indicate that 1,25-VD could prevent PCa progression by interrupting IL-8 signaling, which is required in tumor angiogenesis, and thus applying vitamin D in PCa treatment may be beneficial for controlling disease progression.
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PMID:1alpha, 25-dihydroxyvitamin D3 suppresses interleukin-8-mediated prostate cancer cell angiogenesis. 1662 28

High dietary calcium has been shown in epidemiological studies to be a risk factor for prostate cancer, and it has been postulated that this effect is secondary to calcium induced modulation of the vitamin D axis. In this study, we used LPB-Tag transgenic mice on the CD1 background to examine the impact of dietary calcium on prostate tumor progression. CD1-LPB-Tag mice predictably develop autochthonous, hormone-responsive prostate tumors by 3 months of age. Age matched transgenic and non-transgenic littermates were weaned onto high (2%) or low (0.2%) calcium diets and mice were sacrificed at 5, 7, and 9 weeks of age. The entire urogenital complex was excised, weighed, and processed for histology. There was no significant effect of dietary calcium on tumor weight or on the time course of tumor progression, as monitored using a modified Gleason grade (MGS). Serum calcium was maintained in the normal range in mice on the low and high calcium diet throughout the study. Circulating 1,25(OH)(2)D(3) was elevated by low dietary calcium in 5-week-old mice, but not in older animals. In summary, neither development nor progression of prostate tumors in LPB-Tag mice was accelerated by high dietary calcium.
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PMID:Dietary calcium does not affect prostate tumor progression in LPB-Tag transgenic mice. 1730 54

Low nutritional calcium contributes to disruption of the intestinal epithelial barrier function, to hyperproliferation of colonocytes and increased occurrence of aggressive secondary bile acids in the gut lumen. These mechanisms are also known to be involved in the etiology of colonic inflammation and cancer. We studied in mice and human adenocarcinoma-derived Caco-2 cells the impact of low calcium on markers of inflammation (cyclooxygenase-2; COX-2), of detoxification (pregnane and xenobiotic receptor (PXR)/steroid and xenobiotic receptor (SXR), cytochrome P450 steroid-inducible 3a11 (CYP3A11)), and on expression of the vitamin D system as a protection against tumorigenesis. Caco-2 cells express high COX-2 and low SXR mRNA levels when subconfluent. During differentiation this is reversed, while low calcium enhanced COX-2 protein expression. In vivo low dietary calcium significantly increased the expression of the PXR target gene CYP3A11 in the proximal colon, suggesting compensatory defense mechanisms. In comparison with males, low nutritional calcium elicits a better protective response in females: both the vitamin D synthesizing 25-hydroxyvitamin D(3 )1alpha hydroxylase (CYP27B1) mRNA and the detoxifying CYP3A11 mRNA are augmented more. While it is recognized that colonic vitamin D synthesis may prevent tumor progression, low dietary calcium also elevates the 1,25-(OH)(2)-D(3) catabolic 25-hydroxyvitamin D(3) 24 hydroxylase (CYP24) expression primarily in the proximal colon. Our data suggest the proximal colon as the primary site of response to insufficient calcium intake.
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PMID:Nutritional calcium modulates colonic expression of vitamin D receptor and pregnane X receptor target genes. 1832 73

Vitamin D receptor (VDR) can modulate functionally antagonistic growth regulatory pathways, involving beta-catenin/E-cadherin on one hand and osteopontin (OPN) on the other. This study investigates effects of VDR ligand treatment on the balance of these discordant signals and on associated cell behavior. Treatment of Rama 37 or SW480 cells by 1alpha,25-(OH)(2) D(3) or analogs suppressed beta-catenin/Lef-1/Tcf signaling and upregulated E-cadherin, consistent with a cancer-inhibitory action. Conversely, treatment also increased transcription of OPN that may be implicated in tumor progression. Molecular crosstalk was observed between the antagonistic VDR-dependent signals, in that beta-catenin/Lef-1/Tcf molecules modulated VDR activation of OPN. Treatment effects on cell growth were related to a constitutive balance of OPN and E-cadherin expression. No growth effects were observed in Rama 37 cells that have low OPN and high E-cadherin expression. Conversely, treatment of Rama 37 stably transfected subclones that had high OPN and/or low level E-cadherin induced small but significant increases of cell attachment to fibronectin, anchorage-independent growth or invasion. This study shows that relative expression levels of key VDR downstream genes may influence growth regulation by 1alpha,25-(OH)(2) D(3) or analogs. These findings may be relevant to the cell- or tissue-specificity of vitamin D growth regulation.
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PMID:Vitamin D receptor modulates the neoplastic phenotype through antagonistic growth regulatory signals. 1918 84

Sporadic colorectal cancer is a disease of advancing age and the percentage of the population which reaches an advanced age is strongly increasing. Multiple factors are responsible for the etiology of this cancer since the colorectal mucosa is directly influenced by nutrients reaching the colonic lumen and impacting on mucosal cells. The vitamin D system appears to be central to several preventative molecular pathways. Insufficiency of the serum precursor 25-hydroxyvitamin D3 has been linked by epidemiology to enhanced colon tumor incidence, most likely because it is a major determinant of 1,25-dihydroxyvitamin D3 synthesis in colonic mucosal cells. Bound to its receptor, vitamin D regulates colonic proliferation, differentiation and apoptosis in an autocrine/paracrine manner. During early malignancy, vitamin D synthesis is enhanced to counteract hyperproliferation, whereas in high-grade tumors catabolism by far surpasses synthesis. The colonic vitamin D system is regulated by several known natural factors. One of the most important ones is nutritional calcium that, if supply is low, will result in enhanced catabolism of colonic 1,25-dihydroxyvitamin D3. Estrogenic compounds can increase expression and activity of the synthesizing 25-hydroxyvitamin D-1alpha-hydroxylase. Due to enhanced synthesis of the active metabolite, this can lead to protection against colorectal tumors in women. During tumor progression, expression of 25-hydroxyvitamin D-1alpha-hydroxylase as well as of the catabolizing 25-hydroxyvitamin D-24-hydroxylase appears to be under epigenetic control as demonstrated by studies with phytoestrogens and folate. It is commonly accepted that sporadic colorectal cancer pathogenesis is multifactorial and these are just a few examples of the regulatory capacity of natural (nutrient) substances for improving the colonic vitamin D system. However, protection by vitamin D might have central importance, with nutrients increasing the efficiency of the vitamin D system in a targeted manner. This could result in prevention of hyperproliferation or retardation of progression to clinically manifest primary colonic tumors.
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PMID:Modulation of vitamin D synthesis and catabolism in colorectal mucosa: a new target for cancer prevention. 1966 68

Genetic factors and their interactions with environmental conditions and internal microenvironment influence the prostate cancer (PC) development, so that gene expression couldn't strictly occur on the basis of reductionist determinisms of DNA causality but should also conform to multifactorial and stochastic events, moreover, considering the pre-RNA alternative splicing-mediated multi-protein assemblying mechanisms. Nevertheless, after age and ethnic background, the strongest epidemiological risk factor for PC is a positive family history. However, apart from RNaseL-, ElaC2-, MSR1-genes, there are not other identified high-risk genetic variants which might be considered responsible for hereditary PC, moreover suggesting that familial PC is a genetically heterogeneous disease, many gene loci rather than a specific major susceptibility gene predisposing to it. Gene-environment interactions play a crucial role in cancer development especially when low penetrance genes, such as in case of genetic polymorphisms, are the major players. Several epidemiological studies show, in some families, a possible, either syncronous or metachronous, association of other tumors (breast, brain, gastrointestinal tumors, lymphomas) with PC, thus suggesting a common genetic background. As far as the role of androgen metabolism and androgen receptor (AR)-related genes in the development of familial PC is concerned, a small number of either guanine-guanine-cytosine (< 16) or cytosine-adenine-guanine (< 18) repeats appears to increase the AR activity, resulting in a raising PC risk. Regarding the expression of both androgen and estrogen receptor-related genes in sporadic and hereditary PC, the immunohistochemistry findings show that the percentage of AR-positive cancer cells is higher in hereditary PC than in sporadic forms, whereas the mean number of estrogen-alpha-receptor-positive stromal cells is higher in sporadic PC rather than in that hereditary. As for 5-alpha-steroid-reductase-2 gene, the dinucleotide thymine-adenine repeated 18 times on the last exon, confers an increased PC predisposition, as it is mainly shown in African-American populations. Also VDR gene, that is a component of ligand (steroid)-dependent nuclear transcription factor superfamily, shows various polymorphisms which appear to be associated with PC risk. Except an earlier age of onset, no anatomo-clinical and tumor progression peculiarities between hereditary and sporadic PC have been generally identified. Indeed, tumor progression and metastasis, both in hereditary and sporadic PC, are mainly influenced by a variety of biochemical and immune-mediated tumor microenvironmental conditions rather than by the hereditary genetic factors, thus gene expression associated with invasive ability representing a newly acquired genetic variant rather than a selection of pre-existent gene abnormalities in PC cells. It's questionable whether genetic testing of unaffected men of hereditary PC families might be actually useful. Nevertheless a suitable counselling must be proposed. Family history and/or gene profiling-guided preventive strategies for men at high risk of familial PC, range from dietary to drug measures. Cancer chemopreventive approaches may include 5-alpha-reductase inhibitors, histone deacetylase inhibitors, antioxidans, non-steroidal anti-inflammatory drugs, cholesterol-lowering statins, vitamin D analogues.
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PMID:Hereditary/familial versus sporadic prostate cancer: few indisputable genetic differences and many similar clinicopathological features. 2018 87


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