Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidemiological evidence suggests an inverse relationship between prostate cancer and serum vitamin D levels. We examined the ability of cholecalciferol (vitamin D(3)), a calcitriol precursor, to inhibit or reverse cellular changes associated with malignant transformation and invasion and explored its mechanisms of action. The RWPE2-W99 human prostate epithelial cell line, which forms slow-growing tumors in nude mice, was used because it mimics the behavior of the majority of primary human prostate cancers. Cholecalciferol, at physiological levels: (i) inhibited anchorage-dependent and -independent growth; (ii) induced differentiation by decreasing vimentin expression with a concomitant decrease in motility/chemotaxis; (iii) decreased MMP-9 and MMP-2 activity with concomitant decrease in invasion; and (iv) exerted its effects by up-regulating vitamin D receptor (VDR), retinoid-X receptor-alpha (RXR-alpha), and androgen receptor (AR) in a dose-dependent manner. Furthermore, we found that RWPE2-W99 prostate cancer cells, similar to RWPE-1 cells (Tokar and Webber. Clin Exp Metast 2005; 22: 265-73), constitutively express the enzyme 25-hydroxylase CYP27A1 which is markedly up-regulated by cholecalciferol. Cholecalciferol has effects similar to those of calcitriol on growth, MMP activity, and VDR. The ability of CYP27A1 to catalyze the conversion of cholecalciferol to 25(OH)D(3) and of 25(OH)D(3) to calcitriol has been reported. RWPE2-W99 cells, similar to RWPE-1 cells, appear to have the rare ability to locally convert cholecalciferol to the active hormone calcitriol. Because it can inhibit cellular changes associated with malignant transformation and invasion, we propose that cholecalciferol may be an effective agent for the treatment of prostate cancer.
Clin Exp Metastasis 2005
PMID:Cholecalciferol (vitamin D3) inhibits growth and invasion by up-regulating nuclear receptors and 25-hydroxylase (CYP27A1) in human prostate cancer cells. 1615 55

E-cadherin (CDH1) gene expression is strictly regulated. The transcriptional factors SNAIL and ZEB1 are involved in its repression, whereas activation of vitamin D receptor (VDR) by vitamin D induces its transcription. We study the expression and functional correlation of SNAIL, CDH1, VDR and ZEB1 genes and examine their possible involvement in colon cancer. The expression of these four genes was measured by real time-PCR in 114 patients with colorectal cancer, and tumor characteristics were analyzed in each patient. SNAIL expression was associated with downregulation of CDH1 (P < 0.001) and VDR (P < 0.001) gene products. We also found a positive correlation between CDH1 and VDR expressions. However, the association between SNAIL and CDH1 was not found in patients with high expression of ZEB1. We observed a correlation between downregulation of: a) ZEB1 and presence of polyps in surgical resections; b) VDR and poor differentiation and c) CDH1 and poor differentiation, vascular invasion, presence of lymph node metastases and advanced stages; as well as a trend toward a correlation between SNAIL expression in tumors and vascular invasion. The correlations between SNAIL, CDH1, VDR and ZEB1 and the association between reduced expression of CDH1 and VDR and aggressive tumor characteristics emphasize the value of analyzing these genes in colon cancer patients for prognostic purposes and for predicting response to possible therapies with vitamin D or its analogs.
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PMID:E-cadherin and vitamin D receptor regulation by SNAIL and ZEB1 in colon cancer: clinicopathological correlations. 1620 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

The aromatase inhibitors (AIs) anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are significantly more effective than the selective estrogen-receptor modulator (SERM) tamoxifen in preventing recurrence in estrogen receptor-positive early breast cancer. Aromatase inhibitors are likely to replace SERMs as first-line adjuvant therapy for many patients. However, AIs are associated with significantly more osteoporotic fractures and greater bone mineral loss. As antiresorptive agents, oral and intravenous bisphosphonates such as alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), pamidronate (Aredia), and zoledronic acid (Zometa) have efficacy in preventing postmenopausal osteoporosis, cancer treatment-related bone loss, or skeletal complications of metastatic disease. Clinical practice guidelines recommend baseline and annual follow-up bone density monitoring for all patients initiating AI therapy. Bisphosphonate therapy should be prescribed for patients with osteoporosis (T score < -2.5) and considered on an individual basis for those with osteopenia (T score < -1). Modifiable lifestyle behaviors including adequate calcium and vitamin D intake, weight-bearing exercise, and smoking cessation should be addressed. Adverse events associated with bisphosphonates include gastrointestinal toxicity, renal toxicity, and osteonecrosis of the jaw. These safety concerns should be balanced with the potential of bisphosphonates to minimize or prevent the debilitating effects of AI-associated bone loss in patients with early, hormone receptor-positive breast cancer.
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PMID:Aromatase inhibitors and bone loss. 1698 48

The diagnostic algorithm in cases of suspected bone metastases of genitourinary tumors still starts with a scintigraphic examination. Osseous metastases of hormone-refractory prostate cancer require treatment with zoledronic acid. A potential indication is a hormone-sensitive status. Nephrotoxic substances should not be administered simultaneously. To avoid osteonecrosis of the jaw, prior dental examination, oral hygiene, and if necessary dental reconstruction are recommended. Bisphosphonates can be combined with radiation therapy and chemotherapy; additional administration of calcium and vitamin D is not mandatory. It is recommended that patients with bone metastases of renal cell cancer be treated with bisphosphonates approved for this indication. For urothelial carcinoma and other genitourinary tumors, the available data are not sufficient to give a recommendation.
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PMID:[Diagnostic work-up of bone metastases of genitourinary tumors and their treatment with bisphosphonates. Interdisciplinary consensus conference, Frankfurt, 2006]. 1709 Dec 78

Bone is the primary site of metastases in advanced androgen-independent prostate cancer. These metastases are primarily bone-forming, although the presence of osteolytic response has also been reported. Bone-homing therapy is a strategy based on the popular seed-and-soil relationship between the epithelial malignant cells and the bone stroma. Calcitriol (1,25-dihydroxyvitamin D3) and its synthetic analogs (deltanoids) are drugs that have a direct effect on both the skeleton and the invading metastatic cells and, therefore, are considered useful in the treatment of advanced prostate cancer. In this article, I review the nature of the response induced by the malignant cells in the bone (bone formation or bone resorption) and how it affects the outcome of a vitamin D analog treatment in preclinical models of metastatic bone disease.
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PMID:Responsiveness of osteoblastic and osteolytic bone metastases to vitamin D analogs. 1772 85

Vitamin D deficiency is strongly associated with the risk of developing colorectal cancer (CRC). Because of the propensity of bioactive 1,25-dihydroxyvitamin D3 to cause toxic hypercalcemia, considerable effort has been directed to identifying safer drugs while retaining the efficacy of the parent compound. However, vitamin D precursors do not present toxicity concerns and may be sufficient for CRC chemoprevention or chemotherapy, providing the appropriate enzymes are present in colonic epithelia. We previously showed that CYP27B1 is present at equally high levels in the colon and CRC irrespective of differentiation but was not present in metastases. In this study we used quantitative immunohistochemistry to show that CYP27A1, converting D3 to 25-hydroxycholecalciferol, is present in increasing concentrations in the nuclei of normal colonic epithelia, aberrant crypt foci (ACF), and adenomatous polyps. Whereas total cellular CYP27A1 remains high in CRC and lymph node metastases, the amount of enzyme present in the nuclei decreases with tumor cell dedifferentiation while rising in the cytoplasm. Similarly, increasing amounts of the deactivating enzyme CYP24 are present in the nuclei of normal colonic epithelia, ACFs, and adenomatous polyps. Although the amount of total CYP24 decreases slightly in CRC as a function of tumor cell dedifferentiation and metastasis, location of this enzyme shifts almost entirely from the nuclear compartment to the cytoplasmic compartment. These data indicate that non-toxic vitamin D precursors should be sufficient for CRC chemoprevention, but that neither vitamin D nor its precursors may be sufficient for CRC chemotherapy.
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PMID:CYP27A1 and CYP24 expression as a function of malignant transformation in the colon. 1787 55

Prostate cancer metastasis is a unique disease. The propensity of prostate cancer to metastasize to bone and the prognostic significance of bone metastasis suggest that effective treatment of bone metastasis may provide clinical benefits. Both osteoblasts and osteoclasts have been shown to play a central role in the interactions between the metastatic prostate cancer cells and bone. Although most prostate cancer bone metastasis is osteoblastic, it remains unclear which cell type is initially involved in the process. Other components in the bone, such as the endothelium and stroma, may also play important roles in this process. The osteoblastic feature of prostate cancer bone metastasis has led to therapies focused on targeting osteoblast activity. Clinical trials targeting osteoblasts use radiopharmaceuticals (strontium-89 and samarium-153), the endothelin A receptor inhibitor atrasentan, or the vitamin D analog calcitriol. Agents that target osteoclasts include bisphosphonates; those that target endothelial cells include thalidomide and bevacizumab. Although these clinical trials for bone metastasis may provide effective treatments, novel concepts of how prostate cancer cells selectively metastasize to bone may advance our understanding and provide improved treatments for this difficult clinical problem. We propose a refined "seed" and "soil" view of metastasis. We speculate that in prostate cancer bone metastasis, the seed may comprise the so-called cancer stem cells, whereas the soil may comprise an onco-niche, ie, a unique microenvironment, that facilitate the growth and survival of cancer stem cells. If so, targeting cancer stem cells or the onco-niche may offer another way to improve treatment of prostate cancer bone metastasis.
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PMID:Current trials using bone-targeting agents in prostate cancer. 1830 81

The introduction of organ transplantation in clinical medicine has resulted in a constantly increasing, large population of patients that are chronically on immunosuppressive medication. It is well known that skin cancer, especially SCC, in this population has higher incidence rates, behaves more aggressively and has higher rates of metastasis. OTRs who have been treated for many years with immunosuppressive medication are at the highest risk for developing malignant skin tumors. Therefore, the intensity of surveillance for cutaneous lesions is of high importance in OTRs. A full-body skin exam at least once a year and more frequently if skin cancer or precancerous cutaneous lesions develop is recommended. Clinicians should not hesitate to biopsy or to surgically excise any suspicious skin lesion. Of high importance is also the education of OTRs about their increased risk. Protection against solar and artificial UV-radiation and monthly self-examinations are good ways to prevent and to recognize any new suspicious skin lesions. Patients are advised to always wear solar UV-radiation protection (e.g., clothing, sunscreen) before going outdoors. However, investigations have revealed that solar UV-B-exposure and serum 25(OH)D levels positively correlate with decreased risk for various internal malignancies (e.g., breast, colon, prostate and ovarian cancer) and other severe diseases. As we have shown previously, renal transplant recipients are at high risk of vitamin D deficiency. A sunscreen with a sun protection factor (SPF)-8 reduces the skin's production of vitamin D by 95%. Clothing completely blocks all solar UVB-radiation and this prevents any vitamin D production. Therefore, it is important to detect and treat vitamin D deficiency in solid organ transplant recipients. Optimal management of these patients requires communication between the transplant teams and the treating dermatologist and other clinicians. For advanced or metastatic disease, collaboration between clinicians of different disciplines, including the transplant team, dermatologists and radiation oncologists is also essential. In the future, dermatology clinics that are integrated into transplant centers may make it easier to manage and to treat OTRs, may make an interdisciplinary approach more effective and may thereby improve the clinical outcome in OTRs.
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PMID:Solar UV-radiation, vitamin D and skin cancer surveillance in organ transplant recipients (OTRs). 1834 58

Hypercalcemia is the most common paraneoplastic syndrome in adult malignancies (10%-30%) and rare in pediatric cancers (0.5%-1.3%). Hypercalcemia in malignancies is categorized into two groups: 1) Humoral hypercalcemia of malignancy (HHM)-caused by substances that are produced by the tumor cells and secreted into the blood circulation such as parathyroid hormone-related protein (PTH-rP), parathyroid hormone-intact (PTH-i), the enzyme 1-alpha-hydroxylase that catalyzes the synthesis of the active form of vitamin D (1,25-dihydroxyvitamin D3), and other substances; 2) Hypercalcemia due to bone destruction by metastases. Hypercalcemia occurs in less than 5% of female genital tract malignancies and virtually in all cases (95%) it is HHM. Female genital tract malignancy-associated HHM is caused most often (80%) by PTH-rP. Ovarian cancer is the most common female genital tract malignancy that is associated with HHM. Although HHM occurs in only 5% of ovarian cancers, it occurs in a relatively high percentage in the following rare ovarian tumors: a). Small cell carcinoma of the ovary - a rare tumor that accounts for only 1% of all ovarian cancers and is associated with HHM in 66% of the cases; b). Clear cell carcinoma of the ovary - an uncommon tumor that accounts for 5% of all ovarian cancers and is associated with HHM in 5%-10% of the cases. Since dysgerminoma is the most common malignant ovarian tumor in children, in girls it is the second most common ovarian neoplasm, after ovarian small cell carcinoma, to be associated with HHM.
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PMID:[Hypercalcemia in malignancies of the female genital tract]. 1848 65


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