calcitriol and Skin-Neoplasms

Ultraviolet (UV) radiation is involved in almost all skin cancer cases, but on the other hand, it stimulates the production of pre-vitamin D3, whose active metabolite, 1,25-dihydroxyvitamin D3 (1,25VD3), plays important physiological functions on binding with its receptor (vitamin D receptor, VDR). UV-induced DNA damages in the form of cyclobutane pyrimidine dimers or (6-4)-pyrimidine-pyrimidone photoproducts are frequently found in skin cancer and its precursors. Therefore, removing these lesions is essential for the prevention of skin cancer. As UV-induced DNA damages are repaired by nucleotide excision repair (NER), the interaction of 1,25VD3 with NER components can be important for skin cancer transformation. Several studies show that 1,25VD3 protects DNA against damage induced by UV, but the exact mechanism of this protection is not completely clear. 1,25VD3 was also shown to affect cell cycle regulation and apoptosis in several signaling pathways, so it can be considered as a potential modulator of the cellular DNA damage response, which is crucial for mutagenesis and cancer transformation. 1,25VD3 was shown to affect DNA repair and potentially NER through decreasing nitrosylation of DNA repair enzymes by NO overproduction by UV, but other mechanisms of the interaction between 1,25VD3 and NER machinery also are suggested. Therefore, the array of NER gene functioning could be analyzed and an appropriate amount of 1.25VD3 could be recommended to decrease UV-induced DNA damage important for skin cancer transformation.

Topics: Animals; DNA Damage; DNA Repair; Humans; Melanoma; Pyrimidine Dimers; Skin; Skin Neoplasms; Ultraviolet Rays; Vitamin D; Vitamins

Basal Cell Carcinomas (BCCs) are the most commonly diagnosed tumors among people in the western world. Most BCCs are caused by mutational inactivation of the tumor suppressor Patched (PTCH), which results in activation of Smoothened (SMO) and of the Hedgehog (HH) signaling pathway. Recent studies indicate that BCC progression involves a crosstalk between Hh signaling, vitamin D derivatives and the vitamin D receptor (Vdr) signaling pathway. This has been demonstrated in BCC-bearing Ptch mutant mice and BCC cell lines, in which both vitamin D3 and its active metabolite calcitriol (1alpha-25(OH)2D3) exert antitumor effects. Interestingly, the antitumor effects are mainly ascribed to an inhibition of Hh signaling. Furthermore, as evident from studies in Vdr deficient mice, calcitriol may also repress the activity of Hh signaling in a Vdr-dependent fashion thereby establishing an additional inhibitory feedback on Hh signaling activity. In this chapter, we discuss the current understanding and controversial findings of the inhibition of Hh signaling by vitamin D derivatives and the implication of these findings for BCC carcinogenesis.

Topics: Animals; Carcinoma, Basal Cell; Gene Expression Regulation, Neoplastic; Hedgehog Proteins; Humans; Mice; Mutation; Patched Receptors; Patched-1 Receptor; Receptors, Calcitriol; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Signal Transduction; Skin; Skin Neoplasms; Smoothened Receptor; Ultraviolet Rays; Vitamin D

Cutaneous malignancies including melanomas and non melanoma skin cancers (NMSC) are the most common types of cancer, occurring at a rate of over 1 million per year in the United States. The major cell in the epidermis, the keratinocyte, not only produces vitamin D but contains the enzymatic machinery to metabolize vitamin D to its active metabolite, 1,25(OH)2D, and expresses the receptor for this metabolite, the vitamin D receptor (VDR), allowing the cell to respond to the 1,25(OH)2D that it produces. In vitro, 1,25(OH)2D stimulates the differentiation and inhibits the proliferation of these cells and so would be expected to be tumor suppressive. However, epidemiologic evidence demonstrating a negative relationship between circulating levels of the substrate for CYP27B1, 25OHD, and the incidence of these malignancies is mixed, raising the question whether vitamin D is protective in the in vivo setting. UV radiation (UV), both UVB and UVA, as occurs with sunlight exposure is generally regarded as causal for these malignancies, but UVB is also required for vitamin D synthesis in the skin. This complicates conclusions reached from epidemiologic studies in that UVB is associated with higher 25OHD levels as well as increased incidence of cutaneous malignancies. Based on our own data and that reported in the literature we hypothesize that vitamin D signaling in the skin suppresses UVR induced epidermal tumor formation. In this chapter we will first discuss recent data regarding potential mechanisms by which vitamin D signaling suppresses tumor formation, then focus on three general mechanisms that mediate tumor suppression by VDR in the skin: inhibition of proliferation and stimulation of differentiation, immune regulation, and stimulation of DNA damage repair (DDR).

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Gene Expression Regulation; Humans; Keratinocytes; Receptors, Calcitriol; Signal Transduction; Skin; Skin Neoplasms; Tumor Suppressor Proteins; Ultraviolet Rays; Vitamin D

To briefly review recent work within the vitamin D and cancer field, whereas also providing context relating how these findings may impact clinical care and future research efforts.. Vitamin D has now been convincingly shown both in vitro and in preclinical animal models to alter the differentiation, proliferation, and apoptosis of cancer cells. Whether vitamin D prevents cancer in humans or limits cancer progression, however, remain open questions. Epidemiologic and observational data relating circulating 25(OH)D levels and cancer risk suggest an inverse relationship for most cancers including breast, colorectal, leukemia and lymphoma, and prostate, although for each malignancy there also exist studies that have failed to demonstrate such an inverse relationship. Likewise, a more recent report failed to confirm a previously reported association of increased pancreatic cancer risk in patients with higher 25(OH)D levels. A large prospective study in which patients aged at least 50 years receive 2000 IU vitamin D3 daily for 5 years, with cancer as a primary endpoint, has recently been launched.. Although much effort has attempted to delineate a causal relationship between vitamin D and a wide array of human cancers, we await large-scale randomized controlled trial data for definitive answers.

Topics: Apoptosis; Breast Neoplasms; Clinical Trials as Topic; Colorectal Neoplasms; Female; Hematologic Neoplasms; Humans; Male; Neoplasms; Pancreatic Neoplasms; Prostatic Neoplasms; Receptors, Calcitriol; Risk Factors; Skin Neoplasms; Vitamin D

1,25-dihydroxyvitamin D3[1,25(OH)2D3] is a well-known potent regulator of cell growth and differentiation and there is recent evidence of an effect on cell death, tumour invasion and angiogenesis, which makes it a candidate agent for cancer regulation. The classical synthetic pathway of 1,25(OH)2D3 involves 25- and 1 alpha-hydroxylation of vitamin D3, in the liver and kidney, respectively, of absorbed or skin-synthesized vitamin D3. There is recent focus on the importance in growth control of local metabolism of 1,25(OH)2D3, which is a function of local tissue synthetic hydroxylases and particularly the principal catabolizing enzyme, 24-hydroxylase. The classical signalling pathway of 1,25(OH)2D3 employs the vitamin D nuclear receptor (VDR), which is a transcription factor for 1,25(OH)2D3 target genes. Effects of this pathway include inhibition of cellular growth and invasion. Cytoplasmic signalling pathways are increasingly being recognized, which similarly may regulate growth and differentiation but also apoptosis. 1,25(OH)2D3 has a major inhibitory effect on the G1/S checkpoint of the cell cycle by upregulating the cyclin dependent kinase inhibitors p27 and p21, and by inhibiting cyclin D1. Indirect mechanisms include upregulation of transforming growth factor-beta and downregulation of the epidermal growth factor receptor. 1,25(OH)2D3 may induce apoptosis either indirectly through effects on the insulin-like growth receptor and tumour necrosis factor-alpha or more directly via the Bcl-2 family system, the ceramide pathway, the death receptors (e.g. Fas) and the stress-activated protein kinase pathways (Jun N terminal kinase and p38). Inhibition of tumour invasion and metastasis potential has been demonstrated and mechanisms include inhibition of serine proteinases, metalloproteinases and angiogenesis. The lines of evidence for an effect of vitamin D3 in systemic cancer are the laboratory demonstration of relevant effects on cellular growth, differentiation, apoptosis, malignant cell invasion and metastasis; epidemiological findings of an association of the occurrence and outcome of cancers with derangements of vitamin D3/1,25(OH)2D3 and the association of functional polymorphisms of the VDR with the occurrence of certain cancers. In addition, vitamin D3 analogues are being developed as cancer chemotherapy agents. There is accumulating evidence that the vitamin D3/1,25(OH)2D3/VDR axis is similarly important in malignant melanoma (MM). MM cells express

Topics: Breast Neoplasms; Cell Differentiation; Cell Division; Cholecalciferol; Colonic Neoplasms; Female; Humans; Male; Melanoma; Polymorphism, Genetic; Prostatic Neoplasms; Receptors, Calcitriol; Signal Transduction; Skin; Skin Neoplasms; Vitamin D

Topics: Adult; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Foot Diseases; Humans; Hypophosphatemia; Male; Neoplasm Proteins; Neoplasms, Connective Tissue; Osteomalacia; Paraneoplastic Syndromes; Skin Neoplasms; Toes; Vitamin D

Topics: Antineoplastic Agents; Apoptosis; Bexarotene; CD4-Positive T-Lymphocytes; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Humans; Mycosis Fungoides; Receptors, Calcitriol; Retinoid X Receptors; Sezary Syndrome; Skin Neoplasms; Tetrahydronaphthalenes; Vitamin D; Vitamin D Deficiency

Melanoma cells express the nuclear vitamin D receptor (VDR), indicating that malignant melanoma represents a promising target for treatment with 1,25-dihydroxyvitamin D3 (1,25(OH)(2)D(3)) or its analogs. We previously showed that some melanoma cell lines are resistant to the antiproliferative effects of 1,25(OH)(2)D(3) and that 1,25(OH)(2)D(3)-sensitivity can, at least in part, be restored by co-treatment with the histone deacetylase inhibitor (HDACI) Trichostatin A (TSA) or with the DNA methyltransferase inhibitor (DNMTI), 5-azacytidine (5-Aza). This study aimed at gaining further insights into the molecular mechanisms that underlie the epigenetic modulation of 1,25(OH)(2)D(3)-sensitivity in melanoma cells.. The expression of VDR mRNA, protein and two candidates of VDR microRNAs (miR-125b, miR-27b) were compared in 1,25(OH)(2)D(3)-responsive (MeWo, SK-Mel28) and -resistant (SK-Mel5, IGR) melanoma cell lines and in normal human melanocytes (NHM) using real time PCR and western blot analysis. Additionally, the effect of 1,25(OH)(2)D(3), epigenetic modulating drugs (TSA, 5-Aza) and miR-125b antisense on the expression of VDR messenger RNA (mRNA)/protein, miR-125b and miR-27b was investigated.. Treatment with 1,25(OH)(2)D(3) and/or epigenetic drugs (5-Aza, TSA) modulated the VDR mRNA expression in the 1,25(OH)(2)D(3)-responsive and - resistant melanoma cell lines and in the NHM. Treatment with 5-Aza, but not with TSA, reduced the expression of miR-125b in the 1,25(OH)(2)D(3)-responsive and -resistant melanoma cell lines and in the NHM. Treatment with 1,25(OH)(2)D(3) and/or epigenetic drugs (5-Aza, TSA) reduced the miR-27b expression in three out of four melanoma cell lines. Moreover, no difference was observed in VDR protein expression in the 1,25(OH)(2)D(3)-responsive as compared to the 1,25(OH)(2)D(3)-resistant melanoma cell lines. Transfection with miR-125b antisense did not affect the VDR mRNA/protein expression in the IGR cells.. Responsiveness to 1,25(OH)(2)D(3) corresponds to the expression level of VDR mRNA which in turn might be regulated by VDR microRNAs or epigenetic modulating drugs.

Topics: Antimetabolites, Antineoplastic; Apoptosis; Azacitidine; Blotting, Western; Cell Proliferation; Cells, Cultured; Epigenomics; Humans; Melanocytes; Melanoma; MicroRNAs; Real-Time Polymerase Chain Reaction; Receptors, Calcitriol; RNA, Messenger; Skin Neoplasms; Vitamin D

1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) is the biologically active ligand for the vitamin D receptor (VDR). VDR(-/-) mice have a hair follicle-cycling defect resulting in alopecia. However, mice lacking 25-hydroxyvitamin D(3) 1alpha-hydroxylase (CYP27B1(-/-)), and having no circulating 1,25(OH)(2)D(3), have normal follicular function. These mouse models indicate that VDR functions independently of 1,25(OH)(2)D(3) in regulating hair-follicle cycling. Here, we show that VDR(-/-) mice rapidly develop chemically induced skin tumors, whereas CYP27B1(-/-) and wild-type mice do not, indicating that VDR, and not the 1,25(OH)(2)D(3) ligand, is essential for protection against skin tumorigenesis. Because the majority of human skin cancer results from exposure to UV, the susceptibility of VDR(-/-) mice to this carcinogen was also evaluated. VDR(-/-) mice developed UV-induced tumors more rapidly and with greater penetrance than did VDR(+/+) mice. p53 protein levels were upregulated at similar rates in UV-treated keratinocytes of VDR(-/-) and VDR(+/+) mice. However, rates of thymine-dimer repair and UV-induced apoptosis were significantly lower in VDR(-/-) epidermis compared with the wild type epidermis. UV-induced epidermal thickening was also attenuated in VDR(-/-) skin, indicating that VDR plays a critical role in the repair and removal of severely damaged keratinocytes and adaptation of the skin to chronic UV exposure.

Topics: Adaptation, Physiological; Animals; Apoptosis; Disease Susceptibility; Epidermis; Keratinocytes; Mice; Mice, Knockout; Neoplasms, Radiation-Induced; Penetrance; Pyrimidine Dimers; Receptors, Calcitriol; Skin; Skin Neoplasms; Ultraviolet Rays; Vitamin D