The Impact of Vitamin D in Cancer

The relationship between vitamin D and cancer has previously been reported in the literature. A systemic review and meta-analysis of prospective cohort studies revealed that a 20 nmol/L increase in the 25-hydroxyvitamin D3 (25OHD) levels was associated with an 8% lower mortality in the elderly population (Schöttker et al., 2012). Oncology patients had significantly lower mean serum vitamin D levels than non-cancer primary care patients from the same geographic region (Churilla et al., 2011). In a community oncology experience, vitamin D deficiency is widespread in cancer patients and correlates with advanced stage disease (Churilla et al., 2012). A high prevalent of vitamin D deficiency has been associated with head and neck cancer (Orell-Kotikangas et al., 2011), breast cancer (Crew et al., 2009; Peppone et al., 2012), vulvar cancer (Salehin et al., 2012), prostate cancer (Varsavsky et al., 2011), pancreatic cancer (Wolpin et al., 2011), gastric cancer (Ren et al., 2012), colon and rectal cancer (Tangrea et al., 1997), ovarian cancer (Lefkowitz et al., 1994), oral cavity and esophagus cancers (Lipworth et al., 2009), myelo-proliferative neoplasms and myelo-dysplastic syndromes (Pardanani et al., 2011), multiple myeloma (Ng et at., 2009), non-Hodgkin’s lymphoma (Drake et al., 2010), and chronic lymphocytic leukemia (Shamafelt et al., 2011). On the other hand, a serum 25OHD concentration of 25 nmol/L was associated with a 17% reduction in incidence of cancer, a 29% reduction in total cancer mortality, and a 45% reduction in digestive system cancer mortality (Giovannucci et al., 2006). Improving vitamin D status may also help lower the risk of colorectal cancer (Wu et al., 2011a). In a case-control study, a higher vitamin D intake is associated with a lower risk of esophageal squamous cell carcinoma (Launoy et al., 1998). A meta-analysis revealed that an increase of serum 25OHD by 50 nmol/L was associated with a risk reduction of 59% for rectal cancer and 22% for colon cancer (Yin et al., 2009). High 25OHD levels were associated with better prognosis in breast, colon, prostate cancer, and lung cancer relative to patients with lower 25OHD levels (Robsahm et al., 2004; Zhou et al., 2007). In a murine model, dietary vitamin D may play an important role as a preventive agent in andro‐


Introduction
The relationship between vitamin D and cancer has previously been reported in the literature. A systemic review and meta-analysis of prospective cohort studies revealed that a 20 nmol/L increase in the 25-hydroxyvitamin D 3 (25OHD) levels was associated with an 8% lower mortality in the elderly population (Schöttker et al., 2012). Oncology patients had significantly lower mean serum vitamin D levels than non-cancer primary care patients from the same geographic region ( (Tangrea et al., 1997), ovarian cancer (Lefkowitz et al., 1994), oral cavity and esophagus cancers (Lipworth et al., 2009), myelo-proliferative neoplasms and myelo-dysplastic syndromes (Pardanani et al., 2011), multiple myeloma (Ng et at., 2009), non-Hodgkin's lymphoma (Drake et al., 2010), and chronic lymphocytic leukemia (Shamafelt et al., 2011). On the other hand, a serum 25OHD concentration of 25 nmol/L was associated with a 17% reduction in incidence of cancer, a 29% reduction in total cancer mortality, and a 45% reduction in digestive system cancer mortality (Giovannucci et al., 2006). Improving vitamin D status may also help lower the risk of colorectal cancer (Wu et al., 2011a). In a case-control study, a higher vitamin D intake is associated with a lower risk of esophageal squamous cell carcinoma (Launoy et al., 1998). A meta-analysis revealed that an increase of serum 25OHD by 50 nmol/L was associated with a risk reduction of 59% for rectal cancer and 22% for colon cancer (Yin et al., 2009). High 25OHD levels were associated with better prognosis in breast, colon, prostate cancer, and lung cancer relative to patients with lower 25OHD levels (Robsahm et al., 2004;Zhou et al., 2007). In a murine model, dietary vitamin D may play an important role as a preventive agent in andro-gen-insensitive human prostate tumor growth (Ray et al., 2012). The season in which patients were operated on seemed to have an effect on survival of patients undergoing resection of nonsmall cell lung cancer (Turna et al., 2012). The survival of patients who had surgery in winter was statistically significantly shorter than that of patients who underwent surgery in the summer. In Australia, prostate cancer mortality rates are inversely correlated with solar radiation exposure (Loke et al., 2011). Dietary vitamin D 3 and calcitriol have been shown to demonstrate equivalent anticancer activity in mouse xenograft models of breast and prostate cancers (Swani et al., 2012). The combination of calcitriol and dietary soy resulted in substantially greater inhibition of tumor growth than the inhibition achieved with either agent alone in a mouse xenograft model of prostate cancer (Wang et al., 2012a). Soy diets alone caused a modest elevation in serum calcitriol. Vitamin D 3 treatment significantly suppressed the viability of gastric cancer and cholangiocarcinoma cells and also had a synergistic effect with other anti-cancer drugs, such as paclitaxel, adriamycin, and vinblastine (Baek et al., 2011). The vitamin D analog, 19-Nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D 3 , is a potent cell growth regulator with enhanced chemotherapeutic potency in liver cancer cells (Chiang et al., 2011). Alphacalcidol, a vitamin D analogue, has been demonstrated significant antitumor activity in patients with low-grade non-Hodgkin's lymphoma of the follicular, small-cleaved cell type (Raina et al., 1991). In patient with parathyroid cancer, vitamin D has been shown to prevent or delay the progression of recurrence (Palmieri-Sevier et al., 1993). In locally advanced or cutaneous metastatic breast cancer, topical calcipotriol treatment reduced the diameter of treated lesions that contained vitamin D receptor (VDR) (Bower et al., 1991). In a clinical trial, high-dose calcitriol decreased prostatic-specific antigen (PSA) levels by 50% and reduced thrombosis in prostate cancer patients (Beer et al., 2003(Beer et al., & 2006. In hepatocellular carcinoma, calcitriol and its analogs have been reported to reduce tumor volume, increase hepatocarcinoma cell apoptosis by 21.4%, and transient stabilize serum alpha-fetoprotein levels (Dalhoff et al., 2003;Luo et al., 2004;Morris et al., 2002). These findings suggested a relationship between vitamin D and cancer. In this chapter, we will discuss the role of vitamin D in cancer.

The Major Histocompatibility Complex (MHC) class II molecules
The major histocompatibility complex (MHC) class II molecules play an important role in the immune system and are essential in the defense against infection. The human MHC class II molecules are encoded by three different human leukocytic antigen (HLA) isotypes: HLA-DR, -DQ, and -DP. Studies have suggested that several genes within MHC region promote cancer susceptibility. A chimeric DR4 homozygous transgenic mouse line is reported to spontaneously develop diverse hematological malignancies at a high frequency (Raffegerst et al., 2009). Most of these neoplasms were highly similar to those found in human diseases. HLA-DR antigen expression was correlated with the histopathological type and to the degree of cell differentiation in cutaneous squamous cell carcinomas (Garcia-Plata et al., 1993). The DRB1*03 and DR-B1*13 alleles were significantly more frequent in patients with nasopharyngeal carcinoma compared with controls in southern Tunisia (Makni et al., 2010). The DR1 gene is genetic risk factors for developing tumors. There are five important common polymorphisms within the VDR gene region that are likely to exert functional effects on VDR expression. The anti-carcinogenic potential of vitamin D might be mediated by VDR expression. The association between plasma 25OHD levels and colorectal adenoma was modified by the TaqI polymorphism of the VDR gene (Yamaji et al., 2011). There is a significant association between single nucleotide polymorphisms (SNPs) in the VDR gene and vitamin D intake in African Americans with colorectal cancer (Kupfer et al., 2011). The BsmI polymorphism of the VDR gene also modified the association between dietary vitamin D intake and breast cancer (Rollison et al., 2012). The AA genotype of VDR is reported to be associated with colorectal cancer, with a stronger association in female patients (Mahmoudi et al., 2012). The FokI and BsmI genotypes of VDR gene are implicated in the pathogenesis of renal cell carcinoma (RCC) in a North Indian population (Arjumand et al., 2012). Altered VDR expression was associated with RCC carcinogenesis via the expression of epithelial Ca 2+ channel transient receptor potential vanilloid subfamily 5 and 6 (TRPV5/6) (Wu et al., 2011b). There is a significant association between shorter progression-free survival time in patients with head and neck squamous cell carcinoma and the FokI TT genotype, as well as the Cdx2-FoxI-ApaI haplotype (Hama et al., 2011). In Spanish children, osteosarcoma patients showed a significantly higher frequency of the Ff genotype of the FokI VDR gene than the control group (Ruza et al., 2003). In a German population, the AaTtBb genotype of the VDR gene is associated with basal cell carcinoma risk, whereas the aaTTbb genotype is found at a high frequency in both basal cell carcinomas and cutaneous squamous cell carcinomas compared with controls (Köststner et al., 2012). In a systematic review, TaqI, BsmI and FokI polymorphisms of the VDR gene were found to be associated with malignant melanoma (Denzer et al., 2011). Furthermore, the presence of specific VDR BsmI and TaqI alleles was associated with a higher C-reactive protein (CRP) level in cancer patients with cachectic syndrome (Punzi et al., 2012). In another prospective study, plasma 25OHD levels and common variation among several vitamin D-related genes (CYP27A1, CYP2R1, CYP27B1, CYP24A1, GC, RXRA, and VDR) were associated with lethal prostate cancer risk (Shui et al., 2012). Slattery et al. (2009) examined genetic variants that are linked to the pathway that contribute to colon cancer. They revealed that FoxI VDR polymorphism was associated with CpG Island methylator phenotype (CIMP) positive/Ki-ras mutated tumors, whereas the Poly A and Cdx2 VDR polymorphisms were associated only with Ki-ras mutated tumors.

MicroRNA (miRNA)
MiRNAs are endogenous noncoding RNAs that regulate gene expression through the translational repression or degradation of target mRNA (Bartel, 2004). Aberrant miRNA expression has been well characterized in cancer (Lu et al., 2005). Circulating miRNAs are suggested to be diagnostic and prognostic markers in breast cancer (Cortez et al., 2012). Circulating miR-NA-125b expression is associated with chemotherapeutic resistance of breast cancer (Wang et al., 2012b). Several miRNAs are found to share 125b complementarity with a sequence in the 3'unstranslated region of human VDR mRNA. The overexpression miRNA-125b significantly decreased the endogenous VDR protein level in human breast adenocarcinoma cells lines (MCF-7) to 40% of the control ). This miRNA is down-regulated in cancer tissue and causes high CYP24 protein expression, which catalyzes the inactivation of calcitriol . Stress induced by serum starvation caused significant alteration in the expression of multiple miRNAs including miRNA-182, but calcitriol effectively reversed this alteration in breast epithelial cells (Peng et

Renin-Angiotensin System (RAS)
The primary function of the renin-angiotensin system (RAS) is to maintain fluid homeostasis and regulate blood pressure. The angiotensin converting enzyme (ACE) is a key enzyme in the RAS and converts angiotensin (AT) I to the potent vasoconstrictor AT II (Johnston, 1994). . In a hypertensive Turkish population, the presence of the ACE D allele, which correlates negatively with serum 25OHD levels, is linked to a higher left ventricular mass index value and elevated ambulatory blood pressure measurements (Kulah et al., 2007). In addition, genetic disruption of the VDR gene resulted in overstimulation of the RAS with increased renin and angiotensin II production, which lead to high blood pressure and cardiac hypertrophy. However, treatment with captopril reduced cardiac hypertrophy in VDR-knockout mice (Xiang et al., 2005), suggesting that calcitriol may function as an endocrine suppressor of renin biosynthesis. Moreover, calcitriol suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin core promoter (Yuan et al., 2007) and decreases ACE activity in bovine endothelial cells (Higiwara et al., 1988).

Toll-Like Receptor (TLR)
Toll-like receptors (TLRs) are a group of glycoproteins that functions as surface trans-membrane receptors and are involved in the innate immune responses to exogenous pathogenic microorganisms. Substantial evidence exists for an important role of TLRs in the pathogenesis and outcomes of cancer. TLR2 expression was significantly higher in sporadic colorectal cancerous tissue than in non-cancerous tissue (

The bacillus Calmette-Guerin (BCG) vaccination
The BCG vaccine was developed to provide protection against tuberculosis and has also been demonstrated to offer protection against cancer.

Matrix Metalloproteinase (MMPs)
MMPs are proteolytic enzymes responsible for extracellular matrix remodeling and the regulation of leukocyte migration through the extracellular matrix, which is an important step in inflammatory and infectious pathophysiology. MMPs are produced by many cell types including lymphocytes, granulocytes, astrocytes and activated macrophages. . A vitamin D analog has also been reported to reduce the expression of MMP-2, MMP-9, vascular endothelial growth factor (VEGF) and PTH-related peptide in Lewis lung carcinoma cells (Nakagawa et al., 2005). Taken together, these studies suggest that calcitriol may play an important role in the pathological processes in cancer by down-regulating the level of MMPs and regulating the level of TIMPs.

Wnt/β-catenin
The Wnt/β-catenin signaling pathway plays a pivotal role in the regulation of cell growth, cell development and the differentiation of normal stem cells. Wnt/β-catenin signaling is implicated in many human cancers, including gastrointestinal cancer, gastric cancer, colon cancer, melanoma, HCC, endometrial carcinoma, ovarian carcinoma, cervical cancer, papillary thyroid carcinoma, renal cell carcinoma, prostate cancer, parathyroid carcinoma, and hematological malignancies (

The Mitogen-Activated Protein Kinase (MAPK) pathways
The MAPK pathways provide a key link between the membrane bound receptors that receive these cues and changes in the pattern of gene expression, including the extracellular signalregulated kinase (ERK) cascade, the stress activated protein kinases/c-jun N-terminal kinase . Taken together, these findings suggest that vitamin D may play a role in modulating the inflammatory process in cancer.

Oxidative stress
Reactive oxygen species (ROS) play a major role in various cell-signaling pathways.

The use of vitamin D in cancer treatment
A number of clinical trials have used vitamin D 3 and calcitriol alone or in combination with anti-tumor agents. Most preclinical suggest that that the optimal anti-tumor effect of calcitriol and other analogs is seen with the administration of high dose calcitriol on intermittent schedule. A small number of single agent trials utilizing vitamin D 3 and calcitriol hace been conducted with limited success.

Calcitriol trials -Single agent
In

Conclusion
Vitamin D has a role in the prevention and treatment of cancer. Genetic studies have provided the opportunity to determine what proteins link vitamin D to the pathology of cancer. Vitamin D also exerts its effect on cancer via non-genomic mechanisms. As a result, it is imperative that vitamin D levels in patients with cancer be followed. Many studies use the relationship between serum PTH and 25OHD to define the normal range of serum 25OHD. According to the report on   (7), 293-9. [