Vitamin D and its active metabolites are important nutrients for human skeletal health. UV irradiation of skin converts 7-dehydrocholesterol into vitamin D3, which metabolized in the liver and kidneys into its active form, 1α,25-dihydroxyvitamin D3. Apart from its classical role in calcium and phosphate regulation, scientists have shown that the vitamin D receptor is expressed in almost all tissues of the body, hence it has numerous biological effects. These includes fetal and adult homeostatic functions in development and differentiation of metabolic, epidermal, endocrine, neurological and immunological systems of the body. Moreover, the expression of vitamin D receptor in the majority of immune cells and the ability of these cells to actively metabolize 25(OH)D3 into its active form 1,25(OH)2D3 reinforces the important role of vitamin D signaling in maintaining a healthy immune system. In addition, several studies have showed that vitamin D has important regulatory roles of mechanisms controlling proliferation, differentiation and growth. The administration of vitamin D analogues or the active metabolite of vitamin D activates apoptotic pathways, has antiproliferative effects and inhibits angiogenesis. This review aims to provide an up-to-date overview on the effects of vitamin D and its receptor (VDR) in regulating inflammation, different cell death modalities and cancer. It also aims to investigate the possible therapeutic benefits of vitamin D and its analogues as anticancer agents.

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Vitamin D Signaling in Inflammation and Cancer: Molecular Mechanisms and Therapeutic Implications.

Repurposing vitamin D for treatment of human malignancies via targeting tumor microenvironment.

The pancreatic tumour stroma is composed of phenotypically heterogenous cancer-associated fibroblasts (CAFs) with both pro- and anti-tumorigenic functions. Here, we studied the impact of calcipotriol, a vitamin D3 analogue, on the activation of human pancreatic CAFs and T cells using 2- and 3-dimensional (2D, 3D) cell culture models. We found that calcipotriol decreased CAF proliferation and migration and reduced the release of the pro-tumorigenic factors prostaglandin E2, IL-6, periostin, and leukemia inhibitory factor. However, calcipotriol promoted PD-L1 upregulation, which could influence T cell mediated tumour immune surveillance. Calcipotriol reduced T cell proliferation and production of IFN-γ, granzyme B and IL-17, but increased IL-10 secretion. These effects were even more profound in the presence of CAFs in 2D cultures and in the presence of CAFs and pancreatic tumour cell line (PANC-1) spheroids in 3D cultures. Functional assays on tumour infiltrating lymphocytes also showed a reduction in T cell activation by calcipotriol. This suggests that calcipotriol reduces the tumour supportive activity of CAFs but at the same time reduces T cell effector functions, which could compromise the patients' tumour immune surveillance. Thus, vitamin D3 analogues appear to have dual functions in the context of pancreatic cancer, which could have important clinical implications.

/pdf/the-vitamin-d-analogue-calcipotriol-promotes-an-anti-49voimneh7.pdf

The vitamin D analogue calcipotriol promotes an anti-tumorigenic phenotype of human pancreatic CAFs but reduces T cell mediated immunity.

Pancreatic ductal adenocarcinoma (PDAC) is a gastrointestinal malignancy with a dismal clinical outcome. Accumulating evidence suggests that activated pancreatic stellate cells (PSCs), the major producers of extracellular matrix (ECM), drive the severe stromal/desmoplastic reaction in PDAC. Furthermore, the crosstalk among PSCs, pancreatic cancer cells (PCCs) as well as other stroma cells can establish a growth-supportive tumor microenvironment (TME) of PDAC, thereby enhancing tumor growth, metastasis, and chemoresistance via various pathways. Recently, targeting stroma has emerged as a promising strategy for PDAC therapy, and several novel strategies have been proposed. The aim of our study is to give a profound review of the role of PSCs in PDAC progression and recent advances in stroma-targeting strategies.

The Role of Stellate Cells in Pancreatic Ductal Adenocarcinoma: Targeting Perspectives

1,25-Dihydroxyvitamin D 3 suppresses gastric cancer cell growth through VDR- and mutant p53-mediated induction of p21.

Aims

Vitamin D insufficiency and deficiency are common among patients with pancreatic carcinoma, but epidemiological studies have shown inconsistent results for vitamin D intake/circulation level and pancreatic cancer risk. The study aims were to investigate the effects of vitamin D on patient survival, and the proliferation or survival of pancreatic cancer cell lines.



Methods and results

The present study examined the local expression of vitamin D receptor (VDR) in pancreatic normal and tumour tissues from a cohort of 61 patients, and analysed the potential correlation between VDR and pathological characteristics, including disease prognosis. Among 61 pairs of normal and tumour specimens, VDR was detected in all normal tissues, and was abundantly expressed in 62.5% (15/24) of tumour tissues with high differentiation, but had a significantly lower or undetectable expression level in 75.7% (28/37) of tissues with moderate or low differentiation (P = 0.004). Moreover, high VDR expression was detected in 63.6% (14/22) of small tumours (≤25 mm) and in only 25.6% (10/39) of large tumours (>25 mm) (P = 0.06). Kaplan–Meier analysis showed that a low level of VDR expression in tumour tissues was associated with a poor prognosis (P = 0.037).



Conclusions

VDR expression could be a potential prognostic factor for patients with pancreatic adenocarcinoma, and its effects should be examined in a prospective study. Vitamin D analogues may provide a therapeutic choice for patients with high VDR expression in tumours but a low vitamin D level in the circulation.

Expression of vitamin D receptor as a potential prognostic factor and therapeutic target in pancreatic cancer

Pancreatic cancer is usually diagnosed in the advanced stages and is sensitive to only few therapies. The forkhead box L1 (FOXL1) and protein phosphatase 2A (PP2A) have been recognized to be tumor suppressive in human pancreatic cancers. In the present study, we co-expressed the two tumor suppressive molecules with a '2A peptide' linker, which guaranteed the two molecules were transcribed into one mRNA, whereas they were translated into two separate proteins, in pancreatic cancer Panc‑1 cells, and investigated the inhibition of the two molecules on the proliferation and migration of Panc‑1 cells. Results demonstrated that, either overexpression of FOXL1 or PP2A via adenovirus significantly inhibited the proliferation of Panc‑1 cells, whereas promoted apoptosis in such cells. Moreover, the co-expression of both FOXL1 and PP2A exerted synergistic antitumor effect in Panc‑1 cells, with significantly higher proliferation inhibition and tumor induction. In addition, we found that the overexpressed FOXL1 promoted the TNF‑related apoptosis‑inducing ligand (TRAIL), whereas the overexpressed PP2A downregulated the phosphorylation of c‑MYC. The co-expression of FOXL1 and PP2A presented both functions in Panc‑1 cells. In conclusion, the adenovirus‑mediated co‑expression of FOXL1 and PP2A with the 2A peptide linker exterts synergistic suppression of pancreatic cancer cells via inhibiting the growth and promoting apoptosis of cancer cells, probably via upregulating TRAIL and reducing the phosphorylation of MYC.

/pdf/co-expression-of-foxl1-and-pp2a-inhibits-proliferation-4an5h0tlwv.pdf

Co-expression of FOXL1 and PP2A inhibits proliferation inducing apoptosis in pancreatic cancer cells via promoting TRAIL and reducing phosphorylated MYC.

OBJECTIVE To explore the clinicopathological significance and relationship of Tspan 1 and Integrin α6 expression in pancreatic ductal adenocarcinoma (PDAC) tissue and pancreatic cancer cell lines. METHODS Immunohistochemistry was used to detect the expression of Tspan 1 and Integrin α6 in 95 paraffin-embedded PDAC specimens and 55 adjacent non-cancerous pancreatic tissues which were collected from May 2004 to January 2013.Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detected the protein and mRNA expression in 16 paired fresh PDAC specimens of the pancreas and adjacent non-cancerous pancreatic tissues and 6 different pancreatic cancer cell lines.χ(2) test, Spearman-rank correlation analysis, Kaplan-Meier method and multivariate Cox regression analysis were used to analyze the data. RESULTS Tspan 1 and Integrin α6 were significantly over-expressed in PDAC than in adjacent non-cancerous pancreatic tissues (χ(2) = 7.429, P < 0.05; χ(2) = 15.1, P < 0.01). Lymph node metastasis, TNM stage and post-operation recurrence were positively correlated with the expression of Tspan 1 (χ(2) = 6.688, P < 0.01; χ(2) = 13.055, P < 0.01; χ(2) = 6.116, P < 0.05) . TNM stage was positively correlated with the expression of Integrin α6 (χ(2) = 8.896, P < 0.05) . Tspan 1 was correlated with Integrin α6 (r = 0.223, P < 0.05) . The expressions of Tspan 1 and Integrin α6 were negatively correlated with survival time (χ(2) = 5.263, P < 0.05;χ(2) = 10.124, P < 0.01) . Multivariate analysis revealed that Tspan 1 and Integrin α6 expressions were independent prognostic factors in PDAC patients (χ(2) = 6.152, P < 0.05; χ(2) = 9.479, P < 0.01). Western blot (t = 2.278, P < 0.05; t = 3.153, P < 0.05) and qRT-PCR (t = 2.439, P < 0.05; t = 3.258, P < 0.05) showed that Tspan 1 and Integrin α6 expressions were higher in PDAC tissues than in adjacent non-cancerous pancreatic. Tspan 1 and Integrin α6 were expressed in all six pancreatic cancer cell lines.In SW1990 which derived from metastasis PDAC, Tspan 1 and Integrin α6 expressions were higher than the cell lines from primary tumor. CONCLUSION Tspan 1 and Integrin α6 expression can up-regulate the invasion and metastasis of PDAC and may be used to predict the prognosis of PDAC.

Expression and clinical significance of Tspan 1 and Integrin α6 in human pancreatic ductal adenocarcinoma

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Expression of vitamin D receptor as a potential prognostic factor and therapeutic target in pancreatic cancer

Co-expression of FOXL1 and PP2A inhibits proliferation inducing apoptosis in pancreatic cancer cells via promoting TRAIL and reducing phosphorylated MYC.

Expression and clinical significance of Tspan 1 and Integrin α6 in human pancreatic ductal adenocarcinoma