Vitamin D Enhances Survival in Advanced Pancreatic Cancer

Vitamin D Background:

Biologically active vitamin D is a member of the steroid and thyroid hormone superfamily of hormones. Vitamin D functions to regulate specific gene expression following interaction with its intracellular receptor, the vitamin D receptor (VDR).

The hormonally active form of vitamin D is 1,25-dihydroxy vitamin D3 (1,25-(OH)2D3, also called 1,25-dihydroxycholecalciferol or more commonly calcitriol). Calcitriol functions primarily to regulate calcium and phosphorous homeostasis.

Active calcitriol is derived from ergosterol (produced in plants) and from 7-dehydrocholesterol which is an intermediate in the synthesis of cholesterol that accumulates in the skin. Upon exposure to ultraviolet B wavelength light (UVB: 280nm–315nm) from the sun (or from UVA wavelength light from tanning beds), 7-dehydrocholesterol is converted first to pre-vitamin D3 and then to vitamin D3. Ergocalciferol (vitamin D2) is formed by UVB irradiation of ergosterol. Both vitamin D2 and D3 enter the bloodstream and are taken up by the liver. Within the liver vitamins D2 and D3 undergo the first of two activating hydroxylation reactions. Vitamin D2 and D3, obtained from the diet (e.g. from fortified milk), are processed to D2-calcitriol and D3-calcitriol, respectively, by the same enzymatic pathways in the body as those that convert 7-dehydrocholesterol and ergosterol to their respective calcitriol forms.

In the liver cholecalciferols are hydroxylated at the 25 position by a specific vitamin D 25-hydroxylase generating 25-hydroxy-D3 [25-(OH)D3: more commonly called calcidiol]. Conversion of cholecalciferols to calcidiol is dependent solely upon substrate availability as there is no regulatory mechanism to control the formation of calcidiol. Calcidiol is the major form of vitamin D found in the circulation.

Conversion of calcidiol to its biologically active form, calcitriol, occurs through the activity of a specific 25-hydroxyvitamin D3 1-α-hydroxylase (commonly just called 1-α-hydroxylase) present in the inner mitochondrial membrane of cells of the proximal convoluted tubules of the kidneys, and in several extrarenal sites such as in keratinocytes, macrophages, and placenta.

All of the regulation in the formation of biologically active vitamin D occurs at the reaction catalyzing the synthesis of calcitriol from calcidiol.

The primary functions of calcitriol are exerted in concert with parathyroid hormone (PTH) and involve the regulation whole body calcium and phosphorous homeostasis. PTH is released from the parathyroid gland in response to low serum calcium and induces the production of calcitriol by activating the expression of the renal gene that encodes the 1-α-hydroxylase.

When taken up by cells, calcitriol functions as a steroid hormone inducing the expression of calcium-binding proteins called calbindins that facilitate calcium transport within cells.

Calcidiol and Cancer:

The role of vitamin D in cancer, particular in pancreatic cancer, has been suggested by studies showing the therapeutic potential of vitamin D analogs, acting via the VDR, in tumor cells and supportive cells within the tumor. Of note is the observation of an inverse association between serum calcidiol concentration and risk for cancer. Some clinical studies have shown that there is longer overall survival in patients with pancreatic cancer and sufficient calcidiol levels in the blood.

A recent review, published in the journal, Nutrition Research, demonstrates that there is indeed a positive correlation between calcidiol levels and overall survival rates in patients with advanced pancreatic cancer as evidenced by the results of several retrospective and prospective cohort studies:

25-hydroxyvitamin D concentration is positively associated with overall survival in advanced pancreatic cancer: A systematic review and meta-analysis

All of the studies evaluated in this report involved patients that were 18 years of age or older and were shown, by histological or cytological methods, to be have locally advanced pancreatic cancer with extra-pancreatic extension, thus rendering it nonresectable. All patients were without distant metastases, as well as distant metastatic disease. Additionally, the studies included in this review needed to provide information regarding serum calcidiol levels.

TAKE HOME: The findings from the analysis of several studies clearly demonstrated a positive relationship between the level of calcidiol and the overall survival of patients with advanced pancreatic cancer.