Serum levels of vitamin D metabolites and the subsequent risk of colon and rectal cancer in Finnish men

Joseph Tangrea, Kathy Helzlsouer, Pirjo Pietinen, Philip Taylor, Bruce Hollis, Jarmo Virtamo, and Demetrius Albanes

Large bowel cancer is a major public health problem in western industrialized countries. In the United States, it is the second leading cause of cancer mortality. In 1994, 149,000 new cases of colorectal cancer were diagnosed and 59,000 people died from the disease in the US.1 Over a lifetime, approximately one in 15 people will develop colorectal cancer. Within Finland, it is one of the most common cancers and its incidence has been on the rise since the 1950s. Wide international differences in incidence rates and rapid changes in the prevalence of colorectal cancer among migrants to those of their host country point to strong environmental influences in its etiology.

Epidemiologic evidence suggesting a role for vitamin D in large bowel cancer has been available since the early 1980s. Results from ecologic studies support an inverse relation between level of solar radiation and colorectal cancer mortality and incidence. Since the major source of vitamin D is through sunlight-induced photobiosyn- thesis in the skin, it was hypothesized that the protective effects observed may be mediated by vitamin D levels. In addition, two large prospective cohort studies found an inverse association between vitamin D intake from diet and/or supplements and large bowel cancer risk. Of two nested case-control studies conducted within the same cohort examining the relation between prediagnostic serum levels of vitamin D metabolites and colon cancer risk, only one reported an inverse association. Epidemiologic studies supporting the association between vitamin D and colorectal cancer have been reviewed.

Since its discovery as a ‘nutrient’ over 80 years ago, research on vitamin D has been extensive and evolving. It was first identified as an essential factor in maintaining calcium homeostasis. Observations that the hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25-DIOH D), could both induce the differentiation of mouse myeloid leukemia cells into macrophages and inhibit the growth of a cultured melanoma cell line, along with the discovery of the vitamin D receptor in malignant tissues and several cancer cell lines (osteosarcoma, breast, lung, ovary, colon), stimulated interest in vitamin D’s role in carcinogenesis. Since the 1980s, there have been a number of experimental studies examining the effect of vitamin D and several of its synthetic analogs in both reducing the growth of implanted tumor xenografts and inhibiting the formation of chemical carcinogen-induced tumors of the skin, mammary gland and colon. Indeed, a number of in vitro and experimental studies provide direct evidence that vitamin D plays a role in large bowel carcinogenesis.

The major source of vitamin D (up to 80 percent) in humans is derived from cutaneous synthesis initiated by exposure to the ultraviolet B range of sunlight. Vitamin D is transported in blood predominantly bound to a specific α-globulin, vitamin D binding protein (DBP). Once transported to the liver, it is hydroxylated to its principal circulating form, 25-hydroxyvitamin D (25-OH D), which has an in vivo serum half-life of approximately three weeks. Since this reaction is not regulated homeo- statically, 25-OH D is not retained in the cells but is released to the circulation where it accumulates by bind- ing to DBP. At normal serum concentrations, only small amounts of 25-OH D are released from this pool to enter tissues. Therefore, serum levels of 25-OH D best reflect the overall vitamin D status of an individual. Due to the effect of cutaneous photobiosynthesis, there is substantial seasonal variation in serum levels of 25-OH D, with the highest levels found in late summer and early autumn. The active, hormonal form of the vitamin, 1,25-DIOH D, is formed by hydroxylation of 25-OH D in the kidney which is tightly regulated through a complex process to maintain adequate levels of extracellular cal- cium. Unlike 25-OH D, 1,25-DIOH D is distributed largely intracellularly, where it is present exclusively in the nucleus and cytoplasm bound to a specific protein. As such, levels of 1,25-DIOH D in the circulation are orders of magnitude less than serum 25-OH D. The in vivo serum half-life of 1,25-DIOH D is about four to six hours.

Given the abundant in vitro and experimental evidence of a role for the hormonal form of vitamin D in both normal and malignant cell proliferation and differentia- tion and the modest epidemiologic data suggesting a possible protective association between vitamin D status and large bowel cancer risk, we set out to examine this putative association among a cohort of male smokers who participated in a large clinical trial in southwestern Finland.