Vitamin D activity and colorectal neoplasia: a pathway approach to epidemiologic studies.

The relationship of vitamin D with colorectal and other cancers is a rapidly expanding field of study. The pathway through which vitamin D exerts transcriptional effects is complex and involves the action of other nutrients. Recent epidemiologic work underscores the importance of considering the joint effects of calcium and vitamin D in studies of colorectal neoplasia (1, 2). A key feature of vitamin D is its role in maintaining calcium homeostasis, which further highlights the interrelationship of these nutrients. However, the action of a vitamin A derivative, 9-cis retinoic acid and its receptor, the retinoid X receptor (RXR), has seldom been investigated in epidemiologic studies of vitamin D, despite the importance of RXR to the transcriptional activity of the vitamin D receptor (VDR; ref. 3). The intricate biological relationship among these nutrients makes it difficult to assess their individual roles in the development of colorectal neoplasia. In this commentary, we present a pathway that outlines the independent and interactive effects of nutrients that impact vitamin D activity in the colorectum. Although the pathway that we present is relatively simplified, our purpose is to highlight the various genenutrient relationships that should be considered when conducting studies of vitamin D and colorectal cancer. In this context, we specifically emphasize the actions of 9-cis retinoic acid and RXR, two neglected factors in this pathway. Based on these actions, we recommend that future epidemiologic investigations consider the interrelationships of these nutrients and associated genetic polymorphisms, in addition to studying the effects of each individually. As a brief introduction to the epidemiologic data for the action of vitamin D and related nutrients, there is epidemiologic support for a protective effect of vitamin D on risk of colorectal neoplasia (2, 4); however, the data are equivocal (5). For calcium, there are a wealth of prospective and clinical data indicating that this nutrient is associated with a lower risk of colorectal neoplasia (5-7). In a clinical trial conducted by Baron et al. (6), subjects assigned to daily supplementation with calcium carbonate had a significantly reduced risk of adenoma recurrence compared with the placebo group. Further analyses of this clinical trial revealed that higher serum 25-dihydroxy-vitamin D levels were inversely associated with adenoma recurrence among participants in the calcium-supplemented group and not for those in the placebo group (1); this finding lends further support to the importance of the intricate biological relationship of these two nutrients to colorectal neoplasia (8). Although the role of calcium and vitamin D in colorectal carcinogenesis has been intensively investigated, the activity of 9-cis retinoic acid and RXR have not; this is in spite of the fact that RXR has been established as a component of vitamin D transcriptional activity. Nonetheless, putative protective mechanisms of action for 9-cis retinoic acid, calcium and vitamin D, and colorectal neoplasia have been proposed, as summarized in Fig. 1 and described below. Various chemopreventive properties have been suggested for calcium and include the binding of bile acids (9, 10), decreased fecal water cytotoxicity (11), inhibition of cellular proliferation (12, 13), induction of apoptosis (14), promotion of the tumor suppressor gene, E-cadherin (15), and inhibition of b-catenin (15), a proto-oncogene that has been implicated in several stages of colorectal carcinogenesis (16). For vitamin D and its analogues, the proposed mechanisms include antiproliferative effects (17), increased expression of the cyclindependent kinase inhibitor proteins, p27 (18, 19) and p21 (18, 20), promotion of colorectal carcinoma cell differentiation by induction of E-cadherin (21), and inhibition of b-catenin (16, 21). Furthermore, analogues of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] act as inducers of apoptosis, and have shown the ability to inhibit the expression of bcl-2, a suppressor of apoptosis, in HL-60 cells (22). Investigations of the effects of 9-cis retinoic acid in the colon have been relatively sparse. Until recently, the role of RXR as an important regulatory component has been largely overshadowed by the potent effects of its heterodimer partners, including the peroxisome proliferator–activated receptor-c (23) and VDR (24). Nonetheless, 9-cis retinoic acid has been shown to inhibit growth of breast and bladder cancer cell lines (25, 26). In colon cancer cell lines, 9-cis retinoic acid has been shown to modify the antiproliferative response of 1,25-(OH)2D3, exhibiting an increased antiproliferative response in Caco-2 cells but blocking it in HT-29 cells (17). The reasons for these differential responses are unclear, but the data support a role for 9-cis retinoic as an important modulator of vitamin D activity. In addition to the pathways that describe the downstream biological activities induced by vitamin D, calcium, and 9-cis retinoic acid, the activity of related receptors and binding proteins for these nutrients must also be considered (Fig. 1). The calcium-sensing receptor is necessary for the detection and maintenance of extracellular calcium levels by influencing parathyroid hormone secretion and calcium reabsorption (27). Calcium-sensing receptors may regulate the amount of calcium available to intestinal cells, and variation in the amount or activity of calcium-sensing receptors may have implications for colorectal carcinogenesis. Indeed, polymorphisms of this gene have been associated with risk of advanced stage rectal cancer (28). The vitamin D-binding protein is important for the transport of the two major forms of circulating vitamin D, 25-(OH)D and 2061