Vitamin D deficiency is strongly associated with the risk of developing
colorectal cancer (CRC). Because of the propensity of bioactive
1,25-dihydroxyvitamin D3 to cause toxic
hypercalcemia, considerable effort has been directed to identifying safer drugs while retaining the efficacy of the parent compound. However,
vitamin D precursors do not present toxicity concerns and may be sufficient for CRC
chemoprevention or
chemotherapy, providing the appropriate
enzymes are present in colonic epithelia. We previously showed that
CYP27B1 is present at equally high levels in the colon and CRC irrespective of differentiation but was not present in
metastases. In this study we used quantitative immunohistochemistry to show that CYP27A1, converting D3 to
25-hydroxycholecalciferol, is present in increasing concentrations in the nuclei of normal colonic epithelia,
aberrant crypt foci (ACF), and
adenomatous polyps. Whereas total cellular CYP27A1 remains high in CRC and
lymph node metastases, the amount of
enzyme present in the nuclei decreases with
tumor cell dedifferentiation while rising in the cytoplasm. Similarly, increasing amounts of the deactivating
enzyme CYP24 are present in the nuclei of normal colonic epithelia, ACFs, and
adenomatous polyps. Although the amount of total CYP24 decreases slightly in CRC as a function of
tumor cell dedifferentiation and
metastasis, location of this
enzyme shifts almost entirely from the nuclear compartment to the cytoplasmic compartment. These data indicate that non-toxic
vitamin D precursors should be sufficient for CRC
chemoprevention, but that neither
vitamin D nor its precursors may be sufficient for CRC
chemotherapy.