Vitamin D3 Inhibition of Hedgehog Signaling and Cancer Chemoprevention

描述（由申请人提供）：我们在这个项目中的目标是阐明最近描述的维生素D3对刺猬信号传导的抑制作用，作为癌症死亡率纬度变化的机制。这种变异在近70年前就已为人所知，三十年来，人们一直认为阳光产生的维生素D储存是这种机制联系的主要作用。尽管如此，增加维生素D储存和降低癌症相对风险之间的确切证据仍然难以捉摸。基底细胞癌（bcc）是研究这种联系的理想肿瘤，因为异常的刺猬信号对它们的发展和维持至关重要，有流行病学研究结果表明紫外线辐射不仅在它们的发生中起作用，而且在它们的抑制中也起作用，现在有强大的工具可用于研究它们。我们将结合实验室小鼠模型和人类样本来解决这个问题。具体来说，我们(i)将比较外用维生素D3和口服维生素D3对Cyp27B1可以有条件删除的Ptch1小鼠BCC癌变的影响。因此，基于我们的初步数据表明，局部D3抑制刺猬抑制实验性小鼠BCC致癌性（ii）将比较北方与南方对维生素D3抑制具有抗性的BCC的相对比例，预计暴露在更多阳光下的患者中维生素D3抗性BCC的比例将更高；（iii）将比较紫外线诱导的BCC受试者中维生素D3的产生与BCC患者的这种产生有皮肤鳞状细胞癌。总的来说，我们期望这些研究将提供数据，为开展局部维生素D3抗基底细胞癌化学预防功效的正式人体试验提供令人信服的案例，并将形成基础和模板，将这些研究扩展到皮肤外肿瘤，如结肠肿瘤，这些肿瘤的证据在纬度梯度和hedgehog信号的病理生理作用方面都很好。这项研究现在尤为重要，因为越来越多的人担心皮肤科医生坚持建议避免阳光照射以预防皮肤癌，这可能会增加皮肤外癌症的相对风险，也因为越来越多的人建议全体人口每天摄入维生素D，而口服维生素D补充剂将把明尼苏达州人的癌症风险转化为亚利桑那州人的癌症风险，这一希望尚未得到证实。因此，迫切需要进一步研究维生素D3与癌症风险的关系。

DESCRIPTION (provided by applicant): Our goal in this Project is the elucidation of the role of the recently described inhibition of hedghog signaling by vitamin D3 as a mechanism underlying latitudinal variation in cancer mortality. Such variation has been known for nearly 70 years, and a prime role for sunlight-produced vitamin D stores has been postulated to be the mechanistic connection for three decades. Nonetheless, definitive proof linking increased vitamin D stores and reduction in relative risk of cancer remains elusive. Basal cell carcinomas (BCCs) are an ideal tumor in which to study this connection since aberrant hedghog signaling is pivotal to their development and maintenance, there are epidemiologic findings consistent with a role of ultraviolet radiation not only in their genesis but also in their restraint, and formidable tools now are available for their study. We will integrate both laboratory mouse models and human samples to address this question. Specifically we (i) will compare the effects of topical vs. oral vitamin D3 on BCC carcinogenesis in Ptch1 mice in which Cyp27B1 can be conditionally deleted, thus building on our preliminary data indicating that hedghog inhibition by topical D3 inhibits experimental murine BCC carcinogensis (ii) will compare the relative proportions of BCCs that are resistant to vitamin D3 inhibtion in the North vs. in the South in expectation that the proportion of vitamin D3-resistant BCCs will be higher in patients exposed to more sunlight and (iii) will compare UV-induced vitamin D3 production in subjects who have had BCCs with such production in persons who have had skin squamous cell carcinomas. Overall we expect that these studies will provide data making a compelling case for the conducting of a formal human trial of the anti-basal cell carcinoma chemopreventive efficacy of topical vitamin D3 and will form the foundation and template for extending these studies into extra-cutaneous tumors such as those of the colon, for which evidence is good for both a latitudinal gradient and a pathophysiologic role for hedgehog signaling. This Study is particularly germane now because growing concern that Dermatologists' relentless recommendations for sun avoidance to prevent skin cancers may be increasing the relative risk of extracutaneous cancers and because of the gathering momentum to increase the recommended daily vitamin D intake for the enitire population in unproved hopes that oral vitamin D supplements will convert the cancer risk of Minnesotans to that of Arizonans. Thus there is urgent need for further investigation into the relation of vitamin D3 to cancer risk. PUBLIC HEALTH RELEVANCE: The current rush by many experts to recommend increasing doses of supplemental oral D3 for cancer chemoprevention for the population emphasizes the urgency of obtaining further data bearing on the likely efficacy, let alone safety, of such recommendations. We propose a focused series of mouse and human studies that will illuminate the mechanism of chemoprevention by vitamin D of the most common human cancer, basal cell carcinoma. Not only will this develop the information needed for an interventional trial of BCC chemoprevention but also of great importance, these studies will serve as a model to inform future studies of the influence of vitamin D on the risk of colon and other more deadly extracutaneous cancers.