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抑制Hedghog信号作为癌症死亡率纬度差异的机制的作用。近70年来，这种变异已为人所知，而30年来，阳光生产的维生素D商店的主要作用一直被认为是机械联系。尽管如此，增加维生素D储备和降低相对癌症风险之间的联系仍然缺乏确凿的证据。基底细胞癌(BCC)是研究这种联系的理想肿瘤。由于Hedghog信号的异常对于BCC的发生和维持至关重要，有流行病学研究结果表明紫外线不仅在BCC的发生中起作用，而且在BCC的抑制中起作用，现在有强大的工具可用于BCC的研究。我们将整合实验室小鼠模型和人类样本来解决这个问题。具体地说，我们(I)将比较局部和口服维生素D3对ptch1小鼠BCC癌变的影响，其中Cyp27B1可以有条件地删除，从而基于我们的初步数据，即局部D3抑制Hedghog抑制可抑制实验性小鼠BCC癌变；(Ii)我们将比较北方和南方抵抗维生素D3抑制的BCC的相对比例，以期在暴露于更多阳光的患者中，耐受维生素D3的BCC的比例将更高；(Iii)将患有BCC的受试者在紫外线诱导下产生的维生素D3与患有皮肤鳞状细胞癌的人的这种产生进行比较。总体而言，我们预计这些研究将提供令人信服的数据，为开展局部应用维生素D3的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证据，并将形成将这些研究扩展到皮外肿瘤(如结肠肿瘤)的基础和模板，对于这些肿瘤来说，证据既有利于纬度梯度，也有利于刺猬信号的病理生理作用。这项研究现在特别贴切，因为越来越多的人担心皮肤科医生关于避免阳光照射以预防皮肤癌的无情建议可能会增加皮肤外癌症的相对风险，而且由于越来越多的人开始增加儿童每日推荐的维生素D摄入量，未经证实的希望是，口服维生素D补充剂可以将明尼苏达州人的癌症风险转化为亚利桑那州人的风险。因此，迫切需要进一步研究维生素D3与癌症风险的关系。 与公共卫生相关：目前许多专家急于建议为人群提供更多剂量的补充口服D3，以用于癌症的化学预防，这突显了获得与此类建议的可能有效性有关的进一步数据的紧迫性，更不用说安全性了。我们提出了一系列有针对性的小鼠和人类研究，将阐明维生素D对人类最常见的癌症--基底细胞癌--的化学预防机制。这不仅将开发BCC化学预防的干预性试验所需的信息，而且非常重要，这些研究将成为未来研究维生素D对结肠癌和其他更致命的皮外癌症风险影响的模型。

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.