Hotspot imaging for risk stratification of non-melanoma skin cancer in a pilot st

描述（由申请人提供）： 有新的证据表明，间质微血管的改变可能发生在早期，甚至在癌前阶段的肿瘤过程中不可或缺的参与者。沿着肿瘤细胞不能单独生长的观点，间质微血管改变可能与癌前阶段的致癌作用区（即肿瘤“热点”）的形成密切相关。然而，癌前癌细胞和间质微血管的共同进化是如何发生的尚不清楚，部分原因是在相对较大的区域内详细的致癌性改变在体内不易检测到。目前研究这一概念的关键限制是显微成像和全身小动物成像（即宏观成像）之间的差距。为了克服差距，我们最近开发了一种简单，但有效的成像系统，其中周围的无血管组织可以作为一个相对透明的光学窗口。在我们提出的研究中，我们将建立我们的光谱微血管成像方法，用于实验性非黑色素瘤皮肤癌（NMSC）中“癌前热点”的非侵入性检测。我们假设，在我们的实验性光致癌作用中，关于“癌前热点”的空间和时间改变的信息可以用来准确地预测肿瘤的发生。特别是，我们将确定“热点”是必要的和/或足以发展乳头状瘤和癌。为了验证我们的假设，我们将使用紫外线（UV）B光诱导的NMSC致癌作用的小鼠模型，因为它已被用于测试细胞和分子癌症生物学领域中的几乎所有假设，由于与人类皮肤致癌作用的强烈相似性。此外，长期暴露于阳光下的紫外线照射是迄今为止人类皮肤恶性肿瘤的最大贡献因素。我们提出以下目标：i）确定不仅与肿瘤发生而且与恶性转化（即“恶变前热点”）密切相关的基质微血管的确切时空范围，和ii）检查“恶变前热点”可用于评估对使用非甾体抗炎药的化学预防策略的反应的可行性。我们的“热点”的生物光度映射将潜在地打开新的可能性，以阐明肿瘤发展的潜在责任机制，并显着促进其在各种肿瘤学应用中对NMSC的影响，如风险分层，早期癌症检测，化学预防和肿瘤进展的监测。例如，我们的成像方法将允许一个大的可疑区域的详细可视化，以执行明确的组织病理学变化之前的癌前病变的位点特异性分析，而不依赖于组织制备，繁琐的化验，和外在的对比。我们的生物光度方法将有望识别高危个体，这些个体将从化学预防治疗中受益，并在化学预防治疗过程的早期准确预测治疗反应。

DESCRIPTION (provided by applicant): There is emerging evidence that stromal microvascular alterations may occur early even at premalignant stages of carcinogenesis as indispensable participants in neoplastic processes. Along with the notion that tumor cells cannot grow alone, stromal microvascular alterations may be strongly associated with the formation of a carcinogenesis field (i.e. tumor "hotspot") at a premalignant stage. However, how the coevolution of the premalignant cancer cells and the stromal microvascularity occurs is unclear, in part, because detailed carcinogenic alterations in a relative large area are not easily detected in vivo. A current critical limitation for studying this concept is the gap between microscopic imaging and whole-body small animal imaging (i.e. macroscopic imaging). To overcome the gap, we have recently developed a simple, but effective, imaging system, in which the surrounding avascular tissue can serve as a relatively transparent optical window. In our proposed studies, we will establish our spectroscopic microvascular imaging method for noninvasive detection of the "premalignant hotspot" in experimental non-melanoma skin cancer (NMSC). We hypothesize that information about the spatial and temporal alterations of the "premalignant hotspot" can be used to accurately forecast the occurrence of neoplasia in our experimental photocarcinogenesis. In particular, we will identify the "hotspot" that is necessary and/or sufficient to develop papillomas and carcinomas. To test our hypothesis, we will use a murine model of ultraviolet (UV) B light induced carcinogenesis for NMSC, since it has been used to test almost all hypotheses in the fields of cellular and molecular cancer biology due to strong similarities with human skin carcinogenesis. Moreover, prolonged UV irradiation from sun exposure is by far the biggest contributing factor to human cutaneous malignancy. We propose the following aims: i) To determine the exact spatiotemporal extent of stromal microvascularity that is strongly associated not only with tumorigenesis but also with malignant conversion (i.e. "premalignant hotspot") and ii) To examine the feasibility that the "premalignant hotspot" can be used to assess response to a chemoprevention strategy using a non-steroidal anti-inflammatory drug. Our biophotometric mapping of the "hotspot" will potentially open new possibilities to elucidate underlying responsible mechanisms of tumor development and to dramatically facilitate its implications for NMSC in a variety of oncological applications, such as risk stratification, early cancer detection, chemoprevention, and monitoring of tumor progression. For example, our imaging method will allow detailed visualization of a large suspected area to perform site-specific analyses of premalignant changes prior to overt histopathological changes, without reliance on tissue preparation, cumbersome assays, and extrinsic contrasts. Our biophotometric approach will hold promise for identifying high-risk individuals who will benefit from chemopreventive therapy and for accurately predicting treatment responses early in the course of chemoprevention therapy.