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.
Tissue microvascular changes can be critical for the formation of a tumor hotspot, which serves as a tissue microenvironment for tumor development in non-melanoma skin cancer. Using our newly developed microvascular imaging method, we will study the precancerous hotspot formation in an animal model of ultraviolet induced non-melanoma skin cancer. Given that prolonged ultraviolet irradiation from sun exposure is the biggest contributing factor to non-melanoma skin cancer, our biophotometric mapping of the hotspot can be useful for identifying high-risk individuals for non-melanoma skin cancer and for accurately predicting chemopreventive treatment responses.
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