我們研究的最終目標是闡明腫瘤發生中的起始機制，期能確定早期癌症預防的策略。據 估計，組織內氧擴散不超過75-150 μm。因此，直徑約20 個細胞的小腫瘤塊即會感受缺 氧，而腫瘤缺氧應是腫瘤進展中的早期事件。近年來發炎也已被認為是促進癌症進展的 重要因素。因此這兩個機制應可以代表最早期的腫瘤與微環境的相互作用，也因此可以 用來作癌症預防的標靶。但目前並不清楚這兩個事件是如何相互依存。我們假設原始腫 瘤細胞的缺氧反應會導致代謝異常，這會引發內質網壓力和誘導在微環境中產生發炎反 應。我們將解決一個主要問題： 上皮細胞如何以缺氧反應誘導發炎反應 。最後，我們 將測試可以阻止這些早期事件和預防癌症形成的治療法。我們已經開發了重現缺氧反應 的細胞系統和動物模式。這些實驗系統利用VHL 基因的突變，其通過缺氧誘導因子 （HIF）的上調導致缺氧反應。由於這種病理狀態存在於人的腎細胞癌（一主要類型的 腎癌）中，我們將用臨床腎癌樣品作驗證和分析腫瘤相關免疫細胞。我們提出了三個研 究目標： 1：闡明導致全身炎症反應的上皮細胞內在機制。 2：闡明癌前腎細胞如何引進發炎細 胞。3：測試預防從發炎進展到癌症的治療劑。 ;Study of crosstalk between hypoxic tumor cells and inflammatory microenvironment The ultimate goal of our study is to elucidate the earliest event in tumorigenesis so as to identify strategy for early cancer prevention. It has been estimated that oxygen diffusion does not reach beyond 75-150 μm. Therefore, a small tumor mass of ~20 cells in diameter would begin to experience hypoxia. In other words, tumor hypoxia should be an early event in tumor progression. On the other hand, inflammation has also in recent years been recognized as an important factor in promoting cancer progression. We believe these two events could represent the earliest tumor-microenvironment interaction that can be modulated for cancer prevention. However, it is not clear how these two events may be interdependent. This study aims to address this question. Since tumor microenvironment is a highly complex tissue, we will focus our study on the inflammation, as inflammatory immune cells are the least understood among the stromal components. We hypothesize that hypoxic response in primordial tumor cells leads to metabolic abnormalities, which cause ER stress and induce inflammatory response in the microenvironment. In this study we will address one main questions: how hypoxic response in an epithelial cells induce systemic inflammatory response. Finally we will begin to test therapeutics that can block these early events and prevent cancer formation. We have developed a cellular system and an animal model that recapitulate hypoxic response. These experimental systems utilize the mutation in the VHL gene, which results in the hypoxic response via up-regulation of the hypoxia-inducible factor (HIF). Since such pathological condition is present in the human renal cell carcinoma (a major type of kidney cancer), we will also obtain clinical kidney cancer samples for verification and for analyzing tumor-associated immune cells. Three objectives are proposed: Objective 1: To elucidate the epithelial cell-intrinsic mechanism that leads to inflammatory response. We will analyze the metabolic imbalance and the ER stress in hypoxic cells, and how such abnormalities lead to inflammatory program. Objective 2: To elucidate how precancerous kidney cells recruit inflammatory cells. We will examine how hypoxic cells attract immune cells such as macrophages and neutrophils, and how these cells affect the the characteristics of the primordial tumor cells. Objective 3: To test therapeutics that prevent the progression from inflammation to cancer. Based on the analysis above, we will test therapeutics that intervene in these processes with the goal of cancer prevention.
