Influences of the Microenvironment on Cancer Stem Cells

描述（由申请人提供）：前列腺癌（CaP）是美国男性癌症相关死亡的第二大原因。化疗雄激素合成抑制剂治疗晚期疾病的最新进展已经开始改善结果；然而，许多挑战依然存在。CaP的病因尚不清楚。目前尚不清楚为什么前列腺如此容易发生肿瘤，以及为什么它的形成与慢性感染有关。表观遗传改变在CaP发育中的作用仍然不明确。为什么恶性癌症的发展没有明显的染色体水平改变的迹象？最后，肿瘤是如何对最新形式的化疗和雄激素抑制产生抗药性的？这个“肿瘤微环境的合作研究”UOl应用程序是建立在博士之间的长期合作。Wu和Witte，以及最近涉及Nelson实验室的研究，以及加州大学洛杉矶分校CaP挑战奖之间的协同作用，题为“确定CaP干细胞中的靶点和生物标志物：新的治疗机会”（2008-2011）和弗雷德·哈金森癌症研究中心/华盛顿大学TMEN U54项目，“微环境对CaP启动和进展的意义”（2007-2012）。在这些努力的基础上，我们现在将共同解决涉及“微环境对癌症干细胞的影响”的关键问题。具体来说，我们关注肿瘤微环境在控制正常前列腺干细胞增殖和转化中的作用，以及肿瘤微环境在导致CaP干细胞对当前治疗产生耐药性中的作用。Aim 1研究的第一个问题对癌症有重要意义

DESCRIPTION (provided by applicant): Prostate cancer (CaP) is the second leading cause of cancer-related death in American men. Recent advances in the management of advanced disease with chemotherapy androgen synthesis inhibitors have begun to improve outcomes; however, many challenges remain. The etiology of CaP remains unknown. It is not clear why the prostate is so susceptible to oncogenesis and why its formation is associated with chronic infection. The contribution of epigenetic alteration in CaP development also remains poorly defined. Why do malignant cancers develop without clear signs of chromosomal level changes? Finally, how do tumors become resistant to the newest forms of chemotherapy and androgen inhibition? This "Collaborative Research in Tumor Microenvironment" UOl application is built upon the long term collaboration between Drs. Wu and Witte, and more recent studies involving the Nelson laboratory, and the synergies between the UCLA CaP Challenge Award, entitled "Defining targets and biomarkers in CaP stem cells: New therapeutic opportunities" (2008-2011) and Fred Hutchinson Cancer Research Center/University of Washington TMEN U54 program, "Significance of microenvironment for CaP initiation and progression (2007-2012). Building upon these efforts, we will now jointly address the critical questions involving "Influences of microenvironment on cancer stem cells". Specifically, we focus on the role of the tumor microenvironment in controlling proliferation and transformation of normal prostate stem cells and on the role of the tumor microenvironment in causing CaP stem cells to develop resistance to current therapies. The first question, studied in Aim 1, has significant implications for cancer prevention, since strategies to reduce inflammation and infection could inhibit entry of normal stem cells into the cell cycle. This Aim will also shed light on the mechanisms through which immune tolerance is established and how to sensitize CaPs to immune therapies. The second question, studied in Aim 2, has implications for expanding our understanding of the" landscape" of cancer stem cells and shifts our therapeutic strategy from cancer cell and gene-based target to pathway oriented approaches. Our Specific Aim 3 is designed to address the final question how cancer therapies can change the "benign cellular constituents" associated with neoplastic cells and causes CSC expansion and tumor repopulation. PUBLIC HEALTH RELEVANCE: Despite its enormous impact on male health, the molecular mechanisms underlying the pathogenesis of prostate cancer remain unsolved. A central focus of this application is to investigate whether cells, molecule and regulatory pathways surrounding the prostate stem cells can alter stem cell properties and contribute to prostate cancer development and resistance to therapies. This will help in understanding the origin of the disease and provide rationales for novel, stem cell-targeted treatment.