Influences of the Microenvironment on Cancer Stem Cells

描述(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。用雄激素合成抑制剂化疗治疗晚期疾病的最新进展已经开始改善结果；然而，仍然存在许多挑战。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。表观遗传改变在帽子发育中的作用也仍然不清楚。为什么恶性肿瘤的发展没有明显的染色体水平变化的迹象？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？这一“肿瘤微环境中的合作研究”UOL应用建立在Wu博士和Witte博士的长期合作以及涉及Nelson实验室的更多近期研究的基础上，以及加州大学洛杉矶分校CAP挑战奖“定义CAP干细胞中的靶点和生物标记物：新的治疗机会”(2008-2011年)和弗雷德·哈钦森癌症研究中心/华盛顿大学TMAN U54计划“微环境对CAP启动和进展的重要性(2007-2012年)”之间的协同作用。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。具体地说，我们着重于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抵抗力方面的作用。在《目标1》中研究的第一个问题对癌症有重大影响。 预防，因为减少炎症和感染的策略可能会阻止正常干细胞进入细胞周期。这一目标还将阐明建立免疫耐受的机制，以及如何使CAP对免疫疗法敏感。第二个问题是在目标2中研究的，它有助于扩大我们对癌症干细胞“图景”的理解，并将我们的治疗策略从癌细胞和基于基因的靶点转变为面向途径的方法。我们的具体目标3旨在解决最后一个问题，即癌症治疗如何改变与肿瘤细胞相关的“良性细胞成分”，并导致CSC扩张和肿瘤再生长。 公共卫生相关性：尽管前列腺癌对男性健康有巨大影响，但前列腺癌发病的分子机制仍未解决。这一应用的一个中心焦点是研究前列腺干细胞周围的细胞、分子和调控通路是否可以改变干细胞的特性，并有助于前列腺癌的发展和对治疗的抵抗。这将有助于了解疾病的起源，并为新的干细胞靶向治疗提供理论依据。

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.