Hedgehog signaling in tissue injury and carcinogenesis

描述（由申请人提供）：Hedgehog（Hh）信号传导在正常胚胎模式中起指导作用，但胚胎后组织中的病理途径活性与肿瘤类型的生长相关，这些肿瘤类型共同导致约25%的癌症死亡。Hh信号通路及其姐妹Wnt通路的激活在组织干细胞的更新和维持中具有正常的胚胎后作用。这些发现与癌症具有潜在的相关性，因为癌症干细胞（癌症中能够繁殖的少数细胞）可能来自成体组织干细胞。通路活性和祖细胞池的扩增也与对急性损伤的反应相关，并且慢性组织损伤还导致与Hh和Wnt通路活性相关的类型的癌症的风险增加。因此，癌症生长类似于急性损伤修复的激活状态，并且癌症生长的发生率随着重复损伤的发生而增加。这些观察结果表明，中心假设和几个推论，在这个建议中进行测试，即，癌症的生长代表了组织修复的不受调节的状态的连续操作，连续的Hh通路活动在致癌作用是一个偏离的返回到静止，通常遵循再生，和组织干细胞是相关的细胞类型。该假设将在Hh通路依赖性癌症的背景下通过鉴定和分离癌症干细胞、通过将这些癌症干细胞彼此比较以及与内源性组织干细胞或祖细胞比较、以及通过检查Hh通路激活在组织修复和肿瘤发生中的作用和机制来进行测试。具体目标是：1.鉴定和分离来源于内胚层肿瘤的已建立细胞系或原代细胞培养物中的癌症干细胞，这些细胞依赖Hedgehog途径活性生长。2.从相应的静止或损伤的内胚层器官中鉴定和分离候选干细胞。3.比较肿瘤干细胞和组织干细胞的特性。4.探讨正常组织中损伤诱导的Hh蛋白信号应答的分子基础和肿瘤中持续应答的基础。这些研究将为设计和优化策略以操纵癌症治疗和组织再生中的通路活性提供基本基础。了解调节Hh反应性的机制基础也有可能促进癌症预防的长期战略。

DESCRIPTION (provided by applicant): Hedgehog (Hh) signaling plays instructive roles in normal embryonic patterning, but pathological pathway activity in post-embryonic tissues is associated with the growth of tumor types that together account for approximately 25% of cancer deaths. Normal post-embryonic roles for activation of the Hh signaling pathway and its sister, the Wnt pathway, have been demonstrated in renewal and maintenance of tissue stem cells. These findings are of potential relevance to cancer because of the possible derivation of cancer stem cells, the minority of cells within a cancer that are capable of its propagation, from adult tissue stem cells. Pathway activity and expansion of progenitor cell pools also are associated with the response to acute injury, and chronic tissue injury furthermore results in increased risk for cancers of the types associated with Hh and Wnt pathway activity. Cancer growth thus resembles the activated state of acute injury repair, and the incidence of cancerous growth increases with the occurrence of repeated injury. These observations suggest the central hypothesis and several corollaries to be tested in this proposal, namely, that cancer growth represents the continuous operation of an unregulated state of tissue repair that continuous Hh pathway activity in carcinogenesis is a deviation from the return to quiescence that normally follows regeneration, and that tissue stem cells are the relevant cell types. This hypothesis will be tested in the context of Hh pathway-dependent cancers by identifying and isolating cancer stem cells, by comparing these cancer stem cells to each other and to endogenous tissue stem or progenitor cells, and by examining the role and mechanism of Hh pathway activation in tissue repair and in tumorigenesis. The specific aims are: 1. To identify and isolate cancer stem cells within established cell lines or primary cell cultures derived from endodermal tumors that depend upon Hedgehog pathway activity for growth. 2. To identify and isolate candidate stem cells from corresponding resting or injured endodermal organs. 3. To compare the characteristics of cancer stem cells and tissue stem cells from these endodermal organs. 4. To investigate the molecular basis of injury-induced responsiveness to Hh protein signals in normal tissues and the basis of continuous response in tumors. These studies will provide a fundamental basis for design and optimization of strategies to manipulate pathway activity in cancer therapy and in tissue regeneration. An understanding of the mechanistic basis for regulation of Hh responsiveness also has the potential to foster long-term strategies for cancer prevention.