Hedgehog signaling in tissue injury and carcinogenesis

描述（由申请人提供）：Hedgehog （Hh）信号在正常胚胎模式中起指导作用，但胚胎后组织中的病理通路活性与肿瘤类型的生长有关，这些肿瘤类型约占癌症死亡的25%。Hh信号通路及其姊妹通路Wnt通路的正常胚胎后激活作用已被证明在组织干细胞的更新和维持中起作用。这些发现与癌症具有潜在的相关性，因为癌症干细胞（癌症中能够增殖的少数细胞）可能来源于成体组织干细胞。通路活性和祖细胞池的扩增也与对急性损伤的反应有关，而慢性组织损伤进一步导致与Hh和Wnt通路活性相关的癌症类型的风险增加。因此，肿瘤生长类似于急性损伤修复的激活状态，并且随着重复损伤的发生，肿瘤生长的发生率增加。这些观察结果表明，本提案的中心假设和几个推论有待验证，即，癌症生长代表了组织修复的不受管制状态的持续运行，癌变过程中Hh通路的持续活性偏离了通常在再生后恢复到静止状态，组织干细胞是相关的细胞类型。这一假设将在Hh通路依赖性癌症的背景下得到验证，方法是鉴定和分离癌症干细胞，将这些癌症干细胞相互比较，将它们与内源性组织干细胞或祖细胞进行比较，并检查Hh通路激活在组织修复和肿瘤发生中的作用和机制。具体目标是：1。鉴定和分离依赖Hedgehog途径活性生长的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。2. 从相应的静息或损伤的内胚层器官中鉴定和分离候选干细胞。3. 比较来自这些内胚层器官的肿瘤干细胞和组织干细胞的特性。4. 探讨正常组织损伤诱导Hh蛋白信号反应的分子基础和肿瘤中持续反应的分子基础。这些研究将为设计和优化在癌症治疗和组织再生中操纵通路活性的策略提供基础基础。对Hh反应性调节的机制基础的理解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.