HEDGEHOG SIGNALING IN RESPONSE TO TISSUE INJURY AND IN NEOPLASIA

Hhedgehog(HH)信号在正常胚胎模式中起指导作用，但在病理途径中 胚胎后组织中的活动与肿瘤类型的生长有关，这些肿瘤类型共同解释了 大约25%的癌症死亡。正常胚胎后在激活HH信号中的作用 Wnt通路及其姊妹通路在组织干细胞的更新和维持中已被证明 细胞。这些发现与癌症有潜在的相关性，因为癌症干细胞可能来源于 细胞，癌细胞中能够繁殖的少数细胞，来自成人组织干细胞。 途径活性和祖细胞池的扩张也与急性白血病的反应有关 损伤和慢性组织损伤进一步导致与以下类型的癌症相关的风险增加 HH和WNT途径的活性。因此，癌症生长类似于急性损伤修复的激活状态，并且 随着反复损伤的发生，癌变的发生率也随之增加。这些观察结果 提出了中心假设和几个要在这项提议中检验的推论，即癌症 生长代表着组织修复的一种不受调节的状态的持续运行，即持续的HH 致癌过程中的通路活动偏离了正常情况下的恢复静止状态。 再生，而组织干细胞是相关的细胞类型。这一假设将在 通过比较鉴定和分离肿瘤干细胞来研究依赖于HH途径的癌症 这些肿瘤干细胞相互间和内源性组织干细胞或祖细胞，并通过检测 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 包括： 1.在已建立的细胞系或原代细胞培养体系中鉴定和分离癌症干细胞 来自依赖Hedgehog途径活性生长的内胚层肿瘤。 2.从相应的静息或损伤的内皮器官中鉴定和分离候选干细胞。 3.比较这些内皮器官来源的肿瘤干细胞和组织干细胞的特性。 4.探讨正常人体对HH蛋白信号损伤反应的分子基础 组织和肿瘤持续反应的基础。 这些研究将为操作策略的设计和优化提供基本依据 途径在癌症治疗和组织再生中的活性。对其机理基础的理解 对HH反应性的调节也有可能促进癌症预防的长期战略。

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.