HEDGEHOG SIGNALING IN RESPONSE TO TISSUE INJURY AND IN NEOPLASIA

响应组织损伤和肿瘤的刺猬信号传导

• 批准号: 7049167
• 负责人: PHILIP A BEACHY
• 金额: $ 18.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7049167
• 关键词: Mammalia; injury; neoplasm /cancer; stem cells; tissues

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.

Hedgehog（Hh）信号在正常胚胎发育中起指导作用，但在病理过程中， 胚胎后组织中的活性与肿瘤类型的生长有关， 大约25%的癌症死亡。Hh信号激活的正常胚胎后作用 Wnt通路及其姊妹通路Wnt通路已被证明在组织茎的更新和维持中起重要作用。 细胞这些发现与癌症有潜在的相关性，因为可能的癌症干细胞的衍生 细胞，癌症中能够增殖的少数细胞，来自成体组织干细胞。 通路活性和祖细胞库的扩增也与急性炎症反应相关。 损伤和慢性组织损伤还导致与癌症相关的类型的癌症的风险增加。 Hh和Wnt途径活性。因此，癌症生长类似于急性损伤修复的激活状态， 随着重复损伤的发生，癌生长的发生率增加。这些观察结果 提出了中心假设和几个推论，以测试在这个建议，即，癌症 生长代表了组织修复的不受调节状态的连续操作，即连续的Hh 在癌发生过程中，通路活动偏离了正常情况下随后的恢复平静， 再生，组织干细胞是相关的细胞类型。这一假设将在 通过识别和分离癌症干细胞，通过比较 这些癌症干细胞相互之间以及与内源性组织干细胞或祖细胞之间的关系， 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 为： 1.在已建立的细胞系或原代细胞培养物中鉴定和分离癌症干细胞， 从依赖Hedgehog途径活性生长的内胚层肿瘤中分离出来。 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.目的：探讨损伤诱导的正常人对Hh蛋白信号反应性的分子基础。 组织和肿瘤中持续反应的基础。 这些研究将为操纵策略的设计和优化提供基本依据 在癌症治疗和组织再生中的途径活性。理解机械基础， 调节Hh反应性也有可能促进癌症预防的长期战略。