HEDGEHOG SIGNALING IN RESPONSE TO TISSUE INJURY AND IN NEOPLASIA

Johns Hopkins University, Baltimore MD

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Abstract

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