Hedgehog (Hh) signaling plays instructive roles in normal embryonic patterning, but pathological pathwayactivity in post-embryonic tissues is associated with the growth of tumor types that together account forapproximately 25% of cancer deaths. Normal post-embryonic roles for activation of the Hh signalingpathway and its sister, the Wnt pathway, have been demonstrated in renewal and maintenance of tissue stemcells. These findings are of potential relevance to cancer because of the possible derivation of cancer stemcells, 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 acuteinjury, and chronic tissue injury furthermore results in increased risk for cancers of the types associated withHh and Wnt pathway activity. Cancer growth thus resembles the activated state of acute injury repair, andthe incidence of cancerous growth increases with the occurrence of repeated injury. These observationssuggest the central hypothesis and several corollaries to be tested in this proposal, namely, that cancergrowth represents the continuous operation of an unregulated state of tissue repair, that continuous Hhpathway activity in carcinogenesis is a deviation from the return to quiescence that normally followsregeneration, and that tissue stem cells are the relevant cell types. This hypothesis will be tested in thecontext of Hh pathway-dependent cancers by identifying and isolating cancer stem cells, by comparingthese cancer stem cells to each other and to endogenous tissue stem or progenitor cells, and by examiningthe 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 derivedfrom 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 normaltissues and the basis of continuous response in tumors.These studies will provide a fundamental basis for design and optimization of strategies to manipulatepathway activity in cancer therapy and in tissue regeneration. An understanding of the mechanistic basis forregulation of Hh responsiveness also has the potential to foster long-term strategies for cancer prevention.
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