16 Hh ligands secreted by supportive stroma in lymph nodes, spleen, and bone marrow activated Hh signaling in tumor cells. Hh inhibition resulted in increased apoptosis associated with down regulated Bcl2 expression. Hh inhibition www.selleckchem.com/products/Temsirolimus.html as a CSC-targeted strategy CSC theory states that tumors are comprised of two distinct populations of cells: a majority population of differentiated tumor cells which phenotypically characterize the disease; and a second population of rare, CSC or tumor-initiating cells, with properties of self-renewal and differentiation, responsible for disease maintenance and relapse.58,59 CSC theory attempts to explain the common clinical scenario of complete response to initial chemotherapy followed by relapsed disease propagated by a small population of residual cancer cells which were undetectable following initial therapy.

For many cancers, conventional chemotherapy is effective against the bulk, differentiated tumor cells. Novel strategies targeting the residual CSCs responsible for disease recurrence are needed to prolong remissions, eradicate the tumor-initiating cells, and result in long-term cure. Hh signaling has been identified as a potential CSC-specific target in various cancers.6,13,15,20,51,60�C77 Techniques used to isolate and characterize CSC in vitro include aldehyde dehydrogenase expression, phenotypic markers, side population by Hoechst dye exclusion, and colony-forming assays. To date, the ��gold standard�� for CSC identification has been the ability of this rare population of cells to regenerate tumor consisting of both phenotypic populations, differentiated cells, and CSC in animal models.

78 A detailed discussion of the in vitro and in vivo methods used to characterize CSC in various tumor types is beyond the scope of this review. The reader is referred to Reference 78 for further details of these techniques, as well to the publications cited below concerning Hh signaling and CSC. CSC theory remains controversial due to the varying techniques for identification and the discrepancies in CSC numbers identified in primary samples and required to recreate tumors in mice by different researchers with varying techniques. Also, the inherent heterogeneity among different tumor types as well as within specific cancer types themselves.

Regardless of the exact criteria for identifying CSC or properties of ��stem-ness�� or whether the CSC is a primitive progenitor or a de-differentiated cell, the clinical observation holds that rare populations of cancer cells persist following initial therapy and cause disease recurrence, and novel strategies to target these resistant, persistent cells are needed. In fact, CSC from different cancers may share similar targets, even more so than the CSC and differentiated GSK-3 cell of the same cancer type.