3988

Cancer stem cells (CSC) represent the cellular compartment responsible for the initiation, maintenance, and progression of multiple human cancers. CSC retain the capacity to undergo self-renewal as well as produce differentiated cells that form the bulk of the tumor mass. Embryonic signaling pathways, such as Hedgehog (Hh), Wingless (Wnt), and Notch are required for somatic stem cell development. Aberrant re-activation of these pathways has been demonstrated in many human cancers, however their role in regulating CSC phenotypes has not been tested directly. We investigated the role of Hh signaling in the regulation of CSC by examining pathway activation within distinct cellular compartments that constitute the plasma cell malignancy multiple myeloma (MM), in which clonogenic progenitors resemble post-germinal center B cells. In both MM cell lines and clinical bone marrow samples, expression of the Hh signaling pathway components PATCHED (PTCH), SMOOTHENED (SMO), GLI1 as well as GLI-responsive reporter activity were markedly elevated compared to normal B cells and plasma cells. Furthermore, the expression of PTCH, SMO and GLI reporter activity was significantly higher in the CSC compartment compared to MM plasma cells. Treatment of MM CSC from cell lines or clinical specimens with the SMO antagonist cyclopamine inhibited clonal growth and induced phenotypic evidence of plasma cell differentiation. By contrast, treatment of MM CSC with Hh ligand induced marked expansion of this population without inducing plasma cell differentiation. We conclude that aberrant Hh signaling maintains the CSC population of MM. Inhibition of Hh signaling in MM may represent a novel therapeutic strategy that directly targets MM stem cells.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]