Novel Targets for the Treatment of Pancreatic Cancer II: The Hedgehog Signaling Pathway

Another very promising target for the treatment of pancreatic cancer is the Hedgehog signaling pathway. Currently, a large body of research is focused on modulating solid tumor stem cells as a means to selectively target malignant disease. This strategy is dependent upon the hypothesis that a small, discrete population of stem cells is present in solid tumors that posses an immortal self-renewal capacity with the potential for diverse differentiation. Regulation of cancer stem cells is modulated by a group of signaling molecules with important functions in embryonic development; these include Hedgehog, Notch, Wnt, and bone morphogenic protein/transforming growth factor-β (BMP/TGF-β). Altered regulation of these proteins may occur in a variety of cancer types. One target with particular promise for treating pancreatic cancer is the Hedgehog (Hh) signaling pathway (1, 2).

The Hedgehog signaling pathway is comprised of three creatively named secretory proteins, Sonic Hedgehog (SHH), Indian Hedgehog (IHH), and Desert Hedgehog (DHH). All can modulate cell-cell signaling and are involved in the control of tissue formation or “patterning” during normal embryonic development ( 2 ). In some systems, activation of Hh signaling promotes cell proliferation, whereas in others it can induce differentiation. In tumor cells, aberrant Hh signaling may contribute to the expression of an aggressive malignant phenotype. Recently, it has been a focus for new therapeutic strategies for treating various cancers, including pancreatic tumors ( 3 ).