Stromal Cells Inhibit Pancreatic Tumor Growth and Angiogenesis

Tumor-associated stromal cells have been shown to promote the growth and progression of many cancers, supporting the development of therapeutic agents targeting the tumor microenvironment. Canonical Hedgehog signaling via the sonic hedgehog (Shh) ligand stimulates expansion of desmoplastic stroma in pancreatic ductal adenocarcinoma (PDAC), suggesting that Shh may regulate pancreatic tumor growth. Using an autochthonous mouse model of PDAC, Rhim and colleagues found that conditional deletion of Shh in pancreatic epithelial cells resulted in depletion of tumor-associated stromal cells, but unexpectedly accelerated tumor progression and decreased survival. These more aggressive tumors exhibited Hedgehog pathway activation specifically in mesenchymal-derived stromal cells and were characterized by an undifferentiated histology, enhanced proliferation, and increased vascular density and perfusion, suggesting that paracrine Hedgehog signaling may indirectly suppress tumor angiogenesis in PDAC. In support of this idea, chronic pharmacologic inhibition of Hedgehog signaling phenocopied genetic Shh deletion, promoting the formation of poorly differentiated, highly vascular, aggressive tumors. Furthermore, in patients with PDAC, an undifferentiated tumor phenotype was associated with decreased stroma, reduced canonical Hedgehog activity, and increased vessel density. Consistent with a dependence of these tumors on enhanced vascularity, treatment with a VEGFR2 blocking antibody selectively diminished tumor cell proliferation, augmented tumor necrosis, and prolonged survival in mice harboring Shh-deficient PDAC. Although additional work is necessary to further define the mechanisms by which stromal depletion regulates PDAC growth, these results provide evidence that stromal cells can inhibit tumor angiogenesis and progression in pancreatic cancer and may explain the failure of Hedgehog inhibitors targeting tumor stroma in clinical trials. In addition, these findings suggest that the subset of patients with undifferentiated PDAC may benefit from antiangiogenic therapy.

Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA, et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 2014 May 22 [Epub ahead of print].

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