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Figures S3 to S7 and Tables S1 and S2 from Hypoxia Triggers Hedgehog-Mediated Tumor–Stromal Interactions in Pancreatic Cancer

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posted on 2023-03-30, 21:26 authored by Taly R. Spivak-Kroizman, Galen Hostetter, Richard Posner, Meraj Aziz, Chengcheng Hu, Michael J. Demeure, Daniel Von Hoff, Sunil R. Hingorani, Timothy B. Palculict, Julie Izzo, Galina M. Kiriakova, Mena Abdelmelek, Geoffrey Bartholomeusz, Brian P. James, Garth Powis

Figures S3 to S7 and Tables S1 and S2 - PDF file 532K, S3 Kaplan-Meier patient survival analyses reveals no correlation between survival and PTCH levels. S4 Survival plots based on the univariate table S5 Increased expression of SHH during hypoxia in pancreatic cancer cell lines. S6 A HIF1-�- and SHH-dependent activation of hedgehog signaling in fibroblasts grown in 3D co-cultures with Panc-1 cells. S7, SHH formation by pancreatic cancer cells in hypoxia is mediating the desmoplastic reaction in fibroblasts Table S1 Univariate table showing that high histologic grade Table S2 A pathway array profiling the expression of genes involved in hedgehog signaling in MiaPaca 2 cells transfected with shHIF-1� in normoxia and hypoxia

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ARTICLE ABSTRACT

Pancreatic cancer is characterized by a desmoplastic reaction that creates a dense fibroinflammatory microenvironment, promoting hypoxia and limiting cancer drug delivery due to decreased blood perfusion. Here, we describe a novel tumor–stroma interaction that may help explain the prevalence of desmoplasia in this cancer. Specifically, we found that activation of hypoxia-inducible factor-1α (HIF-1α) by tumor hypoxia strongly activates secretion of the sonic hedgehog (SHH) ligand by cancer cells, which in turn causes stromal fibroblasts to increase fibrous tissue deposition. In support of this finding, elevated levels of HIF-1α and SHH in pancreatic tumors were determined to be markers of decreased patient survival. Repeated cycles of hypoxia and desmoplasia amplified each other in a feed forward loop that made tumors more aggressive and resistant to therapy. This loop could be blocked by HIF-1α inhibition, which was sufficient to block SHH production and hedgehog signaling. Taken together, our findings suggest that increased HIF-1α produced by hypoxic tumors triggers the desmoplasic reaction in pancreatic cancer, which is then amplified by a feed forward loop involving cycles of decreased blood flow and increased hypoxia. Our findings strengthen the rationale for testing HIF inhibitors and may therefore represent a novel therapeutic option for pancreatic cancer. Cancer Res; 73(11); 3235–47. ©2013 AACR.

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