Hypoxia triggers hedgehog-mediated tumor-stromal interactions in pancreatic cancer

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

Research output: Contribution to journalArticle

103 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3235-3247
Number of pages13
JournalCancer Research
Volume73
Issue number11
DOIs
StatePublished - Jun 1 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Spivak-Kroizman, T. R., Hostetter, G., Posner, R., Aziz, M., Hu, C., Demeure, M. J., Von Hoff, D., Hingorani, S. R., Palculict, T. B., Izzo, J., Kiriakova, G. M., Abdelmelek, M., Bartholomeusz, G., James, B. P., & Powis, G. (2013). Hypoxia triggers hedgehog-mediated tumor-stromal interactions in pancreatic cancer. Cancer Research, 73(11), 3235-3247. https://doi.org/10.1158/0008-5472.CAN-11-1433