title: Hypoxia triggers hedgehog-mediated tumor-stromal interactions in pancreatic cancer.
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.
authors: Department of Experimental therapeutics, MD Anderson Cancer Center, Houston, Texas, USA.
authors: Taly R
authors: TR
authors: Spivak-Kroizman
authors: Galen
authors: G
authors: Hostetter
authors: Richard
authors: R
authors: Posner
authors: Meraj
authors: M
authors: Aziz
authors: Chengcheng
authors: C
authors: Hu
authors: Michael J
authors: MJ
authors: Demeure
authors: Daniel
authors: D
authors: Von Hoff
authors: Sunil R
authors: SR
authors: Hingorani
authors: Timothy B
authors: TB
authors: Palculict
authors: Julie
authors: J
authors: Izzo
authors: Galina M
authors: GM
authors: Kiriakova
authors: Mena
authors: M
authors: Abdelmelek
authors: Geoffrey
authors: G
authors: Bartholomeusz
authors: Brian P
authors: BP
authors: James
authors: Garth
authors: G
authors: Powis
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000502:physiology*; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D009150:Mustard Compounds / Q000494:pharmacology; D041681:NIH 3T3 Cells; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010666:Phenylpropionates / Q000494:pharmacology; D011379:Prognosis; D012189:Retrospective Studies; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D014162:Transfection
chemical_list: C492908:2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide; C497442:HIF1A protein, human; D053823:Hedgehog Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009150:Mustard Compounds; D010666:Phenylpropionates; C509239:SHH protein, human; C465570:Shh protein, mouse
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