Hypoxia Triggers Hedgehog-Mediated Tumor–Stromal Interactions in Pancreatic Cancer
| Autor: | Geoffrey Bartholomeusz, Chengcheng Hu, Timothy B. Palculict, Galina Kiriakova, Brian P. James, Galen Hostetter, Sunil R. Hingorani, Daniel D. Von Hoff, Richard G. Posner, Meraj Aziz, Garth Powis, Julie G. Izzo, Taly R. Spivak-Kroizman, Michael J. Demeure, Mena Abdelmelek |
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| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
medicine.medical_specialty Mustard Compounds Stromal cell Cell Communication Transfection Article Mice Cell Line Tumor Internal medicine Pancreatic cancer medicine Animals Humans Hedgehog Proteins Sonic hedgehog Hedgehog Retrospective Studies Phenylpropionates Tumor hypoxia biology Hypoxia (medical) Hypoxia-Inducible Factor 1 alpha Subunit Prognosis medicine.disease Immunohistochemistry Cell Hypoxia Desmoplasia Pancreatic Neoplasms HEK293 Cells Endocrinology Oncology Cancer cell NIH 3T3 Cells biology.protein Cancer research Stromal Cells medicine.symptom Signal Transduction |
| Zdroj: | Cancer Research. 73:3235-3247 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-11-1433 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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