Hypoxia triggers hedgehog-mediated tumor-stromal interactions in pancreatic cancer
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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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HIF-1α is overexpressed in pancreatic cancer even under normoxia and levels of HIF-1α are positively correlated with tumor progression, angiogenesis, cell migration and poor prognosis.
“it was recently found that HIF-1α is overexpressed in pancreatic cancer even under normoxia condition and levels of HIF-1α are positively correlated with tumor progression, angiogenesis, cell migration and poor prognosis [7, 8, 10, 11].”
From Inhibition of HIF-1α by PX-478 enhances the anti-tumor effect of gemcitabine by inducing immunogenic cell death in pancreatic ductal adenocarcinoma (2015) · cites this paper as [10]
The Discussion reports elevated HIF-1α in primary pancreatic cancer compared with normal pancreas and associates high tumor HIF-1α with shorter patient survival. The Introduction links constitutive HIF-1α expression in pancreatic cancer cells to increased tumorigenicity. Neither section establishes overexpression under normoxia or a positive correlation of HIF-1α levels with angiogenesis or cell migration; page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredHIF-1α is an important transcription factor for tumor growth, invasion, angiogenesis, metabolism and drug resistance.
“HIF-1α is an important transcription factor for tumor growth, invasion, angiogenesis, metabolism and drug resistance [7, 10, 25].”
From Inhibition of HIF-1α by PX-478 enhances the anti-tumor effect of gemcitabine by inducing immunogenic cell death in pancreatic ductal adenocarcinoma (2015) · cites this paper as [10]
The Introduction (page unavailable) links HIF-1α to increased tumorigenicity and resistance to chemotherapy, and describes HIF-mediated responses involving anaerobic metabolism and new blood-vessel formation. It mentions metastasis rather than invasion, and attributes the broader hypoxic response to both HIF-1 and HIF-2, not HIF-1α alone. (LLM, conf=0.83)
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“…transcription factor mediating cell adaption to hypoxia [9], it was recently found that HIF-1α is overexpressed in pancreatic cancer even under normoxia condition and levels of HIF-1α are positively correlated with tumor progression, angiogenesis, cell migration and poor prognosis [7, 8, 10, 11].”
Influential
- Authors
- 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.
- Affiliations
- Translational Genomics Research Institute (US)
- Authors' Affiliations: 1Department of Experimental therapeutics, MD Anderson Cancer Center, Houston, Texas; 2TGEN, Phoenix; 3Department of Biostatistics, University of Arizona, Tucson, Arizona; and 4Fred Hutchinson Cancer Research Center, Seattle, Washington
- Corresponding author
- Powis, Garth
- ORCID
- Venue
- Cancer Research
- Published
- 2013-05-30
- Volume
- 73
- Issue
- 11
- Pages
- 3235-3247
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3782107
- OpenAlex
- W2106664677
- Cited by
- 202
- References
- 51
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 15 · 2023: 15 · 2022: 18 · 2021: 14 · 2020: 31 · 2019: 19 · 2018: 10 · 2017: 16 · 2016: 16 · 2015: 17 · 2014: 16 · 2013: 2
- FWCI
- 9.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5u24ca126577-05)
- University of Texas MD Anderson Cancer Center
- National Cancer Institute (CA16672-35, CA095060, CA109552., CA095920, CA126577, CA098920, P01CA017094, R01CA098920, R01CA163541, CA017094, CA0163541, R13CA095920, P01CA109552, P50CA095060, R01CA161112, P30CA016672)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- pancreatic cancer, tumor hypoxia, desmoplasia, tumor-stroma interactions, Sonic hedgehog, Hedgehog signaling, HIF-1α, stromal fibroblasts, tumor microenvironment, HIF inhibitors, feed-forward loop, tumor aggressiveness, treatment resistance, prognostic factors
- MeSH terms
- Animals, Cell Communication, Humans, Immunohistochemistry, Mustard Compounds, Pancreatic Neoplasms, Phenylpropionates, Prognosis, Retrospective Studies, Transfection, Signal Transduction, Cell Hypoxia, Stromal Cells, NIH 3T3 Cells, Cell Line, Tumor, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Hedgehog Proteins, HEK293 Cells
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