Journal
CANCER RESEARCH
Volume 78, Issue 14, Pages 3769-3782Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-17-1076
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Funding
- American Head and Neck Society Pilot Award
- University of Kansas Medical Center
- University of Kansas Cancer Center's CCSG [1-P30-CA168524-02]
- Institutional Development Award (IDeA), National Institute of General Medical Sciences, NIH [P20 GM103418]
- KUMC Biomedical Research Training Program Fellowship
- PA CURE award
- University of Kansas Cancer Center, Biospecimen Repository Core Facility
- [5P20RR021940-07]
- [8P20GM103549-07]
- [CA190291]
- [P30CA047904]
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Despite aggressive therapies, head and neck squamous cell carcinoma (HNSCC) is associated with a less than 50% 5-year survival rate. Late-stage HNSCC frequently consists of up to 80% cancer-associated fibroblasts (CAF). We previously reported that CAF-secreted HGF facilitates HNSCC progression; however, very little is known about the role of CAFs in HNSCC metabolism. Here, we demonstrate that CAF-secreted HGF increases extracellular lactate levels in HNSCC via upregulation of glycolysis. CAF-secreted HGF induced basic FGF (bFGF) secretion from HNSCC. CAFs were more efficient than HNSCC in using lactate as a carbon source. HNSCC-secreted bFGF increased mitochondrial oxidative phosphorylation and HGF secretion from CAFs. Combined inhibition of c-Met and FGFR significantly inhibited CAF-induced HNSCC growth in vitro and in vivo (P < 0.001). Our cumulative findings underscore reciprocal signaling between CAF and HNSCC involving bFGF and HGF. This contributes to metabolic symbiosis and a targetable therapeutic axis involving c-Met and FGFR. Significance: HNSCC cancer cells and CAFs have a metabolic relationship where CAFs secrete HGF to induce a glycolytic switch in HNSCC cells and HNSCC cells secrete bFGF to promote lactate consumption by CAFs. (C) 2018 AACR.
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