Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy affecting 40,000 cases in the USA annually, associated with poor prognosis and significant morbidity. HNSCC tumors are dysplastic with up to 80% fibroblasts. We reported that tumor associated fibroblasts (TAFs) facilitate HNSCC progression. However, the molecular mechanisms that facilitate TAF-mediated tumor growth and metastasis remain unknown. Unlike normal cells, malignant cells often display increased glycolysis, even in the presence of oxygen; a phenomenon known as the Warburg effect. As a consequence, there is an increase in lactic acid (LA) production. It has been reported that HNSCC tumors have high LA levels that correlate with reduced survival. The mechanisms whereby HNSCC tumors survive in highly acidic conditions remain unknown. We reported that activation of the receptor tyrosine kinase, c-Met, by TAF-secreted hepatocyte growth factor (HGF) contributes to HNSCC progression. The role of TAFs-secreted HGF in HNSCC metabolism remains unknown. In addition, we were unable to detect HGF secretion by HNSCC indicating paracrine activation of c-Met. In nasopharyngeal carcinoma, c-Met inhibition down regulates the TP53-induced glycolysis and apoptosis regulator (TIGAR) and NADPH production. We hypothesized that TAF-secreted HGF regulates HNSCC glycolysis via c-Met. Further, HNSCC cells regulate metabolism in TAFs. We found that PF2341066, a c-Met inhibitor significantly decreased glycolysis (p = 0.0023) and hexokinase-II levels in HNSCC cells. These data demonstrate that c-Met regulate glycolysis in HNSCC through modulation of hexokinase-II. In admixed cultures, HNSCC and TAFs demonstrate higher expression of the bi-directional lactate transporter monocarboxylate transporter 1 (MCT-1). Our data demonstrate that TAFs have a higher capacity to proliferate than HNSCC in the presence of LA. Others have reported that NFκB increases MCT-1 levels in tumor associated stroma under high LA conditions. In ongoing studies, we will determine the role of HNSCC in regulating MCT-1 levels in TAFs. Further, the role of c-Met in regulating expression of MCT-1 in HNSCC will be elucidated. Based on the cumulative data we conclude that TAF-secreted HGF regulates HNSCC metabolism and TAFs utilize LA as a carbon source making the microenvironment more conducive to tumor progression.
Keywords : HNSCC, TAFs, HGF, Glycolysis, OXPHOS
Citation Format: Dhruv Kumar, Partha Kasturi, Bennett Van Houten, Sufi Thomas. Tumor-associated fibroblasts facilitate head and neck cancer metabolism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1139. doi:10.1158/1538-7445.AM2015-1139