Cigarette Smoke Induces Metabolic Reprogramming of the Tumor Stroma in Head and Neck Squamous Cell Carcinoma

Abstract

Head and neck squamous cell carcinoma (HNSCC) is comprised of metabolically linked distinct compartments. Cancer-associated fibroblasts (CAF) and nonproliferative carcinoma cells display a glycolytic metabolism, while proliferative carcinoma cells rely on mitochondrial oxidative metabolism fueled by the catabolites provided by the adjacent CAFs. Metabolic coupling between these reprogrammed compartments contributes to HNSCC aggressiveness. In this study, we examined the effects of cigarette smoke–exposed CAFs on metabolic coupling and tumor aggressiveness of HNSCC. Cigarette smoke (CS) extract was generated by dissolving cigarette smoke in growth media. Fibroblasts were cultured in CS or control media. HNSCC cells were cocultured in vitro and coinjected in vivo with CS or control fibroblasts. We found that CS induced oxidative stress, glycolytic flux and MCT4 expression, and senescence in fibroblasts. MCT4 upregulation was critical for fibroblast viability under CS conditions. The effects of CS on fibroblasts were abrogated by antioxidant treatment. Coculture of carcinoma cells with CS fibroblasts induced metabolic coupling with upregulation of the marker of glycolysis MCT4 in fibroblasts and markers of mitochondrial metabolism MCT1 and TOMM20 in carcinoma cells. CS fibroblasts increased CCL2 expression and macrophage migration. Coculture with CS fibroblasts also increased two features of carcinoma cell aggressiveness: resistance to cell death and enhanced cell migration. Coinjection of carcinoma cells with CS fibroblasts generated larger tumors with reduced apoptosis than control coinjections, and upregulation of MCT4 by CS exposure was a driver of these effects. We demonstrate that a tumor microenvironment exposed to CS is sufficient to modulate metabolism and cancer aggressiveness in HNSCC. Implications: CS shifts cancer stroma toward glycolysis and induces head and neck cancer aggressiveness with a mitochondrial profile linked by catabolite transporters and oxidative stress. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/9/1893/F1.large.jpg.

Cancer-Associated Fibroblast Density, Prognostic Characteristics, and Recurrence in Head and Neck Squamous Cell Carcinoma: A Meta-Analysis

“…This is exemplified by the different expression patterns seen in different methods of CAF identification (44). As recent research has shown, CAF function can be altered by environmental factors (19). Many believe that CAFs, like tumor-associated macrophages, may have either pro-tumoral or anti-tumoral effects depending on subtype or activation (78).…”

“…CAFs modulate the TME via the secretion of autocrine and paracrine cytokines, as well as extracellular matrix components that provide scaffolds to support the growing tumor cell nests. Many of the classic "hallmarks of malignancy", as well as emerging hallmarks such as immune evasion and metabolic compartmentalization, are influenced by the presence and functional states of CAFs (6,(16)(17)(18)(19).…”

Development and validation of prognostic index based on autophagy-related genes in patient with head and neck squamous cell carcinoma

“…In HNSCC, autophagy is induced by various risk factors. Major risk factors such as tobacco and alcohol have been found to induce oxidative stress, leading to chronic inflammation and induction of enhanced level of autophagy and finally resulting in oncogenic mutations 14 . HPV, an emerging risk factor for HNSCC, might also induce autophagy by enhancing expression of ARGs 15 .…”

Oxidative Stress and the Intersection of Oncogenic Signaling and Metabolism in Squamous Cell Carcinomas

“…Recent evidence demonstrates the cigarette smoke-induced metabolic reprogramming of cancer-associated fibroblasts (CAFs) towards a highly glycolytic phenotype. The highly glycolytic phenotype induces metabolic coupling and enhances the aggressiveness in HNSCCs, implicating oxidative stress in not only altering squamous metabolism but also shifting tumor stroma into a pro-oncogenic metabolic environment [ 104 ]. Additionally, CAFs may facilitate the glycolytic switch of HNSCCs by secreting HGF, which in turn induces bFGF secretion from HNSCCs to promote fibroblast proliferation [ 105 ].…”