Tumoral microvesicle–activated glycometabolic reprogramming in fibroblasts promotes the progression of oral squamous cell carcinoma

Abstract

Metabolic reprogramming is a hallmark of cancer. Stromal cells could function as providers of energy metabolites for tumor cells by undergoing the “reverse Warburg effect,” but the mechanism has not been fully elucidated. The interaction between the tumoral microvesicles (TMVs) and stroma in the tumor microenvironment plays a critical role in facilitating cancer progression. In this study, we demonstrated a novel mechanism for the TMV‐mediated glycometabolic reprogramming of stromal cells. After being incubated with TMVs, normal human gingival fibroblasts exhibited a phenotype switch to cancer‐associated fibroblasts and underwent a degradation of caveolin 1 (CAV1) through the ERKl/2‐activation pathway. CAV1 degradation further induced the metabolic switch to aerobic glycolysis in the fibroblasts. The microvesicle‐activated fibroblasts absorbed more glucose and produced more lactate. The migration and invasion of oral squamous cell carcinoma (OSCC) were promoted after being cocultured with the activated fibroblasts. Fibroblast–cancer cell glycometabolic coupling ring mediated by monocarboxylate transporter (MCT) 4 and MCT1 was then proved in the tumor microenvironment. Results indicated a mechanism for tumor progression by the crosstalk between tumor cells and stromal cells through the reverse Warburg effect via TMVs, thereby identifying potential targets for OSCC prevention and treatment.—Jiang, E., Xu, Z., Wang, M., Yan, T., Huang, C, Zhou, X., Liu, Q., Wang, L., Chen, Y., Wang, H., Liu, K., Shao, Z., Shang, Z. Tumoral microvesicle–activated glycometabolic reprogramming in fibroblasts promotes the progression of oral squamous cell carcinoma. FASEB J. 33, 5690–5703 (2019). http://www.fasebj.org

Microvesicles in Cancer: Small Size, Large Potential

“…Stimulation of fibroblasts with prostate cancer MV converted them to an activated phenotype and triggered the release of tumor-promoting fibroblast MV [48]. Similar observations were made in oral squamous carcinoma when normal human fibroblasts were treated with tumor-derived MV [49]. In this study, the switch to cancer-associated fibroblasts (CAF) was mainly mediated via metabolic reprogramming of the fibroblasts to aerobic glycolysis, with an increase in glucose uptake and lactate secretion.…”

Extracellular Vesicles in Oral Squamous Cell Carcinoma and Oral Potentially Malignant Disorders: A Systematic Review

“…Injection of a combination of untreated and TMV-treated HCFs with CAL-27 xenograft into nude mice found that treating with TMVs was associated with a significant increase in tumour weight (p < 0.05). The invasive potential of OSCC cells was demonstrated to be increased after being co-cultured with TMV-treated HCGs and partially reversed by knockdown of MCT1 in CaL-27 cells [23].…”

“…Primary normal oral keratinocytes Exposure to OSCC-derived exosomes specifically modulated mRNA transcripts associated with matrix remodeling, cell cycle, differentiation, apoptosis, transcription and translation OSCC & Fibroblasts [33] OSCC line (HSC3) NOF HSC3-exosomes lead to uptake by NOFs with resulting upregulation of expression of non-coding RNA Lnc-CAF [23] OSCC line (Cal-27) HGFs (human gingival fibroblasts)…”

“…OSCC-derived MVs may influence normal fibroblasts that in turn can influence tumour progression. The glycometabolic influence of MVs derived from CAL-27 OSCC cells was studied by Jiang et al (2019) in HGFs (human gingival fibroblasts) from healthy individuals, PNFs (paracancerous normal fibroblasts) and CAFs 3 OSCC patients [23]. HGFs incubated with the OSCC-derived MVs internalized these tumour MVs (TMVs) and subsequently increased levels of CAF markers (FAP and Tn-c).…”

Non-canonical roles for metabolic enzymes and intermediates in malignant progression and metastasis

“…Along with alterations in cancer cell metabolism, perturbations in the metabolism of tumor stroma are emerging as a key driver of metastatic progression. The interactions between cancer-associated fibroblasts, and tumor cells is described as a 'reverse Warburg effect' where cancer cells induce metabolic reprogramming of fibroblasts leading to increased aerobic glycolysis [67], as well as increased expression of monocarboxylate transporter-4 (MCT4) [68] resulting in release of lactate into the tumor microenvironment. This is correlated with upregulated expression of monocarboxylate transporter-1 (MCT1) mediated lactate uptake in cancer cells which has been shown to contribute to survival and growth [68], as well as tumor migration [69].…”