The role of tumor acidification in aggressiveness, cell dissemination and treatment resistance of oral squamous cell carcinoma

• Published in: Life sciences (1973) 2022-01, Vol.288, p.120163, Article 120163
• Main Authors: de Bem Prunes, Bianca, Nunes, Júlia Silveira, da Silva, Viviane Palmeira, Laureano, Natalia Koerich, Gonçalves, Douglas Rodrigues, Machado, Ian Santana, Barbosa, Silvia, Lamers, Marcelo Lazzaron, Rados, Pantelis Varvaki, Kurth, Ina, Hess, Jochen, Jou, Adriana, Visioli, Fernanda
• Format: Article
• Language: English
• Subjects: Acidification; acidity; acidosis; Acids - adverse effects; Alveolar bone; Antineoplastic Agents - pharmacology; Apoptosis; Bone loss; Carcinoma, Squamous Cell - etiology; Carcinoma, Squamous Cell - pathology; Carcinoma, Squamous Cell - therapy; cell culture; Cell migration; Cell Movement; Cell Proliferation; cell structures; Chemoresistance; Cisplatin - adverse effects; culture media; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Fatty liver; Feces; Flora; flow cytometry; fluorescent antibody technique; Gamma Rays - adverse effects; Gene sequencing; Histopathology; Humans; IL-1β; Inflammation; Inflammatory response; Intestinal microflora; Intestine; Lipopolysaccharides; Liver; Liver diseases; Mandible; Molars; Molecular modelling; mouth neoplasms; Mouth Neoplasms - etiology; Mouth Neoplasms - pathology; Mouth Neoplasms - therapy; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - pathology; Neoplastic Stem Cells - radiation effects; Oral cancer; Oral carcinoma; Oral squamous cell carcinoma; Periodontitis; phenotype; radiation resistance; Radiation Tolerance; Radioresistance; radiotherapy; rRNA 16S; Signal transduction; Silk; squamous cell carcinoma; Steatosis; Teeth; Tumor acidosis; Tumor Cells, Cultured; Tumor Microenvironment; Tumors; viability; Western blotting; Zonula occludens-1 protein
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2021.120163

To investigate the role of tumor acidification in cell behavior, migration, and treatment resistance of oral squamous cell carcinoma (OSCC). The SCC4 and SCC25 cell lines were exposed to acidified (pH 6.8) cell culture medium for 7 days. Alternatively, a long-term acidosis was induced for 21 days. In addition, to mimic dynamic pH fluctuation of the tumor microenvironment, cells were reconditioned to neutral pH after experimental acidosis. This study assessed cell proliferation and viability by sulforhodamine B and flow cytometry. Individual and collective cell migration was analyzed by wound healing, time lapse, and transwell assays. Modifications of cell phenotype, EMT induction and stemness potential were investigated by qRT-PCR, western blot, and immunofluorescence. Finally, resistance to chemo- and radiotherapy of OSCC when exposed to acidified environmental conditions (pH 6.8) was determined. The exposure to an acidic microenvironment caused an initial reduction of OSCC cells viability, followed by an adaptation process. Acidic adapted cells acquired a mesenchymal-like phenotype along with increased migration and motility indexes. Moreover, tumoral extracellular acidity was capable to induce cellular stemness and to increase chemo- and radioresistance of oral cancer cells. In summary, the results showed that the acidic microenvironment leads to a more aggressive and treatment resistant OSCC cell population. •Extracellular acidification is a hallmark of solid tumors.•Tumor acidosis acts as selective evolutionary pressure.•The acidic microenvironment hinder response to chemo- and radiotherapy treatment.•pH neutralization restores treatment response, however, increases cell migration.