RESUMO
AIMS: To investigate the role of tumor acidification in cell behavior, migration, and treatment resistance of oral squamous cell carcinoma (OSCC). MAIN METHODS: 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. KEY FINDINGS: 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. SIGNIFICANCE: In summary, the results showed that the acidic microenvironment leads to a more aggressive and treatment resistant OSCC cell population.
Assuntos
Ácidos/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Neoplasias Bucais/patologia , Células-Tronco Neoplásicas/patologia , Tolerância a Radiação , Microambiente Tumoral , Antineoplásicos/farmacologia , Apoptose , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Movimento Celular , Proliferação de Células , Cisplatino/efeitos adversos , Raios gama/efeitos adversos , Humanos , Neoplasias Bucais/etiologia , Neoplasias Bucais/terapia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos da radiação , Células Tumorais CultivadasRESUMO
Metabolic alterations in the tumor microenvironment have a complex effect on cancer progression. Extracellular acidity is a consequence of metabolic switch in cancer and results in cell phenotypes with higher resistance to chemotherapeutics. However, mechanisms underlying the relationship between the extracellular acidity and chemoresistance are not clearly understood. This systematic review was carried out by searching the databases PubMed and EMBASE using the keywords "cancer" and "acidosis" or "acidic" and "chemoresistance" or "drug resistance." In vitro and in vivo studies that evaluated the effects of acidification of the tumor microenvironment on chemotherapeutic treatments were included. Literature reviews, letters to the editor, and articles that were not published in English were excluded. The search resulted in a total of 352 articles. After discarding 75 duplicate references, 277 articles were analyzed by sequentially reading through their titles, abstracts, and finally full-text. A total of 14 articles was selected. Acidification of the tumor microenvironment can trigger resistance through different mechanisms, such as increase in drug efflux transporters, inhibition of proton pumps, induction of the unfolded protein response (UPR), and cellular autophagy.