The acidic tumor microenvironment drives a stem-like phenotype in melanoma cells
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ORIGINAL ARTICLE
The acidic tumor microenvironment drives a stem-like phenotype in melanoma cells Elena Andreucci 1 & Silvia Peppicelli 1 & Jessica Ruzzolini 1 & Francesca Bianchini 1 & Alessio Biagioni 1 & Laura Papucci 1 & Lucia Magnelli 1 & Benedetta Mazzanti 2 & Barbara Stecca 3 & Lido Calorini 1,4 Received: 25 November 2019 / Revised: 14 July 2020 / Accepted: 5 August 2020 # The Author(s) 2020
Abstract Acidosis characterizes the microenvironment of most solid tumors and is considered a new hallmark of cancer. It is mainly caused by both “aerobic” and “anaerobic” glycolysis of differently adapted cancer cells, with the final product lactic acid being responsible of the extracellular acidification. Many evidences underline the role of extracellular acidosis in tumor progression. Among the different findings, we demonstrated that acidosis-exposed cancer cells are characterized by an epithelial-tomesenchymal transition phenotype with high invasive ability, high resistance to apoptosis, anchorage-independent growth, and drug therapy. Acidic melanoma cells over-express SOX2, which is crucial for the maintenance of their oxidative metabolism, and carbonic anhydrase IX, that correlates with poor prognosis of cancer patients. Considering these evidences, we realized that the profile outlined for acid cancer cells inevitably remind us the stemness profile. Therefore, we wondered whether extracellular acidosis might induce in cancer cells the acquisition of stem-like properties and contribute to the expansion of the cancer stem cell sub-population. We found that a chronic adaptation to acidosis stimulates in cancer cells the expression of stem-related markers, also providing a high in vitro/in vivo clonogenic and trans-differentiating ability. Moreover, we observed that the acidosisinduced stem-like phenotype of melanoma cells was reversible and related to the EMT induction. These findings help to characterize a further aspect of stem cell niche, contributing to the sustainment and expansion of cancer stem cell subpopulation. Thus, the usage of agents controlling tumor extracellular acidosis might acquire great importance in the clinic for the treatment of aggressive solid tumor. Key messages • Extracellular acidosis up-regulates EMT and stem-related markers in melanoma cells • Acidic medium up-regulates in vitro self-renewal capacity of melanoma cells • Chronic acidosis adaptation induces trans-differentiation ability in melanoma cells • Melanoma cells adapted to acidosis show higher tumor-initiating potential than control cells • Extracellular acidosis promotes a stem-like phenotype in prostate and colorectal carcinoma cells Keywords Acidosis . Tumor microenvironment . Melanoma . Cancer stem cells
Elena Andreucci and Silvia Peppicelli contributed equally to this work. * Elena Andreucci [email protected]
2
Haematology Unit, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
* Silvia Peppicelli [email protected]
3
Tumor Cell Biology Unit - Core Research Laborator
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