The acidic tumor microenvironment drives a stem-like phenotype in melanoma cells

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-to-mesenchymal 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 acidosis-induced 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

Impact of the acidic environment on gene expression and functional parameters of tumors in vitro and in vivo

“…Recent studies reported that tumor cells adapt to long-term acidosis. Exposing tumor cells to low pH for 4 weeks or longer induced changes in protein expression and functional properties [ 33 – 36 ]. In order to analyze whether the changes in gene expression described above are the result of a short-term acidification (24 h) or can also be found in tumor cells chronically adapted to low pH, AT1 cells were kept for 11 passages (5 weeks) at pH 6.6.…”

Linking Metabolic Reprogramming, Plasticity and Tumor Progression

“…Snail-mediated increase in glucose uptake and lactate production was also shown for gastric cancer [ 137 ]. Regarding breast cancer, Kim with colleagues showed that Snail reprograms glucose metabolism by repressing phosphofructokinase PFKP which switches the glucose flux towards the pentose phosphate pathway [ 150 ]. Physiologically, this dynamic regulation of PFKP allows cancer cells to survive under metabolic stress.…”

“…For example, rapid tumor growth creates a deficit of nutrients [ 151 ], mechanistic hypertension [ 152 ], and acidosis [ 153 , 154 ]. In turn, acidosis drives EMT and stem-like phenotype by inducing TGF-beta [ 52 ] and stem-cell markers [ 150 ]. Using MCF7 breast cancer cells as a model, Sadeghi with colleagues (Sadeghi et al, 2020) has shown that acidosis promoted a partial EMT, conferring the cells with phenotypic characteristics of both epithelial and mesenchymal cells.…”

Recent Advances and Trends in Chemical CPP–Drug Conjugation Techniques

“…One of these characteristics are increased lactic acid production as a result of upregulated aerobic and anaerobic glycolysis. As a consequence, the extracellular tumor cell environment (pH 6.2–7.0), endosomes (pH 5.0–6.5) and lysosomes (pH 4.5–5) become more acidic than healthy tissues and blood (pH ~7.4) [ 76 , 100 , 101 ]. Based on these properties, some acid-sensitive linkers have been designed to facilitate tumor-specific drug release of CPP–drug conjugates ( Figure 5 ), which will be highlighted in the following paragraphs.…”