Abstract
The acidic pH of the tumor microenvironment plays a critical role in driving cancer development toward a more aggressive phenotype, but the underlying mechanisms are unclear. To this end, phenotypic and genotypic changes induced by adaptation of cancer cells to chronic acidosis have been studied. However, the generality of acid adaptation patterns across cell models and their correlation to the molecular phenotypes and aggressiveness of human cancers are essentially unknown. Here, we define an acid adaptation expression response shared across three cancer cell models, dominated by metabolic rewiring, extracellular matrix remodeling, and altered cell cycle regulation and DNA damage response. We find that many genes which are upregulated by acid adaptation are significantly correlated to patient survival, and more generally, that there are clear correlations between acid adaptation expression response and gene expression change between normal and tumor tissues, for a large subset of cancer patients. Our data support the notion that tumor microenvironment acidity is one of the key factors driving the selection of aggressive cancer cells in human patient tumors, yet it also induces a growth-limiting genotype that likely limits cancer cell growth until the cells are released from acidosis, for instance during invasion.
Highlights
Invasive cancers, regardless of their origin, acquire characteristic phenotypic traits during their development, including self-sufficiency with respect to growth signals, apoptosis evasion, profound metabolic changes, chemotherapy resistance, and the ability to invade and spread to secondary niches [1]
E2F1, a key player in the control of cell cycle progression. These analyses show that across multiple cancer cell types, chronic acidosis is associated with gene expression changes expected to reflect a profound metabolic shift, including the downregulation of fermentative glycolysis and upregulation of glutamine- and lipid-based metabolism, and the downregulation of cell division and DNA repair, as wel as changes in extracellular matrix (ECM) remodeling and ion channel activity
Individual genes and pathways have previously been compared between acid-adapted cells and patient tumors (e.g., [15,24,59]), a comprehensive integrative analysis comparing genes upregulated by acidosis, genes upregulated in patient tumors and their relation to patient survival is lacking
Summary
Regardless of their origin, acquire characteristic phenotypic traits during their development, including self-sufficiency with respect to growth signals, apoptosis evasion, profound metabolic changes, chemotherapy resistance, and the ability to invade and spread to secondary niches [1]. These changes are the result of a clonal evolution process, in which the combination of somatic mutations and evolutionary selection pressure leads to the preferential expansion of clones of cells that are fit for survival and expansion in the harsh tumor microenvironment [2,3,4]. The role of extracellular acidosis in this process remains incompletely understood
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