Extracellular Acidosis Modulates the Expression of Epithelial-Mesenchymal Transition (EMT) Markers and Adhesion of Epithelial and Tumor Cells

Abstract

Epithelial-to-mesenchymal transition (EMT) is an important process of tumor progression associated with increased metastatic potential. EMT can be activated by external triggers such as cytokines or metabolic parameters (e.g. hypoxia). Since extracellular acidosis is a common finding in tumors, the aim of the study is to analyze its impact on the expression of EMT markers in vitro and in vivo as well as the functional impact on cell adhesion. Therefore, three tumor and two normal epithelial cell lines were incubated for 24 h at pH 6.6 and the expression of EMT markers was studied. In addition, mRNA expression of transcription and metabolic factors related to EMT was measured as well as the functional impact on cell adhesion, either during acidic incubation or after priming cells in an acidic milieu. E-cadherin and N-cadherin were down-regulated in all tumor and normal cell lines studied, whereas vimentin expression increased in only two tumor and one normal cell line. Down-regulation of the cadherins was seen in total protein and to a lesser extent in surface protein. In vivo an increase in N-cadherin and vimentin expression was found. Acidosis up-regulated Twist1 and Acsl1 but down-regulated fumarate hydratase (Fh). Cell adhesion during acidic incubation decreased in AT1 prostate carcinoma cells whereas preceding acidic priming increased their subsequent adhesion. Low tumor pH is able to modulate the expression EMT-related proteins and by this may affect the stability of the tissue structure.

Ellagic Acid Inhibits Extracellular Acidity-Induced Invasiveness and Expression of COX1, COX2, Snail, Twist 1, and c-myc in Gastric Carcinoma Cells

“…EMT is considered a crucial step for cancer metastasis, and expression of snail or twist1 has been shown to be linked to increased mesenchymal marker expression and high metastatic potential in several tumor cells and multiple mouse models. Recent reports have shown an impact of extracellular acidosis on the induction of several EMT-related genes including snail and twist1 [8,9]. Due to loss of E-cadherin in AGS and SNU601 cells, which is a common event in gastric cancer cells, we could not observe acidity-mediated reduction of E-cadherin expression, which is a critical sign of EMT.…”

“…In addition, acidity increased the mRNA protein expression of transcription factors snail, twist1, and c-myc; these were also reduced by ellagic acid. Together, these results suggest that ellagic acid suppresses acidity-enhanced migration and invasion of gastric cancer cells via inhibition of the expression of multiple factors (COX1, COX2, snail, twist1, and c-myc); for this reason, it may be an effective agent for cancer treatment under acidosis.Nutrients 2019, 11, 3023 2 of 12 to a more mesenchymal-like phenotype [9]. A low-pH environment triggers the loss of E-cadherin expression in melanoma cells, and tumor cells primed at acidic pH have an increased adherence to the surface at normal pH in vitro and a higher metastatic potential in vivo [10,11], implicating the role of acidity in the migration of tumor cells from the original acidic tumor tissue to another non-tumor site.…”

“…Nutrients 2019, 11, 3023 2 of 12 to a more mesenchymal-like phenotype [9]. A low-pH environment triggers the loss of E-cadherin expression in melanoma cells, and tumor cells primed at acidic pH have an increased adherence to the surface at normal pH in vitro and a higher metastatic potential in vivo [10,11], implicating the role of acidity in the migration of tumor cells from the original acidic tumor tissue to another non-tumor site.…”

Pharmacological Inhibition of CA-IX Impairs Tumor Cell Proliferation, Migration and Invasiveness

“…Furthermore, alkaline pHi can foster cancer cell migration by cytoskeletal reorganization [5]. Finally, an acidification of pHe can influence the invasive and metastatic potential of tumors by epithelial-mesenchymal transition (EMT) induction [6,7].…”

The Role of Aberrant Metabolism in Cancer: Insights Into the Interplay Between Cell Metabolic Reprogramming, Metabolic Syndrome, and Cancer

“…Promoting the epithelial to mesenchymal transition (EMT) and subsequent detachment of cancer cells from the extracellular matrix early during metastasis are vital potential mechanisms (24). Lactate accumulation and extracellular matrix acidification due to the enhanced glycolytic rate can promote EMT by regulating the expression of EMT-related proteins (25). Moreover, extracellular acidosis can activate matrix-metalloproteinases (MMPs), which play a crucial role in the degradation of extracellular matrix and subsequent invasion of cancer cells into the vascular wall (26).…”