Acidosis Promotes Metastasis Formation by Enhancing Tumor Cell Motility

Area of Science:

• Oncology
• Cancer Biology
• Metabolic Alterations in Cancer

Background:

• The tumor microenvironment (TME) features hypoxia, acidosis, and metabolic changes impacting cancer progression.
• Acidosis in the TME is increasingly recognized for its role in enhancing cancer cell invasiveness and metastasis.

Purpose of the Study:

• To investigate the effect of acidosis on metastasis formation in rat carcinoma cell lines.
• To analyze the pH dependency of metastasis steps, including invasiveness, cell adhesion, and migration of AT-1 prostate cancer cells in vitro.
• To explore the underlying cell signaling pathways involved in acidosis-induced metastatic potential.

Main Methods:

• In vivo studies using a rat carcinoma cell line animal model to assess metastasis formation under acidic conditions.
• In vitro experiments evaluating invasiveness, cell adhesion (to plastic and endothelial layers), and cellular motility of AT-1 prostate cancer cells at varying pH levels.
• Analysis of reactive oxygen species (ROS) production and key signaling pathways (MAP kinases ERK1/2, p38, Src family kinases) to elucidate mechanisms.

Main Results:

• Acidosis significantly increased lung metastasis formation for both tested tumor cell lines in vivo.
• In vitro, extracellular acidosis did not enhance invasiveness or affect cell adhesion.
• Cellular motility was significantly elevated at pH 6.6, an effect that persisted even when the extracellular pH returned to 7.4. This enhanced motility was linked to increased ROS production.
• Signaling pathways involving MAP kinases ERK1/2, p38, and Src family kinases were not implicated in this acidosis-induced migratory enhancement.

Conclusions:

• Acidosis in the tumor microenvironment can induce sustained enhancement of cancer cell motility.
• This enhanced motility, dependent on ROS production, can persist after tumor cells leave the acidic environment, potentially contributing to increased metastasis.
• The findings highlight a mechanism by which acidic tumor microenvironments promote cancer spread.