Tumor pH and metastasis: a malignant process beyond hypoxia

Area of Science:

• Oncology
• Cancer Biology
• Metabolic Regulation

Background:

• Tumors exhibit decreased extracellular pH (acidosis) due to altered glycolysis and impaired acid metabolite removal.
• Tumor acidosis, independent of hypoxia, is increasingly recognized as a driver of cancer cell metastasis and poorer patient prognosis.

Purpose of the Study:

• To provide a comprehensive overview of how tumor acidosis influences critical steps in the metastatic cascade.
• To elucidate the pH-dependent cellular mechanisms and signaling pathways involved in tumor cell metastasis.
• To discuss potential therapeutic strategies targeting tumor acidosis and associated signaling pathways.

Main Methods:

• Literature review synthesizing current research on tumor microenvironment pH and metastasis.
• Analysis of pH-dependent cellular processes including invasion, angiogenesis, intravasation, and extravasation.
• Examination of proton sensing mechanisms and downstream signaling cascades in cancer cells.

Main Results:

• Low extracellular pH promotes local invasion, angiogenesis, and the epithelial-to-mesenchymal transition (EMT).
• Acidosis facilitates tumor cell detachment, survival in circulation, and subsequent invasion of secondary sites.
• Tumor cells utilize specific ion channels (ASICs, TRPs) and transporters (NHE1) for proton sensing, activating signaling pathways that enhance metastatic potential.

Conclusions:

• Tumor acidosis is a critical factor enabling multiple stages of cancer metastasis.
• Targeting proton sensing mechanisms and signaling pathways offers promising therapeutic avenues to reduce metastatic spread.
• Modulating the tumor microenvironment pH could be a viable strategy to improve cancer patient outcomes.