Acidosis and proteolysis in the tumor microenvironment

Abstract

The glycolytic phenotype of the Warburg effect is associated with acidification of the tumor microenvironment. In this review, we describe how acidification of the tumor microenvironment may increase the invasive and degradative phenotype of cancer cells. As a template of an extracellular acidic microenvironment that is linked to proteolysis, we use the resorptive pit formed between osteoclasts and bone. We describe similar changes that have been observed in cancer cells in response to an acidic microenvironment and that are associated with proteolysis and invasive and metastatic phenotypes. This includes consideration of changes observed in the intracellular trafficking of vesicles, i.e., lysosomes and exosomes, and in specialized regions of the membrane, i.e., invadopodia and caveolae. Cancer-associated cells are known to affect what is generally referred to as tumor proteolysis but little direct evidence for this being regulated by acidosis; we describe potential links that should be verified.

Increased proton-sensing receptor GPR4 signalling promotes colorectal cancer progression by activating the hippo pathway

“…Acidosis has been reported as one of the early events in solid tumours and is defined as a characteristic of the tumour microenvironment [35]. Given that acidosis is a stressor and select cancer cells are suited for an acidic microenvironment, targeting tumour acid homeostasis would be potential strategies.…”

Focus on the morphogenesis, fate and the role in tumor progression of multivesicular bodies

“…Valcz et al identified the most aberrantly expressed MVB markers and revealed the transition of diffuse ALIX signals into a MVB-like pattern during the adenoma-carcinoma sequence, which may provide clues to revealing the interactions between cancer and the surrounding microenvironment, particularly those involving the regulation of tumor growth and metastatic invasion [148]. Moreover, the formation of invadopodia (see above) in many types of cancer drives cell invasion, depending on enhanced MVB docking and fusion with the plasma membrane [85,102,149]. Therefore, we believe that invadopodia formation is the first step in tumor cell invasion and metastasis, in which MVB-mediated transport of MMPs to degrade the extracellular matrix is an important step [85,89,102,149].…”

“…Moreover, the formation of invadopodia (see above) in many types of cancer drives cell invasion, depending on enhanced MVB docking and fusion with the plasma membrane [85,102,149]. Therefore, we believe that invadopodia formation is the first step in tumor cell invasion and metastasis, in which MVB-mediated transport of MMPs to degrade the extracellular matrix is an important step [85,89,102,149]. A recent study revealed that VAMP3-dependent secretion of MT1-MMP enhances the degradation of the extracellular matrix, and induces cancer cell invasion [102].…”

A mitochondrial-targetable dual functional near-infrared fluorescent probe to monitor pH and H2O2 in living cells and mice

“…[1][2][3][4] However, abnormal intracellular pH is associated with cellular dysfunctions such as cancer and neurodegenerative disorders. 5,6 Hydrogen peroxide (H 2 O 2 ), an important member of reactive oxygen species (ROS) mediates signal cascades involved in redox homeostasis. 7 Substantial evidence has showed that excessive H 2 O 2 is relevant to serious diseases including cardiovascular disorders, neurodegenerative diseases, cancer and diabetes.…”