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Review
. 2019 Jun;38(1-2):103-112.
doi: 10.1007/s10555-019-09796-3.

Acidosis and proteolysis in the tumor microenvironment

Kyungmin Ji  1 , Linda Mayernik  1 , Kamiar Moin  1 , Bonnie F Sloane  2
Affiliations
Review

Acidosis and proteolysis in the tumor microenvironment

Kyungmin Ji et al. Cancer Metastasis Rev. 2019 Jun.

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.

Keywords: Acidosis; Caveolae; Exosomes; Invadopodia; Lysosomes.

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Conflict of interest statement

Conflict of interest The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Cartoon illustrating acid-mediated extracellular proteolysis of bone by osteoclasts. A resorption pit comparable to an extracellular lysosome is created between the ruffled border of a multi-nucleated osteoclast and underlying bone. Sealing zones formed by podosome belts isolate the resorption pit. Lysosomes move toward the ruffled border and fuse with the membrane resulting in release of the cysteine protease cathepsin K into the resorption pit and incorporation of the vacuolar H+ ATPase in the lysosomal membrane into the ruffled border membrane. Acidification of the resorptive pit occurs as a result of generation of H+ ions by carbonic anhydrase II, also present in the ruffled border, and secretion of H+ ions into the pit by the vacuolar H+-ATPase. The organic matrix of the bone is degraded by the secreted cathepsin K
Fig. 2
Fig. 2
Cartoon illustrating acidosis-induced changes in trafficking of lysosomes and exosomes in cancer cells and in invadopodial and caveolar membrane structures associated with extracellular proteolysis in cancer cells. The invadopodium illustrated here is similar to the podosomal structures formed in normal cells such as osteoclasts (see Fig. 1) and associated with degradation of extracellular matrices. As in the osteoclast, lysosomes move into the invadopodium and fuse with the membrane resulting in the release of lysosomal proteases and incorporation of the vacuolar H+ ATPase in the lysosomal membrane into the invadopodial membrane. Similarly, secretion of exosomes occurs due to movement of multivesicular bodies (MVBs) into the invadopodium where they fuse with the membrane. This along with the plasma membrane sodium-hydrogen exchanger NHE1 in the invadopodial membrane results in local acidification and matrix degradation. Acidosis also increases secretion of lysosomes and exosomes from cancer cells in membrane regions other than invadopodia. Another membrane structure associated with acidosis and proteolysis is caveolae, which are dynamic membrane structures that transition in response to membrane stressors between flask-shaped invaginations as shown here and flat membranes. The invaginations are formed by oligomers of the major structural protein caveolin-1 (purple). Receptors, including those for proteases, clustered in caveolae facilitate signaling and proteolytic pathways at the surface of cancer cells. NHE1 and NaV1.5 sodium channels also are present in caveolae, leading to increased local acidification
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