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 Na_V1.5 sodium channels also are present in caveolae, leading to increased local acidification