Cancer heterogeneity and metastasis: life at the edge.

There is abundant evidence that the phenotype of cells the tumor at the stromal interface is distinct from the tumor cells that are within the core. Molecular phenotyping of cells at the edge show that they express higher levels of proteins associated with elevated glycolytic metabolism, including GLUT-1, HIF-1, and CA-IX. An end product of glycolysis is the production of acid, and acidosis of tumors is strongly associated with increased metastatic potential across a wide variety of tumor types. The molecular machinery promoting this export of acid is being defined, with close collaboration between carbonic anhydrases, sodium dependent bicarbonate and monocarboxylate transporters. Neutralization of this acidity can prevent local invasion and metastasis, and this has led to the "acid-mediated invasion hypothesis" wherein export of acid from the tumor into the stroma leads to matrix remodeling, which can promote local invasion.