Hsp60 secretion and migration from cancer cells: a proposal for a multistage pathway

Abstract

Hsp60 can be released by tumor cells to promote growth. Hsp60 exits mitochondria, reaches the blood and distant targets by mechanisms not yet understood. We determined Hsp60 levels and secretion in normal and tumor cell lines in cell lysates, medium, exosomes, membranes, lipid rafts, and other materials, by ultracentrifugation, electrophoresis, Western blotting, ELISA, EM, and enzymatic tests. Exosomes were purified and characterized by EM and by presence of ALIX, Hsp90, Hsp70, ATPase, and AChE. The tumor, not the normal cells secreted Hsp60, in the absence of cell death, involving lipid rafts-exosome pathways; Hsp60 associated with lipid-rafts and cell and exosomal membranes. A working model predicts: Hsp60 gets in the cytosol from mitochondria or from synthesis in the cytosol without entering the organelle, arrives at the cell membrane and binds lipid rafts and, through lipid-raft mediated endocytosis, is included in early endosomes and then in multivesicular bodies and, lastly, in exosomes for secretion. Hsp60 in exosomes may then reach components of the innate immune system and trigger inflammation; endothelial cells to elicit neoangiogenesis; and other tumor cells to block apoptosis and promote cancer survival.