The many roles of molecular chaperones and co-chaperones in tumour biology.

Molecular chaperones (heat-shock proteins, Hsps) are proteins that maintain intracellular homeostasis through folding and stabilisation of the conformation of other proteins. Molecular chaperones are critical for survival of cells that undergo cellular stress due to their ability to guard the proteome against misfolded proteins and aggregation. In addition to their canonical role in basic cellular homeostasis and protection against external stress, several molecular chaperones play a fundamental role in malignant cell transformation. The level of molecular chaperones is increased in many solid tumours and haematological malignancies. The increased activity of Hsps in cancer cells reflects the ability of chaperones to compensate for stress caused by hypoxia, increased protein turnover and the presence of numerous mutated and potentially unstable proteins. In addition, chaperones allow tumour cells to tolerate genetic alterations by stabilising tertiary structure of mutated unstable proteins - typically oncoproteins that would otherwise be lethal. From this perspective, chaperones mediate the phenotypic expression of oncogenic mutations and contribute to all the hallmarks of cancer cells. Due to their indispensable roles for cancer cells, chaperones became an attractive group of targets for novel cancer therapies affecting several essential oncogenic pathways simultaneously.