Heat shock proteins and cancer: intracellular chaperones or extracellular signalling ligands?

Abstract

Heat shock proteins (HSPs) are found at elevated concentrations in tumour cells, and this increase reflects the proteotoxic stress experienced by the cells due to expanding levels of the mutated oncoproteins that drive tumorigenesis. The protection of oncogenic proteins by HSPs offers a window of vulnerability in tumour metabolism that has been exploited using Hsp90-targeting drugs. Such compounds have been shown to cause inhibition and degradation of a wide range of proteins essential for oncogenesis. Recently, Hsp90 has also been shown to be secreted by tumour cells and to interact in autocrine or paracrine manners with the surfaces of adjacent cells, leading to increased growth and metastasis. Future studies will address a number of key questions associated with these findings, including the relative importance of intracellular versus extracellular HSPs in tumorigenesis, as well as overcoming potential problems with normal tissue toxicity associated with Hsp90 drugs. Targeting individual members of HSP families and inactivating extracellular HSPs may be desirable future approaches that offer increased selectivity in targeting HSPs in cancer.This article is part of the theme issue 'Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective'.

Keywords: cancer; extracellular HSP90; gene family member; heat shock protein; intracellular HSP90; therapy.

Figure 1.

Addiction of emerging tumour cells to chaperones. We depict three possible fates for oncogenes that become overexpressed in tumour cells. In the upper part of the figure, we depict failed amplification of oncogene levels in the absence of increase in HSP levels, with levels reducing to those in the original cells and absence of cancer signalling. In the middle route, oncogene levels increase coordinately with HSP concentrations. This stable increase in oncogenic protein accumulation permits cancer signalling to proceed as intracellular controls are overcome by the greater oncogene load. In the lower part of the figure, although oncogene and HSP levels increase in tandem, administration of Hsp90 drugs (black dot) inhibits chaperoning and cancer signalling does not proceed. (Online version in colour.)

Figure 2.

Tumorigenic effects of intracellular HSPs. Elevated levels of Hsp27 and Hsp70 are particularly effective in inhibiting oncogene induced senescence and apoptosis but are also important in permitting de novo angiogenesis, invasion and metastasis. Increased levels of Hsp90 affect most areas of tumorigenesis including stimulus-independent tumour cell growth, escape from senescence, invasion of surrounding tissues and metastasis. (Online version in colour.)