Trends in Biochemical Sciences
ReviewSeries: Superlative SequelsHeat Shock Proteins Promote Cancer: It's a Protection Racket
Section snippets
Introduction to HSPs, Chaperones, and Cancer
HSPs are the effector components of a universal, explosive response to cellular stresses, most notably heat shock itself 1, 2. In fact, HSPs are expressed in such quantities after heat shock that they can be visualized as the dominant bands on 1D SDS PAGE gels after Coomassie blue staining; their abundance astonished some of the early investigators in the field. These proteins are synthesized in response to proteomic damage and can be thought of as components of a protein repair kit (Table 1).
HSPs and the Defining Traits of Cancer Cells
When the US President Richard Nixon signed the National Cancer Act in 1971, few would have predicted the complexities that such a ‘war on cancer’ would turn up. However, studies carried out by the cancer research community over the next 30 or so years, led Douglas Hanahan and Robert Weinberg to compile in 2000 a list of accepted ‘Hallmarks’ essential in tumorigenesis including: (i) unregulated proliferation; (ii) evasion of antigrowth signals; (iii) escape from programmed cell death (PCD); (iv)
HSP90: A Pivotal Factor in Evolution, Tumor Progression, and the Origin of Treatment-Resistant Phenotypes
In 1998, the Lindquist Lab made a groundbreaking discovery: that Hsp90 could have a role in Darwinian evolution in cells and organisms [70] (Box 2). Hsp90 appeared to participate in ‘canalization;’ that is, it smoothed over changes in phenotype despite the accumulation of genetic changes that occur naturally. Selection of new traits could be brought about by heat shock in which Hsp90 is sequestered by denatured proteins, or by Hsp90 inhibitors, when mutant conformations are unmasked by
HSF1 and HSPs in Cancer Stem Cells and Tumor Initiation
It has recently become apparent that tumors are heterogeneous at the cellular level and that only a fraction of the cell population is able to seed a new tumor [76]. The small tumor-initiating subpopulations have phenotypes similar to those of tissue stem cells, and are referred to as cancer stem cells (CSCs) (Box 3). The remainder of the tumor cells (nonstem cells, NSC) although continuing to proliferate, have reduced tumor-initiating capacity and therapy resistance and, thus, are not the
HSPs in Transgenic Tumor Models: In Vivo Veritas?
Within tumors, one or more dominant mutation(s) generally occur and these mutated proteins drive the malignant process [87]. Much may be learned about the roles of HSPs in tumorigenesis by studying transgenic mice that have been engineered to express dominant oncogenes. For instance, Sherman et al. discovered an essential role for Hsp70 in the Her2 mouse model [29]. Mammary tumors arising in such mice are a model for the Her2-positive subtype of human breast cancer [29]. In this case, the
Mechanisms: Do We Understand How HSP Levels Increase in Cancer?
We next ask: is there an overall hypothesis to account for the abundance of HSP expression in cancer cells and do such cells have reduced capacity to fold proteins? These questions were directly addressed in studies by Sherman et al., who monitored several criteria associated with cell stress and found that cancer cells do not seem to be in folding deficit [88]. However, there seems little doubt that cancer cells have an increased folding demand. This is evidenced by studies showing that
Extracellular Chaperones: The Jokers in the Pack
Although their existence was originally treated with some skepticism, the biological significance of extracellular HSPs is now growing rapidly. Extracellular HSPs can be proinflammatory in some contexts or show the opposite nature in others 90, 91. When used as vaccines to chaperone tumor antigens, they can stimulate specific tumor immunity and lead to tumor regression [80]. Thus, the direction of their effects appears to depend on the environment. When cells are exposed to elevated Hsp70
Concluding Remarks
There is overwhelming evidence that molecular chaperones, such as Hsp27, Hsp70, and Hsp90, are expressed at elevated levels in a range of cancers and their elevated expression indicates a poor prognosis in most diseases. HSP expression appears essential in many of the distinctive traits of malignant cells, including uncontrolled growth, reduced tumor suppression, enhanced cell survival, and the acquisition of powerful capacities for angiogenesis and metastasis. It was also recently shown that
Acknowledgments
The authors gratefully acknowledge support provided by NIH research grants, RO-1CA119045 and RO-1CA094397 to S.K.C.
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