Impact of Heat-Shock Protein 90 on Cancer Metastasis
Impact of Heat-Shock Protein 90 on Cancer Metastasis
Cancer metastasis is the result of complex processes, including alteration of cell adhesion/motility in the microenvironment and neoangiogenesis, that are necessary to support cancer growth in tissues distant from the primary tumor. The molecular chaperone heat-shock protein 90 (Hsp90), also termed the 'cancer chaperone', plays a crucial role in maintaining the stability and activity of numerous signaling proteins involved in these processes. Small-molecule Hsp90 inhibitors display anticancer activity both in vitro and in vivo, and multiple Phase II and Phase III clinical trials of several structurally distinct Hsp90 inhibitors are currently underway. In this review, we will highlight the importance of Hsp90 in cancer metastasis and the therapeutic potential of Hsp90 inhibitors as antimetastasis drugs.
Cancer is the leading cause of death worldwide, and was responsible for 7.9 million deaths in 2007. However, the major cause of human cancer deaths is metastasis to distant tissues, not growth of the primary tumor itself. Cancer metastasis is the result of a series of sequential and highly orchestrated processes, including alteration of cancer cell adhesion/motility and the ability to induce neoangiogenesis. Cancer cells must rely on a number of signaling proteins that regulate these events. Many of these signaling proteins are 'clients' of heat-shock protein 90 (Hsp90), in that they rely on this molecular chaperone for proper folding, stability and function (Figure 1 & Table 1).
(Enlarge Image)
Figure 1.
Heat-shock protein 90 plays multiple roles in cancer metastasis. EGFR: EGF receptor; HIF: Hypoxia-inducible factor; Hsp90: Heat-shock protein 90; IGF-1R: Type 1 IGF receptor; MMPs: Matrix metalloproteinases; PDGFR: PDGF receptor; VEGFR: VEGF receptor.
Abstract and Introduction
Abstract
Cancer metastasis is the result of complex processes, including alteration of cell adhesion/motility in the microenvironment and neoangiogenesis, that are necessary to support cancer growth in tissues distant from the primary tumor. The molecular chaperone heat-shock protein 90 (Hsp90), also termed the 'cancer chaperone', plays a crucial role in maintaining the stability and activity of numerous signaling proteins involved in these processes. Small-molecule Hsp90 inhibitors display anticancer activity both in vitro and in vivo, and multiple Phase II and Phase III clinical trials of several structurally distinct Hsp90 inhibitors are currently underway. In this review, we will highlight the importance of Hsp90 in cancer metastasis and the therapeutic potential of Hsp90 inhibitors as antimetastasis drugs.
Introduction
Cancer is the leading cause of death worldwide, and was responsible for 7.9 million deaths in 2007. However, the major cause of human cancer deaths is metastasis to distant tissues, not growth of the primary tumor itself. Cancer metastasis is the result of a series of sequential and highly orchestrated processes, including alteration of cancer cell adhesion/motility and the ability to induce neoangiogenesis. Cancer cells must rely on a number of signaling proteins that regulate these events. Many of these signaling proteins are 'clients' of heat-shock protein 90 (Hsp90), in that they rely on this molecular chaperone for proper folding, stability and function (Figure 1 & Table 1).
(Enlarge Image)
Figure 1.
Heat-shock protein 90 plays multiple roles in cancer metastasis. EGFR: EGF receptor; HIF: Hypoxia-inducible factor; Hsp90: Heat-shock protein 90; IGF-1R: Type 1 IGF receptor; MMPs: Matrix metalloproteinases; PDGFR: PDGF receptor; VEGFR: VEGF receptor.