title: Emerging Roles of Extracellular Hsp90 in Cancer.
abstract: Heat shock protein 90 (Hsp90) is a highly expressed chaperone that modulates the function and stability of hundreds of cellular client proteins. In this capacity, Hsp90 impacts human health in myriad ways and it is accordingly a high-interest molecular target in the oncology setting. This interest has led to a large number of clinical trials to evaluate the potential benefit of Hsp90 inhibitors in cancer treatment and, more recently, in combination with chemotherapeutic agents. Although these studies are still ongoing, some issues have arisen, such as toxicity effects associated with administration of these agents. We and others have identified a novel role for Hsp90 outside of cancer cells. This extracellular Hsp90 (eHsp90) was shown to be critical for the regulation of tumor invasiveness and metastasis, central processes associated with cancer lethality. Since these initial papers, a considerable cohort of studies has expanded upon this role, implicating eHsp90 in the activation of a number of proteins that support tumor cell invasion. As eHsp90 is preferentially detected on the surface of tumor cells, and within their surrounding microenvironment, it is possible that drugs capable of selectively targeting eHsp90 may exploit this differential expression. This selectivity may, in turn, enable treatment regimens with reduced target-related toxicity. This review will focus on our current understanding of eHsp90, particularly in cancer, and we will discuss the relevance of eHsp90 as a biomarker for invasive cancer and its potential as a drug target.
authors.affiliation: Graduate Program in Cellular and Molecular Physiology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA.
authors.forename: Daniel Senh
authors.initials: DS
authors.lastname: Wong
authors.affiliation: Department of Developmental, Molecular, and Chemical Biology, School of Medicine, Tufts University, Boston, Massachusetts, USA. Electronic address: daniel.jay@tufts.edu.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Jay
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002465:Cell Movement; D016503:Drug Delivery Systems; D055354:Exosomes / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D021381:Protein Transport; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018841:HSP90 Heat-Shock Proteins; D008565:Membrane Proteins
keywords: Cancer; Exosomes; Extracellular Hsp90; Invasion; Metastasis; Signaling