Extracellular HSP90α Versus Intracellular HSP90β in Wound Healing and Cancer

Abstract

Of ~7000 gene products generated by an average cell, 2-3% of them are accounted for by the Hsp90 family of proteins. Mammals have two members of Hsp90, Hsp90α and Hsp90β, with which they respond to environmental stress, especially during tissue ischemia. Hsp90β fulfills the role of an important intracel-lular chaperone, whereas Hsp90α is dispensable inside the cell. Instead, Hsp90α gets secreted and the extracellular Hsp90α protects surrounding cells from hypoxia-induced cell death and promotes cell migration, during wound healing. The cell surface receptor, LRP-1, binds and mediates extracellular Hsp90α signaling by activating Akt kinases independently of Hsp90α's intrinsic ATPase. Topical application of recombinant Hsp90α promotes healing of acute, diabetic and burn wounds. Tumors take advantage of these protective functions of both intracellular and extra-cellular Hsp90 family proteins to cope with the constant paucity of oxygen and nutrients within the tumor microenvironment. Unlike intracellular Hsp90β which is equally critical to the survival of both tumor and normal cells, secreted Hsp90α is non-essential for maintaining physiological homeostasis. In contrast, tumor cells constitutively secrete Hsp90α and use secreted Hsp90α to prevent tumor cell death under hypoxic conditions and to promote tumor cell invasion and metastasis. Monoclonal antibodies that selectively target tumor-secreted Hsp90α may prove more effective and less toxic than those that target the ATPase of the intracellular Hsp90β.