Unconventional Secretion of Heat Shock Proteins in Cancer

Abstract

Heat shock proteins (HSPs) are abundant cellular proteins involved with protein homeostasis. They have both constitutive and inducible isoforms, whose expression levels are further increased by stress conditions, such as temperature elevation, reduced oxygen levels, infection, inflammation and exposure to toxic substances. In these situations, HSPs exert a pivotal role in offering protection, preventing cell death and promoting cell recovery. Although the majority of HSPs functions are exerted in the cytoplasm and organelles, several lines of evidence reveal that HSPs are able to induce cell responses in the extracellular milieu. HSPs do not possess secretion signal peptides, and their secretion was subject to widespread skepticism until the demonstration of the role of unconventional secretion forms such as exosomes. Secretion of HSPs may confer immune system modulation and be a cell-to-cell mediated form of increasing stress resistance. Thus, there is a wide potential for secreted HSPs in resistance of cancer therapy and in the development new therapeutic strategies.

Keywords: cancer; exosomes; heat shock proteins; unconventional secretion.

Figure 1

Functions of extracellular HSPs in cancer. Secreted HSPs whose functions were described as (A) anti-tumor immunomodulation; (B) pro-tumor immunomodulation; (C) cell proliferation; (D) angiogenesis; (E) cell invasion. APC, antigen presenting cell; DC, dendritic cell.