The dark-side of the outside: how extracellular heat shock proteins promote cancer

Abstract

In addition to exerting several essential house-keeping activities in the cell, heat shock proteins (HSPs) are crucial players in a well-structured molecular program activated in response to stressful challenges. Among the different activities carried out by HSPs during emergency, they reach the extracellular milieu, from where they scout the surroundings, regulate extracellular protein activity and send autocrine and paracrine signals. Cancer cells permanently experience stress conditions due to their altered equilibrium and behaviour, and constantly secrete heat shock proteins as a result. Other than supporting anti-tumour immunity, extracellular heat shock proteins (eHSPs), can also exacerbate cancer cell growth and malignancy by sustaining different cancer hallmarks. eHSPs are implicated in extracellular matrix remodelling, resistance to apoptosis, promotion of cell migration and invasion, induction of epithelial to mesenchymal transition, angiogenesis and activation of stromal cells, supporting ultimately, metastasis dissemination. A broader understanding of eHSP activity and contribution to tumour development and progression is leading to new opportunities in the diagnosis and treatment of cancer.

Inflammation, Extracellular Matrix Remodeling, and Proteostasis in Tumor Microenvironment

“…Molecular chaperones are first-line players of the proteostasis network due to their ubiquitous expression and their ability to stabilize proteins in their native conformation, re-fold denatured polypeptides, inhibit unfolded protein aggregation, and direct misfolded proteins to proteasomal and autophagic degradation [ 99 , 100 ]. The wide and heterogeneous family of molecular chaperones comprises, among others, the heat shock proteins (HSPs), a family of stress-proteins that are induced in response to physical, chemical, and biological insults to support cell survival [ 101 ]. According to their molecular weight, HSPs are currently classified into six groups.…”

“…The function of extracellular HSPs (eHSP) in the TME is not limited to the canonical function of stress proteins that counteract protein unfolding (reviewed in Richter K. et al) [ 107 ]. More recent studies highlighted that eHSPs take part in the complex signaling network that influences the fate of cancer cells with different outcomes depending on the stage of the pathology [ 101 ]. They counteract tumor growth due to their ability to bind antigenic peptides and activate anti-tumor innate immunity [ 108 ], thus promoting immune surveillance and inhibiting inflammation [ 109 ].…”

“…They counteract tumor growth due to their ability to bind antigenic peptides and activate anti-tumor innate immunity [ 108 ], thus promoting immune surveillance and inhibiting inflammation [ 109 ]. However, they favor tumor progression and metastasis formation by sustaining cancer proliferation, cell migration and invasion, neo-angiogenesis, and immune escape [ 101 ].…”

“…The eHSPs interact directly with cell surface receptors and consequently engage intracellular signaling pathways that influence cell behavior [ 101 ]. Low-density lipoprotein receptor-related protein 1 (LRP1) is a common receptor for many extracellular chaperones, both in normal and cancer cells where its expression is often upregulated [ 110 ].…”

Hyperthermic Intraperitoneal Chemotherapy: A Critical Review

“…Others have shown, however, potentially adverse effects of local heating on overall tumor immunity [43]. HSPs s can promote cancer growth and malignant behavior by the induction of extracellular matrix remodeling, resistance to apoptosis, epithelial to mesenchymal transition, tumor angiogenesis, and metastasis [44]. A recent phase-2 clinical trial investigated the potential additional value of autologous tumor antigen-loaded αDC1 vaccine in patients undergoing CRS and HIPEC for peritoneal metastases.…”