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As an extension of their orchestration of intracellular pathways, secretion of extracellular heat shock proteins (HSPs) is an emerging paradigm of homeostasis imperative to multicellular organization. Extracellular HSP is axiomatic to the survival of cells during tumorigenesis; proportional representation of specific HSP family members is indicative of invasive potential and prognosis. Further significance has been added by the knowledge that all cancer-derived exosomes have surface-exposed HSPs that reflect the membrane topology of cells that secrete them. Extracellular HSPs are also characteristic of chronic inflammation and sepsis. Accordingly, interrogation of extracellular HSPs secreted from cell culture models may represent a facile means of identifying translational biomarker signatures for targeting in situ. In the current study, we evaluated a simple peptide-based multivalent HSP affinity approach using the Vn96 peptide for low speed pelleting of HSP complexes from bioreactor cultures of cell lines with varying invasive phenotype in xenotransplant models: U87 (glioblastoma multiforme; invasive); HELA (choriocarcinoma; minimally invasive); HEK293T (virally transformed immortalized; embryonic). Proteomic profiling by bottom-up mass spectrometry revealed a comprehensive range of candidate biomarkers including primary HSP ligands. HSP complexes were associated with additional chaperones of prognostic significance such as protein disulfide isomerases, as well as pleiotropic metabolic enzymes, established as proportionally reflective of invasive phenotype. Biomarkers of inflammatory and mechanotransductive phenotype were restricted to the most invasive cell model U87, including chitinase CHI3L1, lamin C, amyloid derivatives, and histone isoforms.


Steven G Griffiths, Alan Ezrin, Emily Jackson, Lisa Dewey, Alan A Doucette. A robust strategy for proteomic identification of biomarkers of invasive phenotype complexed with extracellular heat shock proteins. Cell stress & chaperones. 2019 Nov;24(6):1197-1209

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PMID: 31650515

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