Grp94 in complexes with IgG is a soluble diagnostic marker of gastrointestinal tumors and displays immune-stimulating activity on peripheral blood immune cells.
Glucose-regulated protein94 (Grp94), the most represented endoplasmic reticulum (ER)-resident heat shock protein (HSP), is a tumor antigen shared by different types of solid and hematological tumors. The tumor-specific feature of Grp94 is its translocation from the ER to the cell surface where it displays pro-oncogenic functions. This un-physiological location has important implications for both the tumor pathology and anti-tumor therapy. We wanted to address the question of whether Grp94 could be measured as liquid marker in cancer patients in order to make predictions of diagnostic and therapeutic relevance for the tumor. To this aim, we performed an in-depth investigation on patients with primary tumors of the gastrointestinal (GI) tract, using different methodological approaches to detect Grp94 in tumor tissues, plasma and peripheral blood mononuclear cells (PBMCs). Results indicate that Grp94 is not only the antigen highly expressed in any tumor tissue and in cells of tumor infiltrates, mostly B lymphocytes, but it is also found in the circulation. However, the only form in which Grp94 was detected in the plasma of any patients and in B lymphocytes induced to proliferate, was that of stable complexes with Immunoglobulin (Ig)G. Using a specific immune-enzyme assay to measure plasma Grp94-IgG complexes, we showed that Grp94-IgG complexes were significantly increased in cancer patients compared to healthy control subjects, serving as diagnostic tumor biomarker. Results also demonstrate that the stimulation of patient PBMCs with Grp94-IgG complexes led to an increased secretion of inflammatory cytokines that might drive a potentially beneficial anti-tumor effect.
Department of Biology, University of Padua, 35121 Padua, Italy.
Elisa
E
Tramentozzi
Department of Statistical Sciences, University of Padua, 35121 Padua, Italy.
Erlis
E
Ruli
Division of General Surgery, University of Padua, 35121 Padua, Italy.
Imerio
I
Angriman
Division of General Surgery, University of Padua, 35121 Padua, Italy.
Romeo
R
Bardini
Department of Surgical and Diagnostic Sciences (DISC), University of Genova, 16132 Genova, Italy.
Michela
M
Campora
Department of Medicine, DMED, University of Padua, 35121 Padua, Italy.
Vincenza
V
Guzzardo
Istituto Oncologico Veneto IOV, I.R.C.C.S., 35128 Padua, Italy.
Rita
R
Zamarchi
Department of Surgery, Oncology and Gastroenterology, Oncology Section, University of Padova, Padova, Italy & IOV-IRCCS, Padova, Italy.
Elisabetta
E
Rossi
Department of Medicine, DMED, University of Padua, 35121 Padua, Italy.
Massimo
M
Rugge
Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35131 Padua, Italy.
Paola
P
Finotti
D000917:Antibody Formation / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014408:Biomarkers, Tumor; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000175:diagnosis* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology* / Q000378:metabolism; D056747:Immunomodulation; D018836:Inflammation Mediators / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D008954:Models, Biological; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011485:Protein Binding
D014408:Biomarkers, Tumor; D016207:Cytokines; D007074:Immunoglobulin G; D018836:Inflammation Mediators; D008562:Membrane Glycoproteins; C053387:endoplasmin
biomarkers; gastrointestinal neoplasms; heat shock Proteins; immunoglobulins; immunomodulation
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