Research Papers:

Grp94 in complexes with IgG is a soluble diagnostic marker of gastrointestinal tumors and displays immune-stimulating activity on peripheral blood immune cells

Elisa Tramentozzi, Erlis Ruli, Imerio Angriman, Romeo Bardini, Michela Campora, Vincenza Guzzardo, Rita Zamarchi, Elisabetta Rossi, Massimo Rugge and Paola Finotti _

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Oncotarget. 2016; 7:72923-72940. https://doi.org/10.18632/oncotarget.12141

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Elisa Tramentozzi1, Erlis Ruli2, Imerio Angriman3, Romeo Bardini3, Michela Campora4, Vincenza Guzzardo7, Rita Zamarchi5, Elisabetta Rossi6, Massimo Rugge7, Paola Finotti8

1Department of Biology, University of Padua, 35121 Padua, Italy

2Department of Statistical Sciences, University of Padua, 35121 Padua, Italy

3Division of General Surgery, University of Padua, 35121 Padua, Italy

4Department of Surgical and Diagnostic Sciences (DISC), University of Genova, 16132 Genova, Italy

5Istituto Oncologico Veneto IOV, I.R.C.C.S., 35128 Padua, Italy

6Department of Surgery, Oncology and Gastroenterology, Oncology Section, University of Padova, Padova, Italy & IOV-IRCCS, Padova, Italy

7Department of Medicine, DMED, University of Padua, 35121 Padua, Italy

8Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35131 Padua, Italy

Correspondence to:

Paola Finotti, email: [email protected]

Keywords: gastrointestinal neoplasms, heat shock proteins, immunoglobulins, immunomodulation, biomarkers

Received: March 23, 2016     Accepted: September 12, 2016     Published: September 20, 2016


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.

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