Regulation of somatostatin receptor 4-mediated cytostatic effects by CD26 in malignant pleural mesothelioma

Abstract

Background:Malignant pleural mesothelioma (MPM) is an aggressive neoplasm arising from mesothelial lining of pleura. CD26 molecules preferentially expressed on epithelioid type of MPM. This study investigates the molecular mechanisms of CD26 regulating MPM cells in vitro and in vivo.Methods:Biochemical and cell biological approaches were used for identifying a novel molecular target of MPM. Its contribution to tumour expansion has been also assessed using animal models. The clinical samples of MPM were also assessed for its expression.Results:We identify that cytostatic effects in MPM are mediated by somatostatin (SST) receptor 4 (SSTR4), being inhibited by the interaction of CD26 molecules. We also indicates that SSTR4-mediated cytostatic effects are regulated by SHP-2 PTP, and that this inhibitory effect by SST agonist is enhanced via lipid raft clustering of associated molecules following crosslinking of anti-CD26 antibody. Finally, using an in vivo xenograft model, we demonstrate that the anti-tumour effect of anti-CD26 mAb is enhanced when combined with SSTR4 agonist treatment, and that SSTR4 is highly coexpressed with CD26 on epithelioid or biphasic types of MPM tissues obtained from patients' surgical specimens.Conclusions:Combination therapy with humanised anti-CD26 mAb and SSTR4 agonist may therefore potentiate anti-tumour effect on MPM.

Regulation of Pulmonary Graft-versus-Host Disease by IL-26+CD26+CD4 T Lymphocytes

“…A total of 1 × 10 5 A20-luc cells was inoculated via tail vein on day +28 posttransplantation. Tumor dissemination was monitored every week using in vivo bioluminescence imaging, as previously described in the literature (36). …”

International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature

“…When expressed in malignant pleural mesothelioma cells, human SST 4 activates SHP-1 and SHP-2. Downstream signaling through SHP-2 is required for cytostatic effects of SST 4 observed in these cells ( Yamamoto et al, 2014 ). In transfected CHO cells, SST 4 causes PI3K-dependent activation of NHE1 and increases extracellular acidification rate ( Smalley et al, 1999 ).…”

“…SST 4 and CD26 are highly coexpressed and interact through their cytoplasmic domains in malignant pleural mesothelioma cells. The SST 4 –CD26 interaction reduces cytostatic effects of SST 4 agonists ( Yamamoto et al, 2014 ). Their efficacy was enhanced by suppression of CD26 as well as by treatment of cells with anti-CD26 mAbs.…”

Development of novel monoclonal antibodies with specific binding affinity for denatured human CD26 in formalin-fixed paraffin-embedded and decalcified specimens

“…A human MPM cell line MSTO-211H (MSTO parent), a human lung cancer cell line A549 and a human T-cell leukemia line Jurkat (Jurkat parent) were obtained from the American Type Culture Collection (Rockville, MD). MSTO parent cells were stably transfected with a full-length human CD26 (MSTO-CD26) using the Lipofectamine2000 reagent (Invitrogen, Carlsbad, CA), and selected with G418 (Sigma-Aldrich, St Louis, MO) [23]. The human MPM cell line JMN was a kind gift from Dr. Brenda Gerwin (Laboratory of Human Carcinogenesis, National Institutes of Health, Brethesda, MD).…”

“…Besides our work over the past three decades characterizing its role in the immune system, our group has also had a long-standing interest in the role of CD26 in cancer biology. We have previously demonstrated that anti-CD26 monoclonal antibody (mAb) treatment resulted in both in vitro and in vivo inhibition of tumor cell growth, migration and invasion, and enhanced survival of mouse xenograft models inoculated with T-cell lymphoma, RCC or MPM via multiple mechanisms of action [19–23]. These findings have led to our focus on CD26 as a novel therapeutic target for various tumors, and the development of YS110, a humanized mAb with high affinity to the CD26 antigen.…”