Activation of the macrophage-stimulating protein (MSP)-RON axis in malignant pleural mesothelioma.

Abstract

e17508 Background: Evidence supports a role for macrophage activity in mesothelioma genesis. Malignant pleural mesothelioma (MPM) is resistant to chemotherapy, and receptor tyrosine kinases (RTK) represent novel therapeutic targets. We previously identified macrophage stimulating 1 receptor (MST1R/RON) as frequently activated in MPM. Immunohistochemistry (IHC) studies found high positivity for RON staining was an independent predictor of favourable prognosis (J Clin Oncol 28:15s, 2010 (suppl; abstr 10583). The RON ligand, macrophage stimulating protein (MSP), promotes phagocytosis and terminal differentiation of macrophages. We hypothesized that MSP may play a role in MPM genesis. Methods: We investigated the expression and function of MSP in MPM. IHC was performed for MSP on a TMA array of FFPE samples resected from 352 patients. MSP was immunoprecipated from MPM cell conditioned medium and detected by Western Blot analysis. ELISA was used to study MSP in serum derived from n=20 patients with MPM vs n=20 normal. Expression of RON was analysed on a second set of FFPE samples of MPM. We repeated IHC using antisera specific for full length RON. Results: Immunoprecipitation and western blot analysis detected MSP in conditioned medium from MPM cell lines. The presence of MSP message was confirmed by RT-PCR in MPM cells. On ELISA, sera from patients with MPM contained immunoreactive MSP, although amounts were not significantly different from control patients. IHC was performed on a TMA array of FFPE samples. Ninety three % showed MSP expression as follows: weak (32%), moderate (38%), intense (21%). Full length RON was detected in mesothelioma using specific antisera. Most mesotheliomas (86%) were double positives (RON/MSP), small subpopulations expressed MSP (5%) or RON (6%) alone, and 2% were double negatives. Correlation of the IHC scores with clinico-pathological and outcomes variables is ongoing. Conclusions: RON staining is an independent predictor of favourable prognosis. MSP is frequently expressed in MPM. Co-expression of MSP and RON in MPM cells may indicate an autocrine signalling pathway and paracrine activation of macrophages. The MSP-RON axis may be a novel therapeutic target in mesothelioma.