Complement Protein C1q Binds to Hyaluronic Acid in the Malignant Pleural Mesothelioma Microenvironment and Promotes Tumor Growth.

Chiara Agostinis,Fabrizio Zanconati,Romana Vidergar,Violetta Borelli,Alessandro Mangogna,Beatrice Belmonte,Marco Confalonieri,Roberta Bulla,Pietro Geri,Claudio Tripodo,Francesco Tedesco,Uday Kishore,Leonardo Amadio

doi:10.3389/fimmu.2017.01559

Abstract

C1q is the first recognition subcomponent of the complement classical pathway, which acts toward the clearance of pathogens and apoptotic cells. C1q is also known to modulate a range of functions of immune and non-immune cells, and has been shown to be involved in placental development and sensorial synaptic pruning. We have recently shown that C1q can promote tumor by encouraging their adhesion, migration, and proliferation in addition to angiogenesis and metastasis. In this study, we have examined the role of human C1q in the microenvironment of malignant pleural mesothelioma (MPM), a rare form of cancer commonly associated with exposure to asbestos. We found that C1q was highly expressed in all MPM histotypes, particularly in epithelioid rather than in sarcomatoid histotype. C1q avidly bound high and low molecular weight hyaluronic acid (HA) via its globular domain. C1q bound to HA was able to induce adhesion and proliferation of mesothelioma cells (MES) via enhancement of ERK1/2, SAPK/JNK, and p38 phosphorylation; however, it did not activate the complement cascade. Consistent with the modular organization of the globular domain, we demonstrated that C1q may bind to HA through ghA module, whereas it may interact with human MES through the ghC. In conclusion, C1q highly expressed in MPM binds to HA and enhances the tumor growth promoting cell adhesion and proliferation. These data can help develop novel diagnostic markers and molecular targets for MPM.

Highlights

Malignant pleural mesothelioma (MPM) is a rare form of cancer that develops from cells of the pleural mesothelium and is most commonly associated with exposure to asbestos [1]
We initially looked for the presence of C1q in a panel of invasive MPM specimens, including epithelioid, biphasic, and sarcomatoid (Figure 1A) histotypes
The cells did not seem to interact with globular head of C1q A chain (ghA). Since both HMW-Hyaluronic acid (HA) and low molecular weight (LMW)-HA are present in the tumor microenvironment, we investigated the adhesion of mesothelioma cells (MES) to LMW-HA alone or in combination with C1q and we compared the results with the adhesion to HMW-HA with or without C1q

Summary

Introduction

Malignant pleural mesothelioma (MPM) is a rare form of cancer that develops from cells of the pleural mesothelium and is most commonly associated with exposure to asbestos [1]. MPM typically develops after a long latency period, which averages 30–40 years, and the average age of patients is 60 years [2]. Low in metastatic potential, metastasis in MPM are more frequent postsurgery; at the autopsy, metastatic diffusion is observed in 50% of patients [3]. MPM shows mainly one of the three patterns: epithelioid, sarcomatoid, or biphasic [4]. MPM is an aggressive malignancy; most patients succumb within 2 years of being diagnosed [5]. The resistance of MPM to conventional treatment and poor prognosis has renewed interest in basic research in order to understand the MPM biology fully with the aim of identifying possible new molecular therapeutic targets

Methods

Results

Conclusion