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

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.

Context-dependent roles of complement in cancer

“…Patients with low C4d plasmatic levels at diagnosis had a significantly better overall survival. In another cohort, C1q staining of tumor and infiltrating myeloid cells was strong 85 . In this context C1q was shown to bind to hyaluronic acid and promote cell adhesion and proliferation in complement cascadeindependent manner.…”

gC1qR/HABP1/p32 Is a Potential New Therapeutic Target Against Mesothelioma

“…Since mAb 60.11 is directed specifically against the C1q binding site of gC1qR, these findings support the hypothesis that gC1qR-C1q interactions in the tumor cell microenvironment contribute to mesothelioma tumor growth. Interestingly, recent immunohistochemical studies report the presence of C1q in mesothelioma (38). The observed anti-angiogenic effect of 60.11 therapy likely contributes to the overall in vivo effect of 60.11 therapy.…”

Complement in Metastasis: A Comp in the Camp

“…C1q promote angiogenesis and lung metastasis in a syngeneic model of murine melanoma (72). In malignant pleural mesothelioma, C1q binds to hyaluronic acid in the tumor microenvironment and enhances tumor proliferation (73). C1q secreted by mesenchymal stromal cells mediates the activation of β-catenin in chronic lymphocytic leukemia and enhances malignant progression (74).…”