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

Our plain-English summary of Complement Protein C1q Binds to Hyaluronic Acid in the Malignant Pleural Mesothelioma Microenvironment and Promotes Tumor Growth, by C. Agostinis, R. Vidergar, B. Belmonte, et al (Frontiers in Immunology, 2017).

The study

• Authors: C. Agostinis, R. Vidergar, B. Belmonte, A. Mangogna, L. Amadio, P. Geri, V. Borelli, F. Zanconati, F. Tedesco, M. Confalonieri, C. Tripodo, U. Kishore, R. Bulla
• Journal: Frontiers in Immunology
• Published: 2017;8:1559
• Cited by: 49 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study of C1q, an immune-system protein, in malignant pleural mesothelioma did not measure asbestos exposure. Pleuroscopy patients had reported asbestos exposure; no fiber type was given. In tumor tissue samples, the authors found strong C1q staining in every mesothelioma type examined, particularly the epithelioid type. In three pleural fluid samples, C1q measured about 76 µg/ml, roughly two- or threefold lower than in control serum. In lab experiments, C1q bound to hyaluronic acid, abundant in mesothelioma tissue, without activating the complement cascade. Tumor cells were grown from five patients with epithelioid mesothelioma. Four of these populations stuck to surfaces more when C1q was bound to hyaluronic acid than on hyaluronic acid alone. In separate experiments, C1q bound to hyaluronic acid increased tumor-cell multiplication more than either substance alone. C1q also increased cell migration but did not protect the cells from cell death caused by oxidative stress. A genetic test (qPCR) detected no messages from the three C1q genes in five cultured cell populations. The authors concluded that C1q is abundant in mesothelioma tissue, interacts with hyaluronic acid, and interferes with tumor-cell adhesion, migration and proliferation.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: staining of human tumor tissue, measurement in pleural fluid, and test-tube and cell-culture experiments on tumor cells isolated from patients
• Who was studied: Malignant pleural mesothelioma patients diagnosed and followed at University Hospital of Cattinara, Trieste, Italy. Five male patients with reported asbestos exposure had pleuroscopy, and tumor cells were grown from five patients with epithelioid MPM. Three pleural fluid samples came from the Hospital of Monfalcone. A commercial mesothelial cell line (Met5A) served as a non-tumor comparison. The number of tissue specimens stained and the study dates are not given.
• Exposure: The study examined the protein C1q and hyaluronic acid, not asbestos. Patients had reported asbestos exposure, but no fiber type, job or dose is given.
• Main results:
  • C1q staining was strongly positive in all tumor specimen types examined (epithelioid, biphasic, sarcomatoid), particularly the epithelioid type.
  • In three pleural fluid samples, C1q was about 76 µg/ml (plus or minus 8 µg/ml), roughly two- or threefold lower than control serum (about 200 µg/ml).
  • C1q bound to hyaluronic acid with no statistically significant difference between low and high molecular weight forms.
  • C1q bound to hyaluronic acid did not activate complement; only C1q bound to IgG did.
  • The A-chain globular head of C1q (ghA) bound hyaluronic acid better than ghB and ghC.
  • qPCR for the three C1q chains (C1qA, C1qB and C1qC) was positive in none of five cultured cell populations (data not shown).
  • In adhesion tests, mesothelioma cells adhered considerably more to C1q bound to hyaluronic acid than to hyaluronic acid alone. Met5A cells adhered better to hyaluronic acid.
  • The adhesion tests used four mesothelioma cell populations. All four behaved the same on C1q bound to hyaluronic acid, while adhesion to C1q alone varied considerably between patients' samples.
  • Mesothelioma cell adhesion to C1q appeared to be mediated by ghC, and to a lesser extent ghB.
  • C1q bound to hyaluronic acid increased mesothelioma cell proliferation compared with hyaluronic acid or C1q alone. The article does not state how many patients' cell populations were used in this assay.
  • In the migration assay, C1q (60%) was more effective than hyaluronic acid (about 20%).
  • C1q did not protect mesothelioma cells from apoptosis induced by oxidative stress.
  • ERK1/2, SAPK/JNK and p38 signaling was significantly higher in cells on C1q bound to hyaluronic acid than on hyaluronic acid alone.
• The authors' conclusion: The authors concluded that C1q is abundantly present in mesothelioma tissue, interacts with hyaluronic acid, and interferes with mesothelioma cell adhesion, migration and proliferation, and that its role is likely to depend on the tumor microenvironment.

Topics

Medical terms in this study, explained in our Lexicon: Hyaluronic Acid, Pleural Mesothelioma, Angiogenesis, Metastasis, Epithelioid, Sarcomatoid, Mesothelioma.

Related studies

• Insulin-Like Growth Factor 2 mRNA Binding Protein 3 Promotes Cell Proliferation of Malignant Mesothelioma Cells by Downregulating p27Kip1 — I. Endo, V.J. Amatya, et al. (2021)
• Inhibitor of apoptosis protein-1 promotes tumor cell survival in mesothelioma — G.J. Gordon, K. Appasani, et al. (2002)
• Histochemical demonstration of hyaluronic acid in pleural mesotheliomas — J.C. Wagner, D.E. Munday, et al. (1962)
• Pleural effusion hyaluronic acid as a prognostic marker in pleural malignant mesothelioma — J. Creaney, I.M. Dick, et al. (2013)
• Hyaluronic acid in the pleural fluid of patients with malignant pleural mesothelioma — N. Fujimoto, K. Gemba, et al. (2013)
• Serum mesothelin has a higher diagnostic utility than hyaluronic acid in malignant mesothelioma — B. Grigoriu, B. Chahine, et al. (2009)

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