Complement factor H–deficient mice develop spontaneous hepatic tumors
Jennifer Laskowski, … , Raphael A. Nemenoff, Joshua M. Thurman
Jennifer Laskowski, … , Raphael A. Nemenoff, Joshua M. Thurman
Published May 5, 2020
Citation Information: J Clin Invest. 2020;130(8):4039-4054. https://doi.org/10.1172/JCI135105.
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Research Article Immunology Oncology

Complement factor H–deficient mice develop spontaneous hepatic tumors

Abstract

Hepatocellular carcinoma (HCC) is difficult to detect, carries a poor prognosis, and is one of few cancers with an increasing yearly incidence. Molecular defects in complement factor H (CFH), a critical regulatory protein of the complement alternative pathway (AP), are typically associated with inflammatory diseases of the eye and kidney. Little is known regarding the role of CFH in controlling complement activation within the liver. While studying aging CFH-deficient (fH–/–) mice, we observed spontaneous hepatic tumor formation in more than 50% of aged fH–/– males. Examination of fH–/– livers (3–24 months) for evidence of complement-mediated inflammation revealed widespread deposition of complement-activation fragments throughout the sinusoids, elevated transaminase levels, increased hepatic CD8+ and F4/80+ cells, overexpression of hepatic mRNA associated with inflammatory signaling pathways, steatosis, and increased collagen deposition. Immunostaining of human HCC biopsies revealed extensive deposition of complement fragments within the tumors. Investigating the Cancer Genome Atlas also revealed that increased CFH mRNA expression is associated with improved survival in patients with HCC, whereas mutations are associated with worse survival. These results indicate that CFH is critical for controlling complement activation in the liver, and in its absence, AP activation leads to chronic inflammation and promotes hepatic carcinogenesis.

Authors

Jennifer Laskowski, Brandon Renner, Matthew C. Pickering, Natalie J. Serkova, Peter M. Smith-Jones, Eric T. Clambey, Raphael A. Nemenoff, Joshua M. Thurman

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Figure 8

Complement deposition in fH–/– liver tumors.

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Complement deposition in fH–/– liver tumors. (A) C3b-iC3b/C3d deposition...
(A) C3b-iC3b/C3d deposition in WT liver tumors (A, bottom) is sparse and focal. Generally dense C3b-iC3b/C3d deposition is seen throughout fH–/– tumors and the surrounding parenchyma (A, top), with distinct regions lacking C3b (white arrow). Scale bars: 100 μm (A, WT), 20 μm (A, WT inset), and 50 μm (A, fH–/–); n = 10 (fH–/–) and 2 (WT) males with liver tumors (≥15 months). Images shown are from 20-month-old mice with visible liver tumors. (B and C) Variable patterns of C3b-iC3b/C3d and GPC3 within and surrounding individual fH–/– tumors. Sinusoidal C3b and iC3b/C3d deposition surrounding fH–/– tumors with membranous GPC3 deposition (B), and dense C3b within the tumor (B, arrowhead). Nearly absent C3b deposition (C, top) and granular iC3b/C3d deposition (C, bottom) in a fH–/– tumor with cytoplasmic GPC3 deposition. Scale bars: 50 μm; n = 10 fH–/– males with liver tumors (≥15 months). (D and E) CD46 expression with C3b (D) and iC3b/C3d (E) deposition in tumor-bearing fH–/– livers. C3b is absent from (D, white box) and iC3b/C3d (E, arrow) is reduced in regions with dense CD46. Additionally, iC3b/C3d deposition is seen colocalizing with CD46 (E, arrowhead). Scale bars: 50 μm (D), 20 μm (E); shown n = 5 tumor-bearing fH–/– livers. Representative images from n > 5 (A) and 4 (B–E) independent experiments.