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 9

Complement activation and factor H in human HCC.

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Complement activation and factor H in human HCC. (A) iC3b/C3d and GPC3 d...
(A) iC3b/C3d and GPC3 deposition in human HCC biopsies. Scale bars: 50 μm (left panels), 20 μm (right panels); n = 6. (B and C) Kaplan-Meier plots and statistical analysis based on the work of the TCGA Firehose Legacy study, showing the effect of increased CFH mRNA expression (B) and CFH mutations (C) within the tumors of HCC patients, on survival and disease progression. Increased tumor-associated CFH mRNA improved both progression-free survival (B, top, **P = 0.0020; n = 18 relapse out of 45 [high CFH mRNA], 161 out of 280 [unaltered]) and overall survival (B, bottom: *P = 0.0265; n = 11 deceased out of 50 [high CFH mRNA] and 121 out of 326 [unaltered]). Tumor-associated CFH mutations reduced the number of disease/progression-free months (C, top: P = 0.0778; n = 4 relapsed/progressed out of 5 [CFH mutation] and 175 out of 320 [unaltered]) and overall survival (C, bottom: *P = 0.0308; n = 4 deceased out of 7 [CFH mutation] and 128 out of 369 [unaltered]). Median months survival and progression-free survival shown in parentheses for each group. Data were analyzed by log rank Mantel-Cox test.