Intracellular Factor H Drives Tumor Progression Independently of the Complement Cascade.
Marie V DauganMargot RevelRomane ThouenonMarie-Agnès Dragon-DureyTania Robe-RybkineCarine TorsetNicolas S MerleRémi NoéVirginie VerkarreStephane Marie OudardArnaud MejeanPierre ValidireXavier CathelineauRafael Sanchez-SalasMathew C PickeringIsabelle CremerAudrey Mansuet-LupoMarco AlifanoCatherine Sautès-FridmanDiane DamotteWolf H FridmanLubka T RoumeninaPublished in: Cancer immunology research (2021)
The complement system is a powerful and druggable innate immune component of the tumor microenvironment. Nevertheless, it is challenging to elucidate the exact mechanisms by which complement affects tumor growth. In this study, we examined the processes by which the master complement regulator factor H (FH) affects clear cell renal cell carcinoma (ccRCC) and lung cancer, two cancers in which complement overactivation predicts poor prognosis. FH was present in two distinct cellular compartments: the membranous (mb-FH) and intracellular (int-FH) compartments. Int-FH resided in lysosomes and colocalized with C3. In ccRCC and lung adenocarcinoma, FH exerted protumoral action through an intracellular, noncanonical mechanism. FH silencing in ccRCC cell lines resulted in decreased proliferation, due to cell-cycle arrest and increased mortality, and this was associated with increased p53 phosphorylation and NFκB translocation to the nucleus. Moreover, the migration of the FH-silenced cells was reduced, likely due to altered morphology. These effects were cell type-specific because no modifications occurred upon CFH silencing in other FH-expressing cells tested: tubular cells (from which ccRCC originates), endothelial cells (human umbilical vein endothelial cells), and squamous cell lung cancer cells. Consistent with this, in ccRCC and lung adenocarcinoma, but not in lung squamous cell carcinoma, int-FH conferred poor prognosis in patient cohorts. Mb-FH performed its canonical function of complement regulation but had no impact on tumor cell phenotype or patient survival. The discovery of intracellular functions for FH redefines the role of the protein in tumor progression and its use as a prognostic biomarker or potential therapeutic target.See article by Daugan et al., p. 891 (36).
Keyphrases
- poor prognosis
- cell cycle arrest
- long non coding rna
- squamous cell carcinoma
- endothelial cells
- induced apoptosis
- signaling pathway
- cell death
- innate immune
- stem cells
- reactive oxygen species
- small molecule
- type diabetes
- mesenchymal stem cells
- bone marrow
- inflammatory response
- cell proliferation
- climate change
- high throughput
- radiation therapy
- toll like receptor
- vascular endothelial growth factor
- lps induced
- binding protein
- coronary artery disease
- free survival
- human health