An early report linked FGL2 with development of T cell leukemia. More recently, Thuluvath et al (Chaerkady et al., Journal of Proteome Research, 2008) have used a quantitative proteoQ to identify differentially regulated proteins in hepatocellular carcinoma (HCC). More than 600 proteins were quantitated of which 59 proteins were over-expressed and 92 proteins under-expressed in HCC compared to normal adjacent tissue. A subset of these proteins (six from the upregulated and down-regulated groups) was further validated using immunoblotting and immunohistochemical labeling. FGL2/Fibroleukin was identified as a highly sensitive marker for hepatocellular carcinoma. Western blots and immunohistochemical labeling confirmed differential expression of fibroleukin in the majority of HCC analyzed. In an animal model of malignant mesothelioma, Ireland et al. reported the involvement of CD4+CD25+ Treg cells in development of solid tumors through suppression of anti-cancer immunity. Microarray analysis of Treg cells isolated from the tumors revealed that fgl2 expression was 16-fold greater in intra-tumoral CD4+CD25+ Treg cells compared to naive CD4+CD25+ Treg cells, suggesting FGL2 as a potential new target for anti-cancer immunotherapy (Ireland et al., PhD Thesis, The University of Western Australia, 2006). Kohno et al. have demonstrated a loss of fgl2 transcripts in patients with acute and chronic adult T cell leukemia, a lymphoproliferative disorder of T helper cells, suggesting a potential role for FGL2 in regulation of T cell proliferation (Kohno et al., Jpn. J. Cancer Res., 2000). This observation support our animal work showing the in targeted deletion of FGL2 results in enhanced proliferation of T cells upon stimulation with alloantigens, anti-CD3/anti-CD28 monoclonal antibodies, and Concanavalin A in a dose-dependent manner (Chan et al., J. Immunol., 2003).
Fgl2 expression was detected in tumor tissues that were collected from 127 out of 133 patients as well as tumor tissues that were 21 obtained from human HCC nude mice. Fgl2 was found to be highly expressed in cancer cells and interstitial inflammatory cells which include macrophages, NK cells, CD8+ T lymphocytes and vascular endothelial cells (Su et al., World J. Gastroenterol., 2008). Y. Liu et al., recently reported in the International Liver Congress (Berlin, Germany, April 2011) about the role FGL2 plays in tumor growth. According to their study, fgl2 expression was found to be up-regulated in HCCLM6 cell line, a highly aggressive HCC derived cell line, upon tumor necrosis factor-α (TNF-α) stimulation. Depletion of fgl2 in HCCLM6 cells led to a delayed tumor growth and vascularization of HCC xenografts in nude mice, which were associated with decreased phosphorylation of extracellular signal-regulated kinases (ERK) but not p38 mitogen-activated protein kinase (p38-MAPK) in vivo. In vitro, depletion of fgl2 in HCCLM6 cells resulted in decreased proliferation and lower expression of pro-angiogenic factors following stimulation with TNF-α. This was associated with a higher susceptibility to TNF-α induced apoptosis. Based on their data they conclude that FGL2 contributes to HCC tumor growth and angiogenesis through the MAPK pathway (Published as an abstract in the International Liver Congress 2011).