IFNγ-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice

Abstract

Approximately 20% of human cancers are estimated to develop from chronic inflammation. Recently, the NF-κB pathway was shown to play an essential role in promoting inflammation-associated cancer, but the role of the JAK/STAT pathway, another important signaling pathway of proinflammatory cytokines, remains to be investigated. Suppressor of cytokine signaling-1 (SOCS1) acts as an important physiological regulator of cytokine responses, and silencing of the SOCS1 gene by DNA methylation has been found in several human cancers. Here, we demonstrated that SOCS1-deficient mice (SOCS1−/−Tg mice), in which SOCS1 expression was restored in T and B cells on a SOCS1−/− background, spontaneously developed colorectal carcinomas carrying nuclear β-catenin accumulation and p53 mutations at 6 months of age. However, interferon (IFN)γ−/−SOCS1−/− mice and SOCS1−/−Tg mice treated with anti-IFNγ antibody did not develop such tumors. STAT3 and NF-κB activation was evident in SOCS1−/−Tg mice, but these were not sufficient for tumor development because these are also activated in IFNγ−/−SOCS1−/− mice. However, colons of SOCS1−/−Tg mice, but not IFNγ−/−SOCS1−/− mice, showed hyperactivation of STAT1, which resulted in the induction of carcinogenesis-related enzymes, cyclooxygenase-2 and inducible nitric oxide synthase. These data strongly suggest that SOCS1 is a unique antioncogene which prevents chronic inflammation-mediated carcinogenesis by regulation of the IFNγ/STAT1 pathways.

Characterizing tumor-promoting T cells in chemically induced cutaneous carcinogenesis

“…Herein we reveal the tumor-promoting capacity of CD8 ϩ T cells, and the aggregate expression profile of this candidate T-pro population is notably consistent with reports that TNF␣ Ϫ/Ϫ (28) and COX-2 Ϫ/Ϫ (29) mice are resistant to DMBA/PMA-mediated carcinogenesis. These data are also consistent with the recent finding of spontaneous colorectal carcinoma development in suppressor of cytokine signaling-1-deficient mice through an INF␥/STAT1-dependent pathway (30). The potential role of IFN␥ in promoting inflammationassociated carcinogenesis is more enigmatic, especially given the high susceptibility of IFN␥ Ϫ/Ϫ , IFNGR1 Ϫ/Ϫ , and STAT1 Ϫ/Ϫ mice to a variety of spontaneous or specific regimens of chemically induced tumors (5,6).…”

SOCS proteins in regulation of receptor tyrosine kinase signaling

“…It is also evident that SOCS1 is important for preventing chronic inflammation-mediated carcinogenesis. SOCS1 knockout mice develop colon cancer due to hyper activation of STAT1 [82]. A report with a small patient group (19 patients) of classical Hodgkin lymphoma described a loss of function deletion mutation in SOCS1 gene of eight patients that led to nuclear accumulation of activated STAT5 [83].…”

FSP1+ Fibroblasts Promote Skin Carcinogenesis by Maintaining MCP-1-Mediated Macrophage Infiltration and Chronic Inflammation

“…Promotion requires repeated exposure of the skin to TPA, which boosts tumor development via induction of chronic inflammation. 14 Considering the fact that most of human neoplasias are of epithelial origin, and 20% of the cancers are clearly associated with chronic inflammation, [15][16][17] it is interesting to analyze the role of fibroblasts during skin carcinogenesis with the well established DMBA/TPA model.…”