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. 2006 Jun 12;203(6):1391-7.
doi: 10.1084/jem.20060436. Epub 2006 May 22.

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

Toshikatsu Hanada  1 , Takashi Kobayashi, Takatoshi Chinen, Kazuko Saeki, Hiromi Takaki, Keiko Koga, Yasumasa Minoda, Takahito Sanada, Tomoko Yoshioka, Hiromitsu Mimata, Seiya Kato, Akihiko Yoshimura
Affiliations

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

Toshikatsu Hanada et al. J Exp Med. .

Abstract

Approximately 20% of human cancers are estimated to develop from chronic inflammation. Recently, the NF-kappaB 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 beta-catenin accumulation and p53 mutations at 6 months of age. However, interferon (IFN)gamma-/- SOCS1-/- mice and SOCS1-/- Tg mice treated with anti-IFNgamma antibody did not develop such tumors. STAT3 and NF-kappaB activation was evident in SOCS1-/- Tg mice, but these were not sufficient for tumor development because these are also activated in IFNgamma-/- SOCS1-/- mice. However, colons of SOCS1-/- Tg mice, but not IFNgamma-/- 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 IFNgamma/STAT1 pathways.

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Figures

Figure 1.
Figure 1.
Colorectal tumors in SOCS1−/−Tg mice. (A) Percentage of histologically determined colitis (red circle) and tumor (black circle) incidence in SOCS1−/−Tg mice. (B) Macroscopic view of colon tumors in SOCS1−/−Tg mice. Arrows indicate tumors. (C–L) HE-stained sections of colitis and grades of dysplasia and neoplasia in SOCS1−/−Tg mice. The top and bottom panels in each row show medium- and high-magnification views of the mucosa, respectively. (C and D) Histology of a wild-type control mouse. (E and F) Colitis, indefinite for dysplasia in SOCS1−/−Tg mice. (G and H) Mildly active cryptitis with neutrophilic infiltration and goblet cell depletion are evident. The nuclei are mildly swollen but uniform in size and shape. Epithelial maturation toward the surface is preserved. (G and H) Low-grade dysplasia with villous configuration in SOCS1−/−Tg mice. The crypts are uniformly lined with tall epithelial cells containing mildly elongated and hyperchromatic nuclei. (I and J) Colitis with high-grade dysplasia in SOCS1−/−Tg mice. Eroded and inflamed mucosa with cryptoabscesses can be seen. In addition, the tubuli show an irregular arrangement and budding. The nuclei are elongated, hyperchromatic, and pseudostratified. (K and L) High-grade dysplasia and intramucosal carcinoma in SOCS1−/−Tg mice. The desmoplastic stroma has assumed early invasive growth. Bars: (C, E, G, I, K) 200 μm; (D, F, H, J, I) 50 μm. (M) Immunohistochemical staining for β-catenin, total p53 (CM1), and mutant p53 (CM5) in colon tumors from SOCS1−/−Tg mice and WT littermates. Bars, 50 μm.
Figure 2.
Figure 2.
Anti-IFNγ mAb but not anti-TNFα mAb treatment ameliorated the colitis and colon tumor development in SOCS1−/−Tg mice. SOCS1−/−Tg mice at 2 mo of age were treated either with control IgG, anti-IFNγ, or anti-TNFα mAb for 4 mo. The colitis score (A) and tumor incidence (B) are shown. (C) The representative HE staining of the colonic sections from the SOCS1−/−Tg mice after antibody treatment. Bars, 100 μm.
Figure 3.
Figure 3.
Activation of STAT1, STAT3, and NF-κB in SOCS1−/−Tg colons. (A) Western blot analysis of whole colon samples from indicated mice were performed with the indicated antibodies. The data are representative of three independent experiments each experiment using two mice per group. (B) Immunostaining for phospho-STAT1, phospho-STAT3, and NF-κB (p65) in the colons of SOCS1+/+Tg and SOCS1−/−Tg mice. Arrows indicate nuclear accumulation of p65. Bars, 50 μm.
Figure 4.
Figure 4.
Expression of tumorigenic factors in SOCS1-deficient colons. (A) Immunostaining for PCNA and TUNEL staining in the colons of SOCS1+/+Tg and SOCS1−/−Tg mice at 6 mo of age. Bars, 50 μm. The average numbers of PCNA-positive cells and TUNEL-positive cells per one side of the colonic crypts are indicated in the bar graph. Error bars represent ± SE. *, P < 0.05 compared with SOCS1+/+Tg mice. White bars, SOCS1+/+Tg; gray bars, SOCS1−/−Tg nontumor; black bars, SOCS1−/−Tg tumor. (B) Western blot analysis of the Bcl-xL, c-Myc, iNOS, COX-2, and STAT5 levels in whole colonic extracts from indicated mice. (C) Immunostaining for iNOS, COX-2, and F4/80. Bars, 50 μm. (D) Western blot analysis of the COX-2 and iNOS expression in response to IFNγ in the macrophages from SOCS1+/+Tg and SOCS1−/−Tg mice and MEFs from WT and SOCS1−/− mice.
Figure 5.
Figure 5.
A model for tumor progression caused by proinflammatory cytokines. Aberrantly activated STAT3 and NF-κB signals induce cell proliferation and antiapoptotic factors. Aberrantly activated STAT1 signal induces cellular stress responses and leads to DNA damage, resulting in clonal selection of resistant cells. These signals orchestrate tumor formation in the colon.
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