Transforming Growth Factor Subverts the Immune System into Directly Promoting Tumor Growth through Interleukin-17

Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Korea.
Cancer Research (Impact Factor: 9.28). 06/2008; 68(10):3915-23. DOI: 10.1158/0008-5472.CAN-08-0206
Source: PubMed

ABSTRACT Overexpression of the immunosuppressive cytokine transforming growth factor beta (TGF-beta) is one strategy that tumors have developed to evade effective immunesurveillance. Using transplantable models of breast and colon cancer, we made the unexpected finding that CD8+ cells in tumor-bearing animals can directly promote tumorigenesis, by a mechanism that is dependent on TGF-beta. We showed that CD8+ splenocytes from tumor-bearing mice expressed elevated interleukin (IL)-17 when compared with naive mice, and that CD8+ T cells could be induced to make IL-17 on addition of TGF-beta and IL-6 in vitro. Treatment of mice with anti-TGF-beta antibodies in vivo reduced IL-17 expression both in the tumor and the locoregional lymph nodes. Although IL-17 has not previously been shown to act as a survival factor for epithelial cells, we found that IL-17 suppressed apoptosis of several tumor cell lines in vitro, suggesting that this altered T-cell polarization has the potential to promote tumorigenesis directly, rather than indirectly through inflammatory sequelae. Consistent with this hypothesis, knockdown of the IL-17 receptor in 4T1 mouse mammary cancer cells enhanced apoptosis and decreased tumor growth in vivo. Thus, in addition to suppressing immune surveillance, tumor-induced TGF-beta may actively subvert the CD8+ arm of the immune system into directly promoting tumor growth by an IL-17-dependent mechanism.

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    • ". Although the question for IL-17A as an anti-tumor or promoting tumor factor in different types of human cancers is still incompletely answered [16] [17] [18] [19] [20] [21] [22], recent studies have provided considerable evidence that IL-17A is involved in the colorectal carcinogenesis [23] [24]. Several studies have provided the evidence that IL-17A can promote the development of colon cancer in animals [25] [26] [27]. Wu et al. showed that the induction of colon cancer in mice by inflammation was via the activation of TH17/IL-17 [26], and Chae et al. demonstrated that blocking of IL-17A decreased the formation of hyperplasia and cancer in mice [25]. "
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    ABSTRACT: Abstract Objectives. Interleukin (IL)-17A is an important pro-inflammatory cytokine and involved in the colorectal carcinogenesis. In this study, the authors evaluated the dynamic change of IL-17A expression in the tumor microenvironment throughout the colorectal adenoma-carcinoma sequence. Materials & methods. Using quantitative real-time PCR (polymerase chain reaction) and semi-quantitative immunohistochemistry, the authors examined the expression level of IL-17A in 50 of human colorectal adenoma tissues, 50 of colorectal cancer (CRC) tissues and 15 controls. The relationship between IL-17A expression and clinicopathological parameters throughout the sequence was also evaluated. Results. The results revealed a step-up increased IL-17A mRNA level throughout the colorectal adenoma-carcinoma sequence, which began to increase in the adenomas and became even higher in the CRCs; notably, the increase of IL-17A mRNA level in the adenomatous tissues was associated with the severity of dysplasia. Immunohistochemical analysis confirmed the real-time PCR results and revealed gradually increasing IL-17A cells in both the stroma and adenomatous/cancerous epithelium. In addition, the quantitative real-time PCR result has also revealed an increased expression of TH17-stimulating factors throughout the sequence. Conclusions. IL-17A and TH17 are highly activated throughout the colorectal adenoma-carcinoma sequence.
    Scandinavian Journal of Gastroenterology 09/2012; 47(11):1304-12. DOI:10.3109/00365521.2012.725089 · 2.33 Impact Factor
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    • "Under a " corruption hypothesis " (Figure 6), antitumor CD8 + CTLs may redirect into CD8 + T-pro that inhibit CTLs (for example, through IL-10), enhance chronic inflammation (for example, through IL-17A and IL-17F), and facilitate tumor proliferation (for example, through amphiregulin and Gro-1). Consistent with this, Wakefield and colleagues showed that CD8 + PBL isolated from tumor-bearing mice will produce IL-17A under the in vitro influence of TGF-β and IL-6, and revealed that IL-17A itself suppresses tumor cell-line apoptosis by a yet unknown mechanism (Nam et al., 2008). Furthermore, several investigators have reported on the potential of IL-17 to directly increase tumor progression, including by its pro-angiogenic effects (Sfanos et al., 2008;Zhu et al., 2008;Zhang et al., 2009). "
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    Journal of Investigative Dermatology 11/2009; 130(6):1726-36. DOI:10.1038/jid.2009.362 · 6.37 Impact Factor
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    • "Conversely, TGF-b's role as a tumor promoter is supported by many in vitro and in vivo studies (Pardali and Moustakas, 2007). TGFb's ability to enhance tumor cell invasiveness and migration (Dalal et al., 1993), and to modulate the vascular and immune cell compartment of the tumor stroma (Nam et al., 2008), are mechanisms proposed to underlie this tumor-promoting activity. Epithelial-to-mesenchymal transition (EMT) is a process during which epithelial cells acquire the attributes of mesenchymal cells, including increased motility and invasiveness (Shook and Keller, 2003; Thiery, 2003; Hay, 2005; Peinado et al., 2007; Gregory et al., 2008). "
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