Subsequent studies demonstrated that IL-17A also enhances development of colitis associated cancer (CAC) induced by the pro-carcinogen azoxymethane (AOM) and the irritant dextran sulphate sodium (DSS) (Hyun et al

Subsequent studies demonstrated that IL-17A also enhances development of colitis associated cancer (CAC) induced by the pro-carcinogen azoxymethane (AOM) and the irritant dextran sulphate sodium (DSS) (Hyun et al., 2012; Tanaka et al., 2003; Tong et al., 2012). were sacrificed at 5 months of age and cells from spleen, mesenteric lymph nodes (MLN), normal colon tissue (Normal) and colonic tumors (Tumor) were collected and stained for CD45.1 and CD45.2 and analyzed by flow-cytometry. Live CD45+ cells were gated on in the graphs. Percentages of donor-originated CD45.1/CD45.2 double positive cells indicate the rate of reconstitution. (C) Q-RT-PCR analysis of mRNAs corresponding to the indicated genes in normal colon (N) and tumor (T) tissues from CPC-APC mice that received heterozygous or locus. strain for deletion of the cassette to generate the conditional knockout. (D) Bright-field images of WT and gene were sacrificed at 5 months of age for Q-RT-PCR analysis of the indicated genes in mesenteric lymph nodes (MLN), normal (N) colon and tumor (T) tissues. n=9. Data represent averages S.E.M. * p 0.05. NIHMS645387-supplement-5.pdf (662K) GUID:?74D9A4AC-D5B7-4A84-B069-5D2DC03A8416 6: Figure S6. IL-17 does not affect normal crypt proliferation, related to Figure 4 (A) Immunostaining of colon cryosections from 1 week after tamoxifen injection. Data represent averages KIAA0078 S.E.M. * p 0.05. Scale bar = 100 m. NIHMS645387-supplement-6.pdf (610K) GUID:?0A15BF7B-78F0-4930-8F03-A1927ADD73D0 7: Supplemental Table 1: List of primers used in Q-RT-PCR analysis, related to Experimental Procedures. NIHMS645387-supplement-7.pdf (1.6M) GUID:?B467A1CA-3CBD-4017-82C5-7D4BCF33A8CB Summary Interleukin-17A FAI (5S rRNA modificator) (IL-17A) is a proinflammatory cytokine linked to rapid malignant progression of colorectal cancer (CRC) and therapy resistance. IL-17A exerts its pro-tumorigenic activity through its type A receptor (IL-17RA). However, how IL-17RA engagement promotes colonic tumorigenesis is unknown, as IL-17RA is expressed in many cell types in the tumor microenvironment, including hematopoietic, fibroblastoid and epithelial cells. Here we show that IL-17RA signals directly within transformed colonic epithelial cells (enterocytes) to promote early tumor development. IL-17RA engagement activates ERK, p38 MAPK and NF-B signaling and promotes the proliferation of tumorigenic enterocytes who just lost expression of the APC tumor suppressor. Although IL-17RA signaling also controls production of IL-6, this mechanism makes only a partial contribution to colonic tumorigenesis. Combined treatment with chemotherapy, which induces IL-17A expression, and an IL-17A neutralizing antibody enhanced the therapeutic responsiveness of established colon tumors. These findings establish IL-17A and IL-17RA as therapeutic targets in colorectal cancer. Introduction A link between inflammation and cancer has long been suspected, but direct experimental evidence linking the two pathological processes has only become available in recent decades. Chronic inflammation associated with infection and autoimmune disease increases cancer risk and accelerates progression FAI (5S rRNA modificator) of many malignancies, including stomach, liver and colon cancers (Balkwill and Mantovani, 2001; Grivennikov et al., 2010). FAI (5S rRNA modificator) Pro-inflammatory cytokines and tumor infiltrating myeloid and immune cells play critical roles in almost every stage of tumorigenesis, from initiation and tumor promotion to malignant progression and metastatic spread. Even in cancers that do not arise in the context of underlying inflammation, a tumor-evoked inflammatory response plays an important promoting role in FAI (5S rRNA modificator) malignant progression (Grivennikov et al., 2012). Amongst inflammatory cytokines that promote tumor development, the interleukin-17 (IL-17) family, which includes IL-17A, B, C, D, E and F (Dungan and Mills, 2011), occupies an important position in both mouse models and human cancer. IL-17A and F are the closest members of this family, and both bind to IL-17 receptors A (IL-17RA) and C (IL-17RC), whose engagement activates mitogen-activated protein kinases (MAPK), nuclear factor-kappa B (NF-B) and CCAAT-enhancer binding protein (C/EBP) signaling pathways through the adaptor proteins Act1 and TRAF6 (Iwakura et al., 2011; Reynolds et al., FAI (5S rRNA modificator) 2010). IL-17A and F are produced by Th17 cells, T cells, natural killer T (NKT) cells, and subsets of innate lymphoid cells (ILCs) (Reynolds et al., 2010; Sutton et al., 2012; Zou and Restifo, 2010). Initial evidence for involvement of IL-17 cytokines in cancer development came from studies of mouse colonic tumorigenesis. Using the (ETBF) bacteria triggers colitis and accelerates tumor development that is dependent on IL-17A (Wu et al., 2009). Neutralization of IL-17A with a specific antibody prevented.

Comments are closed.