Lung cancer development is associated with extensive pulmonary inflammation. In addition, the linkage between chronic obstructive pulmonary disease (COPD) and lung cancer has been demonstrated in population-based studies. IL-17-producing CD4 helper T cells (Th17 cells) play a critical role in promoting chronic tissue inflammation. Although Th17 cells are found in human COPD and lung cancer, their role is not understood. We have thus used a mouse model of lung cancer, in which an oncogenic form of K-ras (K-ras CD11b+ myeloid cells recruited by IL-17 play a protumor role. Taken together, our data demonstrate a critical role for Th17 cell-mediated inflammation in lung tumorigenesis and suggest a novel way for prevention and treatment of this disease.interleukin 17 | lung adenocarcinoma

BackgroundTreatment of breast cancer patients with antiestrogens and aromatase inhibitor(s) or Herceptin have shown significant success in steroid receptor positive or Her-2+ breast cancers respectively. However, choice of treatments for breast cancer patients with negative status for estrogen, progesterone receptors and HER2/neu is limited. As a result, search for appropriate therapy regimen for these triple negative breast cancers (TNBC) has become a major focus of investigations for many laboratories. Recently, Deguelin, a natural product isolated from African plant Mundulea sericea (Leguminossae) has shown both antiproliferative actions in various cancers including breast as well as chemoprenventive activity against carcinogen induced experimental cancers. In this report we evaluated efficacy and mechanism of action of Deguelin in triple negative breast cancer cell lines.Methods/FindingsIn vitro, Deguelin in a dose and time dependent manner inhibited the growth of MDA-MB-231, MDA-MB-468, BT-549 and BT-20 cells. Deguelin (2 or 4 mg/kg body weight), when injected intraperitoneally, reduced the in vivo tumor growth of MDA-MB-231 cells transplanted subcutaneously in athymic mice. Moreover it was nontoxic as evident from daily observations on mobility, food and water consumption and comparison of bodyweight and other visceral organ weights with those in control animals at the termination of the study. The western blot analyses and immunostaining studies indicated that the deguelin effects may be mediated through EGFR-PAKT/c-Met p-ERK and NF-κB by down regulating their downstream targets such as p-STAT3, c-Myc, Survivin.Conclusion/SignificanceThese results suggest that Deguelin may have a significant therapeutic value for the treatment of TNBC patients.

Cancer related deaths in breast cancer patients are due to metastasis of the disease. Murine 4T1 cells (Murine mammary cancer cell line developed from 6-thioguanine resistant tumor) provide an excellent research tool for metastasis related studies because these cells are highly aggressive and readily metastasize to the lungs. In this study we determined the effect of Deguelin on in vivo/vitro growth and metastasis of 4T1 cells. Deguelin inhibited the in vitro growth of 4T1 cells in a time and dose dependent manner accompanied with reduced nuclear PCNA immunostaining. In cells treated with Deguelin, reduced expression of nuclear c-Met, and its downstream targets such p-ERK and p-AKT was observed. Deguelin reduced the cell migration in 4T1 cells as determined by scratch wound assay. Combined treatment with Deguelin + ERK or PI3K/AKT inhibitor had no additional effect on cell migration. These results indicated that the action of Deguelin on cell migration may be mediated by AKT and ERK mediated signaling pathways. In vivo, Deguelin treatment significantly inhibited growth of 4T1 cells. Deguelin also reduced the occurrence of metastatic lung lesions by 33% when cells were injected intravenously into Balb/c female mice. There was no difference in the body weight as well as liver and spleen weights between vehicle treated control and Deguelin treated animals indicating that Deguelin was nontoxic at the dose used in the present study. These results provide rationale for developing Deguelin as a chemotherapeutic agent for triple negative breast cancer patients.

Breast cancer is a second leading cause of cancer related deaths in women. Cancer related deaths in breast cancer patients are due to metastasis of disease. Thus new drugs which could successfully inhibit metastatic disease spread are highly desired. However till date there are only a few experimental models available to study metastatic progression of breast cancer. Murine 4T1 mammary breast cancer cells when transplanted s.c./or into mammary gland metastasizes to lungs, liver and bone similar to that observed in women with stage IV metastatic disease. Thus this model is highly appropriate for studies related to breast cancer metastasis. Previously we have shown that Deguelin, originally isolated from an African plant Mundulea sericea significantly inhibits the growth of triple negative breast cancer and that the Deguelin effect is mediated through inhibition of WNT signaling pathway. However their therapeutic effect in vivo is still unexplored. We evaluated the effects of Deguelin on growth (in vitro and in vivo) and lung metastasis of 4T1 cells. In vitro, Deguelin inhibited growth of 4T1 cells in time and concentration depended manner; optimum growth inhibition was obtained at 250nM Deguelin concentration after 72 hr. treatment. Toxicity study performed in 4-6 weeks old female BALB/c mice suggested that Deguelin administered as a suspension (saline/gum Arabic/Deguelin) daily for two weeks by intraperitoneal (i.p.) injection was well tolerated up to 16mg/kg body weight, and no toxicity (loss of appetite, body weight loss, mobility, morbidity, death) was observed in Deguelin treated animals. In vivo, as compared to vehicle treated animals, Deguelin (2 or 6mg/kg body weight) administered daily for 21 days i.p significantly (P<0.05) inhibited growth of 4T1 cells (0.5 million cells/mouse) transplanted s.c. in to 4-6 weeks old female BALB/c mice. Similarly Deguelin also reduced (27-33%, P< 0.02) the number of metastatic lesions in the lungs subsequent to i.v. injection of 7500 to 10,000 4T1 cells in syngeneic mice as compared to vehicle treated control group. Immunohistochemical analysis of control/Deguelin treated 4T1 cells, and lung metastatic lesions suggest that Deguelin inhibited Ki67 expression suggesting its antiproliferative action in this model. In addition, phospho AKT, cyclin D1, Cox-2 and Hif-1α protein expressions were down regulated. Our results suggest that Deguelin effect on the growth and metastasis may be mediated by targeting signaling molecules involved in pAKT, HIF-1, Cox-2 pathway. These results provide a promising lead for a potential therapeutic agent to treat metastatic breast cancer. This work was supported in part by the National Cancer Institute grant CA140321. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3829. doi:1538-7445.AM2012-3829

significantly decreased total phosphatidylinositols. Analyzing the quantities of individual lipid species we found that a HFD altered the quantity of 4 phospholipid species compared to control diet fed mice. Additionally, the presence of colitis-associated tumors altered the quantity of 17 and 8 phospholipid species compared to their healthy control and HFD counterparts, respectively. Furthermore, we found differential quantities of 10 phospholipid species in tumor bearing mice fed a control diet compared to tumor bearing mice fed a HFD. Stool from tumor-bearing mice fed a HFD had 5 unique phosphatidylcholine species which were not present in the stool of the other groups. CONCLUSIONS: Colitis-associated tumors are associated with a distinct stool lipid profile. A HFD alters the composition of individual lipids without changing the total amount of lipid in stool. Lipidomic analysis of stool may be useful as a biomarker in colitis-associated cancer, especially to detect dysplasia. As lipids from the microbiota are also analyzed using this method, additional studies will address the contribution of host versus microbiome metabolism in shaping the lipidome. P-207BACKGROUND: Inflammatory bowel disease (IBD) is a complex polygenic disorder causing a chronic relapsing inflammation and thought to result from a dysregulated and aberrant immune response to intestinal flora in a context of genetic predisposition. Recently, human IL17REL, a member of interleukin-17 receptor family, was identified through a genome-wide association study for ulcerative colitis. However, it is unknown how IL-17REL is involved in the development of ulcerative colitis. On the basis of the substantial homology between human IL-17REL and the extracellular domains of IL-17RE, it is likely that IL-17REL binds to the ligand of IL-17RE. METHODS: We recently demonstrated IL-17RE is induced in a subset of CD4 helper T cells, Th17 cells, and is a receptor for a cytokine IL-17C. IL-17C-IL-17RE signaling plays a critical role to promote inflammation in chronic autoimmune disease. In addition, we reported IL-17C is crucial for the regulation of an acute experimental colitis by controlling the expression of the tight junction molecule occludin by colonic epithelial cells. Therefore, we hypothesize during chronic intestinal inflammation, induction of IL-17C in the inflamed intestine recruits Th17 cells via IL-17RE and IL-17C-IL-17RE signaling modulates Th17 cell function and play a pathogenic role in mediating inflammation. RESULTS: First, we found out that the expression of IL-17C and IL-17RE is increased in colon and small intestine of mice during chronic colitis. IL-17C expression was found in colonic epithelial cells and it was reduced upon antibiotic treatment, suggesting IL-17C expression is maintained by microbiota in the colon. IL-17RE expression, on the other hand, was not only found in Th17 cells but also in regulatory T cells isolated from colon and small intestine. Therefore, we adopted a CD4 transfer colitis model, where Il17re deficient CD45RB h...