The Role Of IL-23R Expressing Cells In Colorectal Cancer & Surgical Strategy For Synchronous Colorectal Cancer Liver Metastases

BackgroundColorectal cancer is one of the most common malignant tumors in the world, whose incidence rate has risen to the second place in the large and medium-sized cities of China. Inflammatory bowel disease(IBD), which has been proved to be the major cause of colorectal cancer, plays a critical role in the pathogenesis of colorectal cancer. A considerable number of basic, clinical and epidemiological studies have confirmed that inflammation is a clear risk factor of cancer. The tumorigenic mechanism of IBD is mainly related to the inflammatory cytokines, such as TNF-α, IL-31, IL-45 and IL-23. These cytokines play important roles in the development of colitis associated colorectal cancer through the activation of NF-κB signaling pathway.IL-23 is a heterodimeric cytokine composed of p40 subunit, which is shared with IL-12, and a unique subunit p19. IL-23 receptor(IL-23R) is also composed of two subunits. One is IL-12Rβ1, sharing with IL-12R. The other is the newly found IL-23R. IL-23 plays an important role in autoimmune diseases, chronic inflammation and cancer. In recent years, the role of IL-23 in the development of colitis associated cancer is wildly studied.ObjectiveIL-23 needs to combine with its receptor to exert its effect. Since IL-23R is expressed on many different types of cells. It is still unclear which types of IL-23R expressing cells are responsible for the progression of colitis associated colorectal cancer. The aim of this study is to investigate the mechanism of IL-23 in colorectal tumorigenesis.Methods Firstly, we constructed the IL-23R conditional knockout mice, including myeloid cell specific knockout IL-23R mice and T lymphocyte specific knockout IL-23R mice. AOM(azoxymethane)/DSS(dextran sodium sulfate) mouse CAC model was applied in this study. Bone marrow cells from different species of conditional knock out mice and wild type mice were adoptive transferred to the wild type mice before AOM injection. We sacrificed the mice and compared the tumor development among these groups of mice after 17 weeks of AOM injection. Subsequently, we analyzed the phenotypes of tumor infiltrated immune cells and mesenteric lymph node(MLN) cells by FACS.ResultsWe found that the tumor incidence rate is 57.1% in the mice transferred with bone marrow cells from wild type mice(WT BM), and the incidence rates in mice transferred with cells from T cells specific knock out IL-23R mice (Lck-IL-23R-/- BM)and from myeloid cells specific knock out IL-23R mice (Lyz- IL-23R-/- BM) were 50% and 22.2%, respectively. Tumor number and size of Lyz- IL-23R-/- BM and Lck- IL-23R-/- BM groups were decreased compared with that in WT BM control group. Although WT BM group has the highest incidence rate, the most tumor numbers and largest tumor size, they are statistically insignificant. Comparison of bowel weight showed that the bowel weight was significantly reduced in Lyz- IL-23R-/- BM mice and Lck- IL-23R-/- BM mice(P = 0.0014, P =0.0318).Analysis of MLN cells showed that the percentage of Thl7 cells was decreased by 2-3 folds both in Lck- IL-23R-/- BM mice and Lyz- IL-23R-/- BM mice compared with that of the WT BM control group. While the percentages of CD4+IFN+ T cells and CD8+IFN+ T cells were slightly increased in Lck- IL-23R-/- BM group. However,after analysis of the tumor infiltrated immune cells, we found that there were almost no Thl7 cells infilatred in the colon In Lyz- IL-23R-/- BM group, tumor infiltrated CD4+IFNγ+ T cells were remarkably increased(accounting for 13.4% of all CD4+T cells) in Lyz-IL-23R-/- BM group. But this change was not observed in all the mice of Lck- IL-23R-/ BM and WT BM groups(Bowel infiltrated CD4+IFNγ+ T cells account for 5.29% of all CD4+T cells). CD4+IFNγ+ T cell can produce and secrete IFNy. It participates in the immune response of CD8+ T cells and plays an important role in anti-tumor immunity. In addition, we also found that after knocking out IL-23R, the percentage of CDllb+Grl+MDSC (Myeloid-derived suppressor cells) infiltrating in tumor tissues decreased from 9.33% in the control group to 0.69% in Lyz- IL-23R-/- BM group and 1.18% in Lck- IL-23R-/- BM group.ConclusionKnocking out IL-23R will slow the progression of colorectal tumor to some extent. Besides the Thl7 cells pathway, IL-23 can combine to IL-23R expressed on myeloid cells to promote the progression of colitis associated colorectal cancer by inhibiting Thl cells or promoting MDSC cells.PART IIBackgroundColorectal cancer patients are often diagnosed with advanced cancer. Synchronous liver metastases, indicating poor outcome, represent 13% to 25% of all colorectal cancer. Surgery is the only potential means of curing colorectal cancer liver metastases (CRLM). Surgeons used to conduct delayed hepatic resections to treat these patients. In present, simultaneous resection of synchronous colorectal cancer liver metastases (SCRLM) is more commonly adopted than in the past. However, the safety and survival benefit of this simultaneous operative approach are still in debated.ObjectiveWe retrospectively analyzed the clinical data of patients with synchronous colorectal cancer liver metastases who treated in our center and discussed the safety and survival impact of simultaneous hepatic resection and delayed hepatic resection brought to patients in this study.MethodsAll patients with SCRLM diagnosed before initial treatment between January 2009 and September 2013 were retrospectively included in our study. The general condition, tumor stage, surgery data, detail of postoperative complication and postoperative hospital stay time are compared between the simultaneous hepatic resection group and the delayed hepatic resection group. Univariate and multivariate analyses of prognosis were performed by Log-rank test and Cox regression model, respectively, to understand the risk factors influencing the prognosis of patients, and to identify the prognostic factors and influence of the two types of operation on the survival of SCRLM patients.ResultsAmong the 73 patients diagnosed with SCRLM, simultaneous colorectal and hepatic resection was performed in 60 patients (82.2%), while delayed hepatic resection was performed in 13 patients (17.8%). The mortality rate was zero. The postoperative complication rate after delayed resection was higher than, but not significantly different from, that after simultaneous resection (46% versus 23%, P=0.166). The duration of operating time (240 min versus 420 min, P<0.05) and postoperative hospital stay time (11 days versus 18 days, P<0.05) were shorter in the simultaneous resection group. After the initial treatments were given, the 1-,2-, and 3-year survival rates in the simultaneous resection group were 77%,59%, and 53%, respectively, whereas those in the delayed resection group were 67%,42%, and 10%, respectively. The 5-year survival rate in the simultaneous resection group was 23%; overall survival differed significantly between the two groups (P =0.037). Median disease-free survival (DFS) times were 19.1 months in the simultaneous resection group and 8.8 months in the delayed resection group. DFS differed significantly between the two groups (P =0.02)ConclusionSimultaneous colorectal and hepatic resection is a safe procedure in selective patients. It provides shorter operation time and postoperative stay time. Patients who received simultaneous resection have better survival in OS and DFS than those with delayed colorectal and hepatic resection. Simultaneous/delayed resection, preoperative chemotherapy and distribution of liver metastases are independent prognostic factors of colorectal cancer liver metastases.