MRI Study Of Colorectal Cancer With Distant Metastasis And Epithelial-mesenchymal Transition

Purpose:Distant metastasis and chemotherapy resistance are important factors affecting prognosis in patients with colorectal cancer（CRC）.Epithelial-mesenchymal transition（EMT）can aggravate distant metastasis behavior and chemotherapy resistance of CRC.MRI is the most commonly used imaging modality for preoperative assessment for CRC.Therefore,preoperative identification of CRC with EMT by using noninvasive MRI and screening the high-risk CRC patients of distant metastasis is important for the selection of personalized treatment strategies.Our study aimed to investigate the value of MRI in predicting synchronous distant metastasis in patients with rectal cancer,and to assess the feasibility of MRI in identifying CRC with EMT（CRC/EMT）,and evaluating the early chemotherapy resistance of CRC/EMT tumor by establishing CRC xenograft models.Methods:1.Clinical characteristics and MRI features of 271 patients with pathologically confirmed rectal adenocarcinoma were retrospectively reviewed.Univariate and multivariate logistic analysis were performed to identify the independent risk factors for synchronous distant metastasis in rectal cancer.2.EMT was induced by overexpressing Snail1 gene in CRC cell line HCT116（HCT116/Snail1）.Real-time quantitative PCR and Western blot were performed to compare Snail1,E-cadherin,and vimentin expressions between HCT116/Control and HCT116/Snail1 cells.The morphologic changes,migration,invasion capacity,and distant metastasis capacities were also compared.T2WI and DKI were performed for CRC/Control and CRC/EMT xenograft tumors models.The apparent diffusion coefficient（ADC）,Diffusivity,and Kurtosis coefficients were compared,and correlations between the parameters and E-cadherin,Ki-67 expressions were analyzed.3.CRC/Control and CRC/EMT xenograft tumors were established before 5-Fu or DMSO was injected intraperitoneally for 14 days.The tumor size was measured every other day and the relative tumor volume was calculated(RTV=V_dx/V_d0).T2WI and DKI were perormed at Day 0,Day7,and Day14 after 5-Fu or DMSO treatment.The differences of ADC,Diffusivity,and Kurtosis between groups at different days and among groups at the same day were analyzed.Correlations between ADC,Diffusivity,and Kurtosis and Ki-67 expression were assessed.Results:1.Among the 271 patients,a total of 49 patients（18.1%）were confirmed to have synchronous distant metastasis.CEA level,mr T staging,MRI-predicted lymph nodes staging（mr N staging）,and MRI-predicted mesorectal fascia（mr MRF）status were correlated with synchronous distant metastasis.Multivariate logistic regression model demonstrated that elevated CEA level,positive mr N staging,and mr MRF involvement were independent risk factors.The accuracy and specifcity for predicting synchronous distant metastasis by evaluating positive mr N combined with elevated CEA were improved to 87.8%and 94.6%,respectively.2.HCT116/Snail1 cells showed typical characteristics of mesenchymal cells.The expressions of Snail1 and vimentin were significantly increased,and E-cadherin expression was significantly decreased in HCT116/Snail1 cells,in which the migration,invasion,and distant metastasis capacities were also increased.3.ADC and Diffusivity in CRC/EMT xenograft tumors were significantly lower（P=0.007 vs.P=0.002）,and Kurtosis was significantly higher（P<0.001）than those in the CRC/Control.ADC and Diffusivity were both negatively correlated with Ki-67 expression（P=0.011 vs.P=0.007）,and Kurtosis was positively correlated with Ki-67 expression（P<0.001）.Diffusivity was positively and Kurtosis was negatively correlated with E-cadherin expression（P=0.023 vs.P=0.006）.4.The mean RTV at Day14 in CRC/Control treatment group was significantly lower than that in the CRC/EMT treatment group（P<0.001）.ADC and Diffusivity of CRC/Control treatment tumors gradually increased at Day0,Day7,Day14,and Kurtosis values decreased gradually with significant differences（P<0.001for all）after 5-Fu treatment.However,ADC,Diffusivity,and Kurtosis showed no significant differences in CRC/EMT treatment group.The ADC and Diffusivity of the xenograft tumors in CRC/Control treatment group were significantly higher,and Kurtosis was significantly lower than those in CRC/Control control group（ADC,P=0.022;D,P=0.021;K,P=0.009）at Day14.There were no significant differences in ADC,Diffusivity,and Kurtosis values of xenograft tumors between the CRC/EMT control and treatment groups at Day0,Day7,and Day14.ADC and Diffusivity were negatively and Kurtosis was positively correlated with Ki-67 expression（P=0.003,P=0.002,P=0.004,respectively）.Conclusions:1.Pretreatment positive mr N and elevated CEA level are independent risk factors for synchronous distant metastasis in rectal cancer and combination of both factors could improve the accuracy and specificity and help to recognize the patients with high risk for synchronous distant metastasis.2.DKI could help to identify EMT in CRC xenograft tumors.Diffusivity and Kurtosis were significantly correlated with Ki-67 and E-cadherin expressions.3.5-Fu chemoresistance existed in the CRC xenograft tumors with EMT,and DKI could potentially assess 5-Fu early chemotherapy response in CRC with EMT.