Imaging technology is the most commonly used tool in the evaluation for the initial diagnosis, staging, restaging and monitoring treatment of CRC, especially those cannot traversed colonoscopically. MRI has a significant advantage in assessing T staging of primary rectal cancer because of the capacity to differentiate the intestinal wall laminar structure [14]. However, evaluation of N and M stage in patients with CRC using conventional procedures was still present challenges until the emergence of whole-body 18F-FDG PET/CT. PET/CT integrate morphologic and molecular data to detecting tumor biological behavior, furthermore provide lymph nodes and distant metastases information.
In this study, we detected the semi-quantitative (SUVmax,SUVmean, TLG and MTV) derived from FDG and the expression of tumor markers (GLUT-1 and MACC1) in patients with different stages of CRC which consistent with pathological results. Our finding demonstrated that a significant correlation was found between SUVmax, TLG and MTV values and T status (P=0.002, 0.002 and 0.001, respectively), meanwhile another correlation was found between SUVmean values and M status (P=0.000) of primary CRC. The area under the curve (AUC) of SUVmax, SUVmean, TLG and MTV was 0.838, 0.819, 0.941 and 0.96, respectively. For distinguish T3 status from T4 of CRC, the SUVmax cut-off value of 18.75 showed sensitivity of 100%, specificity of 70.6%, SUVmean cut-off value of 11.7 showed sensitivity of 66.7%, specificity of 87% and TLG cut-off value of 275.85 showed sensitivity of 100%, specificity of 88.2%. For distinguish M status of CRC, MTV cut-off value of 30.5 showed sensitivity of 100%, specificity of 82.4%. Those results suggested that enhanced glucose uptake is associated with malignant tumor progression, similarly FDG parameters data provide metabolic characteristic that have the capacity to distinguish tumor T stage and M stage of CRC. The same results consistent with previous study, it is considered that SUV value of FDG PET/CT is more suitable for assessment tumor stage compared with CT and MRI, and the combination of colonoscopy will be more beneficial for CRC staging [15, 16]. Clinically, PET/CT scanning is an essential project to evaluate T, N and M stage preoperative in patients with CRC.
In previous meta-analysis, overexpressed GLUT-1 was considered to be associated with clinical features including lymph node metastasis, T stage, higher Dukes stage and disease-free survival of CRC [4]. Overexpressed MACC1 was contribute to the transformation of malignant degree and metastatic potential of CRC, primarily for adenoma transform into Tis further transform into invasive CRC[7, 17]. Our results demonstrated a significant relationship between GLUT-1/MACC1 expression and T status (P=0.006 and 0.002),differentiated degree (P=0.009 and 0.014), CRC patients with high T-status and poorly differentiated tended to have higher GLUT-1/MACC1 expression levels. Our data reveal that GLUT-1 and MACC1 has a prognostic capacity for stratified tumor pathological factors (T status and differentiated degree). Furudoi, A. et al. study suggest that the GLUT-1 expression at the deepest invasive site was significantly with clinicopathologic features including lymph node and Duke’s stage [18]. Our finding also consistent with Aifen Lin’s study, shown that high expression of MACC1 was correlation with T stage of CRC and was a valuable prognostic and risk stratification biomarker of CRC[17]. Shirahata A. et al. found that MACC1 expression was significantly correlated with peritoneal dissemination and higher TNM stage of CRC [19]. Inconsistent with previous study, the average expression of GLUT-1 and MACC1 were higher in M1 and N2 specimen but did not reach the statistical difference which may due to the limitation of small sample volume in our experiment. Moreover our study found that the expression of MACC1 was higher than GLUT-1 in the same patient, MACC1 protein may be superior to GLUT-1 in predicting the biological characteristics of CRC.
Subsequently, our finding revealed the relationship between biomarker and radio-parameters derived from FDG PET. Our multivariate analysis shown a significantly correlation between GLUT-1 and SUVmax, MTV (R2=0.42, P=0.013 and 0.004, respectively), another correlation was found between MACC1 and TLG (R2=0.372, P=0.000). In most studies, SUVmax was the most commonly used parameter to evaluate FDG uptake, however, tumor volumetric parameters of FDG such as MTV and TLG provides more comprehensive informations on tumor metabolism and reflect tumor biological characteristics more accurately [20]. In our study, the volumetric parameters of MTV and TLG show a power in evaluating the expression of GLUT-1 and MACC1 in CRC specimen. The mechanism of FDG uptake was acknowledged to be mainly mediated by GLUT family, and GLUT-1 was one of the most important contributor. Enhanced FDG uptake reflect the heterogeneity of glucose metabolism. The correlation between GLUT-1 and FDG uptake was found in multiple malignancies such as breast cancer[21], lung cancer[22], cervical cancer[23],pancreatic cancer[24] and colorectal cancer[12] et al. However, Ran Hong’s study show that the GLUT-1 expression was not associated with FDG uptake, the discrepancy between two studies may be caused by differences in FDG parameters, only one radio-parameter was included in Ran Hong’s research [25]. There was few study regarded to the relationship between MACC1 and FDG uptake, the present study demonstrated a statistical correlation between MACC1 expression and TLG of CRC patients for the first time. The expression levels of MACC1 in primary CRC lesion may better reflect the character of tumor total lesion glycolysis. This correlation may explained as high MACC1 levels is related to tumor progression, overexpressed MACC1 enhanced the tumor Warburg effect which increasing the glucose metabolism activity of CRC [17, 26]. Consistent with Jing Liu study, demonstrates that MACC1 overexpression promotes 18F-FDG uptake in mice bearing NCI-N87 xenograft [27]. To investigating the relationship between biomarkers and FDG uptake will deeply understanding tumor biological behavior and lead to a clearer interpretation of PET imaging.