CRC is one of the deadliest malignancies worldwide, mainly due to chemotherapy failure that results in recurrence and metastasis in patients . To date, no simple, economically-friendly and practical CRC biomarker has been identified. Therefore, prospecting for new powerful biomarkers is necessary to guide development of chemotherapeutical approaches, alleviate the risk of recurrence and progression, as well enhance prognosis of the disease. In the present study, we found that preoperative FPR not only indicated disease burden, but also predicted complete response to chemotherapy, impaired chemosensitivity and chemoresistance. Specifically, high FPR was associated with poor survival of CRC patients, with circulating differential FPR accounted for survival differences between right- and left-sided patients with stage III and IV disease. Moreover, FPR was an independent prognostic factor for each stage of the disease, with nomogram containing FPR effectively predicting survival of CRC patients.
Previous studies have demonstrated the key roles played by Fib and pAlb in acute and chronic phases of malignancies such as CRC . Particularly, Fib is a driver of chronic low-grade inflammation, owing to its effect on platelets, eukocyte migration and role in promoting carcinogenic properties. In addition, it has been shown to function as a scaffold for cancer growth, migration and metastasis [23–25]. On the other hand, Alb and pAlb represent the main sources of energy and nutrition for tumor growth. Previous studies have demonstrated that inflammatory cytokines produced from CRC microenvironment and kupfer cells, including interleukin-6, effectively suppress Alb and preAlb synthesis by hepatocytes . Consequently, CRC patients, especially those at advanced stages, have been found to commonly manifest malnutrition or hypoalbuminemia [20, 27]. In the present study, we found significantly higher circulating FPR in large cancer bulk and distal metastatic subgroups than those with small cancer bulk and non-distal metastatic patients, respectively, although this was gradually elevated according to increased cancer bulk. These findings indicate that circulating FPR is determined by the cancer, and can be attributed to an uncontrolled inflammatory response. Consequently, this factor can be used to evaluate cancer burden.
In our previous studies, we found an association between circulating high FPR and poor prognosis in stage II-III and IV CRC patients [20, 28]. In the current study, univariate Cox regression revealed a significant association between high FPR and poor disease outcomes across each stage. Adjusting for common confounders, CEA, CA199 and tumor location, it revealed that high FPR was still robustly associated with poor prognosis of patients across each disease stage. Although we found significant differences in survival outcome between left- and right-sided patients with stage III and IV disease, there was no association between them following adjustment for other confounders, including FPR. These findings indicated that preoperative FPR, and not tumor laterality, was an independent prognostic factor for CRC patients at each stage of disease progression. Moreover, we found significantly higher preoperative FPR in right- than left-sided patients with stages III and IV CRC, indicating presence of high-grade inflammation in right-sided cases. A significantly higher high-FPR distribution in stage III and IV of right-sided relative to left-sided patients, might have contributed to the observed differences in survival outcome. Additionally, time-dependent FPR AUCs were superior to CEA, CA199 and tumor location in predicting the prognosis at each stage of disease progression, whereas c-indexes and AUCs from prognostic nomograms (FPR) found to be significantly higher than those from single factor or non-FPR nomograms. This indicates that preoperative FPR was an effective biomarker for predicting disease outcomes, therefore it can be used to improve prediction efficacies of prognostic nomogram in patients with all stage of CRC.
Previous studies have shown that an interaction among cancerous or stem cells, different immune and inflammatory cells as well as various mediators, such as cytokines and gut microbiota, sharpens the inflammatory microenvironment and promotes initiation and progression of CRC [29–30]. For example, cancer-associated stromal and inflammatory cells, such as fibroblast, macrophages and neutrophils, as well as colon cancer cells, were found to activate mitogen-activated protein kinase (MAPK), NF-kB, PI3K signaling pathway thereby promoting resistance to various conventional chemotherapy agents [31–33]. Moreover, gut microbiota, such as Fusobacterium nucleatum, have been implicated in regulation of a molecular network of the Toll-like receptor, microRNAs, and autophagy, thereby promoting chemoresistance . In the current study, chemotherapy-treated patients with preoperative FPR < 15 exhibited the best outcomes, whereas those with FPR ≥ 20 had the worst, in both stages III and IV of CRC. Moreover, clinical outcomes of chemotherapy-treated stage III and IV patients with FPR ≥ 15 were superior to those without chemotherapy as well as those who underwent chemotherapy with FPR ≥ 20. However, there were no significant differences between survival rates of chemo-treated stage III and IV patients with severe chronic inflammation (FPR ≥ 20) and those who did not undergo chemotherapy. These results indicated that FPR might be an indicator for effective chemotherapy in CRC patients. Particularly, FPR < 15 might indicate complete response to chemotherapy, 15 ≤ FPR < 20 could imply impaired sensitivity to adjuvant chemotherapy, whereas FPR ≥ 20 might denote chemoresistance. Overall, these findings show that clinical outcomes of right-sided stage III and IV patients are worse than those of left-sided counterparts, and high FPR effectively predicts poor survival rates in CRC patients.
This is the first study reporting a comprehensive analysis of prognostic and predictive significance of preoperative FPR in chemotherapy across stages I-IV in CRC patients, with different tumor locations. Based on results from a large sample size, used herein, it is evident that high-grade chronic inflammation attenuated chemosensitivity or triggered chemoresistance, and conferred poor outcomes within patients with the stage III and IV disease. Preoperative FPR was a robust predictor and prognostic factor for CRC patients, following chemotherapy. However, other prospective studies are needed to validate our findings. Specifically, functional and mechanistic analyses should be carried out to elucidate the association between FPR, inflammation and chemoresistance.