Abstract
BackgroundMacrophage extracellular traps (METs) and tumor-infiltrating macrophages contribute to the progression of several diseases. But the role of METs and tumor-infiltrating macrophages in colon cancer (CC) has not been illuminated. In this study, we aimed to clarify the prognostic value of METs for CC patients and to explore the interaction between CC cells and METs in vitro and in vivo.MethodsA training cohort consisting of 116 patients and a validation cohort of 94 patients were enrolled in this study. Immunofluorescence (IF) staining was conducted to determine METs formation in CC patients. Cox regression was used to perform prognostic analysis and screen out the best prognostic model. A nomogram was established to predict 5-year overall survival (OS). The correlation between METs with clinicopathological features and inflammatory markers was analyzed. The formation of METs in vitro was detected by SYTOX® green and IF staining, and the effect of METs on CC cells was detected by transwell assays. PAD2-IN-1, a selective inhibitor of peptidylarginine deiminase 2 (PAD2), was introduced to destroy the crosstalk between CC cells and METs in vitro and in vivo.ResultsMETs levels were higher in CC tissues and were an independent prognostic factor for CC patients. The prognostic model consisting of age, tumors local invasion, lymph node metastasis and METs were confirmed to be consistent and accurate for predicting the 5-year OS of CC patients. Besides, METs were correlated with distant metastasis and inflammation. Through in vitro experiments, we confirmed that there was a positive feedback loop between CC cells and METs, in that METs promoted the invasion of CC cells and CC cells enhanced the production of METs, in turn. This interaction could be blocked by PAD2-IN-1 inhibitors. More importantly, animal experiments revealed that PAD2-IN-1 inhibited METs formation and CC liver metastasis in vivo.ConclusionsMETs were the potential biomarker of CC patient prognosis. PAD2-IN-1 inhibited the crosstalk between CC cells and METs in vitro and in vivo, which should be emphasized in CC therapy.
Highlights
Colorectal cancer (CRC) is one of the most common malignancies, which can be further divided into colon cancer (CC) and rectal cancer (RC)
A total of 102 patients (87.9%) had T3/T4 tumors, while 45 patients (38.8%) had lymph node metastasis (LNM) and 11 patients (9.5%) had distant metastasis, and all of them were in stage III/IV
83 patients (88.3%) had T3/T4 tumor, 34 patients (36.2%) had LNM, and 5 patients (5.32%) had distant metastasis, and all of them were in stage III/IV
Summary
Colorectal cancer (CRC) is one of the most common malignancies, which can be further divided into colon cancer (CC) and rectal cancer (RC). The prognosis of patients with metastatic CRC (mCRC) who have received postoperative adjuvant chemoradiotherapy and radiofrequency therapy is still poor, with a 5-year overall survival (OS) rate less than 15%, which is the main challenge for CRC treatment at present [2]. Non-malignant cells such as stromal cells, immune cells, and other cells infiltrate the tumor, and the dynamic interaction network among the different cell sub-classes regulates the biological behavior of tumor cells and determines tumor progression, the prognosis of tumor patients, and the response to the onco-therapy. The targeted treatment of immune cells in CRC should be emphasized and studies on more effective predictors related to immune cells are necessary, in order to greatly improve. We aimed to clarify the prognostic value of METs for CC patients and to explore the interaction between CC cells and METs in vitro and in vivo
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