Cooperation Between the Inflammation and Coagulation Systems Promotes the Survival of Circulating Tumor Cells in Renal Cell Carcinoma Patients

Abstract

Most renal cell carcinoma (RCC) patients die from metastasis or recurrence after the spread of cancer to another organ, but the mechanisms underlying the intravascular survival of circulating tumor cells (CTCs) have not been completely deciphered. Additionally, although elevated plasma C-reactive protein (CRP) levels and thrombocytosis are strongly correlated and both indicate a poor prognosis for RCC patients, the bridge connecting inflammation and coagulation remains poorly understood. To explore the complicated relationship among inflammation, the coagulation system and CTC survival, we obtained viable CTC counts and clinical information from 106 treatment-naïve patients. In addition, we performed RNA sequencing on peripheral blood leukocytes from 21 of these patients. Patients with elevated CRP and fibrinogen (FIB) levels had higher CTC counts than patients with normal levels of these indexes. Each pair of the three variables (CTC count, CRP level and FIB level) was positively correlated. According to transcriptomic analysis of blood leukocytes, the functions of the 257 genes identified as being positively correlated with the CTC count indicated neutrophil extracellular trap (NET) formation. Indeed, gene set enrichment analysis (GSEA) suggested that NET formation or increased levels of NET markers would promote CTC viability. Additionally, the calculated NET score was positively correlated with the plasma FIB concentration, and both of these values were increased in patients with elevated CRP levels. Moreover, immunofluorescence staining showed that NETs were entangled with viable renal cancer cells and that the NET frameworks were decorated with NET-derived tissue factor (TF). Finally, analysis of 533 RCC samples from The Cancer Genome Atlas (TCGA) indicated that the NET score and TF value are independent prognostic factors for RCC patients. Collectively, NETs formed by intravascular neutrophils further activate the coagulation system. Both the DNA scaffold sprouted and fibrin net triggered by NETs anchor and shield CTCs from attack. Thus, degrading this framework maybe could destroy the double shelter of CTCs, the pioneers of metastasis.

EMT-Associated Heterogeneity in Circulating Tumor Cells: Sticky Friends on the Road to Metastasis

“…Supporting these experimental data, NETs have been associated with a poor prognosis in several cancer types and with cancer-associated VTE [260,261]. Recapitulating these relationships in renal cell carcinoma patients, Wen et al reported that a high CTC count correlates with elevated levels of fibrinogen and RNA expression of NET's markers in blood leukocytes [262].…”

<p>Prognostic Value of the Combination of CEA and Fibrinogen/Albumin Ratio in Resectable Gastric Cancer</p>

“…2 Inflammation is a hallmark of cancer, and malignant tumors compromise the coagulation, anticoagulation, and fibrinolysis systems of the body through various mechanisms, resulting in abnormal coagulation function and fibrinogen elevation. 3 Fibrinogen is an acute-phase-response protein that can increase under systemic inflammatory conditions. Previous studies have shown that increased plasma fibrinogen indicates poor prognosis of various cancers including GC.…”

<p>Combination of Hematology Indicators and Oncological Characteristics as a New Promising Prognostic Factor in Localized Clear Cell Renal Cell Carcinoma</p>

“…28 Our previous research also pointed out that the abnormality of inflammation and coagulation indexes is correlated with viable CTCs, which is the premise of tumor recurrence and metastasis, and the neutrophil extracellular traps (NETs) induced by circulating neutrophils could protect the survival of circulating tumor cells, thus promoting postoperative recurrence and metastasis in patients with RCC. 11 Therefore, it is reasonable to construct a prognostic model for local renal cell carcinoma based on the combination of hematological indicators FIB, CRP, and NLR.…”

“…We have reported that the plasma concentrations of FIB, CRP and neutrophils were positively correlated with the circulating tumor cells (CTCs), which was a prerequisite for recurrence and metastasis. 11 In this study, we evaluated the preoperative blood indexes to explore a risk classification for predicting disease-free survival (DFS) in patients with stage I-III ccRCC. The inclusion criteria of the study were as follows: (1) no primary cancer of any other organs before the operation; (2) no chronic inflammatory allergic disease; (3) no history of taking anticoagulants such as for cardiovascular or cerebrovascular thrombosis; (4) exact pathological diagnosis of ccRCC; (5) complete resection of the tumor, which was defined as a negative incisal margin; (6) complete clinicopathological characteristics and follow-up data; and (7) no evidence of extrarenal metastasis.…”