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.
Highlights
The global incidence of renal cancers ranked 16th among 35 common cancers in 2018 [1], renal cancers carry a poor prognosis
We investigated the preoperative viable circulating tumor cells (CTCs) counts and other clinical characteristics of the 106 enrolled patients and confirmed that the oHSV1-hTERT-GFP method was feasible in renal cell carcinoma (RCC) patients (Figure S1)
Most RCC patients die from cancer that relapses after CTCs spread to other organs rather than from early localized carcinoma
Summary
The global incidence of renal cancers ranked 16th among 35 common cancers in 2018 [1], renal cancers carry a poor prognosis. The prognosis of renal cell carcinoma (RCC), the most common kidney tumor, is poor; the 5-year survival rate decreases sharply to 8% in metastatic patients [2]. Most RCC patients die from the metastasis or recurrence of the cancer after it spreads to another organ. Little is known about the mechanisms by which circulating tumor cells (CTCs) survive intravascularly, which, in turn, reduces the opportunities to inhibit metastasis. The first aspect involves CTC self-changes, such as the antiphagocytic signal CD47 being overexpressed in circulating colorectal cancer cells [5]. The other aspect is the self-arming and self-protection of CTCs with suppressive cellular components; for example, CTCs recruit platelets to aggregate on their surface [6], and neutrophils adhere to circulating liver tumor cells expressing Mac-1 [7]
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