Platelets promote CRC by activating the C5a/C5aR1 axis via PSGL-1/JNK/STAT1 signaling in tumor-associated macrophages

Abstract

Rationale: Platelets can influence the progression and prognosis of colorectal cancer (CRC) through multiple mechanisms, including crosstalk with tumor-associated macrophages (TAMs). However, the mechanisms underlying the crosstalk between platelets and TAMs remain unclear. The present study aimed to investigate the role of intratumoral platelets in regulating the function of TAMs and to identify the underlying mechanisms. Methods: The interaction of platelets with macrophages was assessed in the presence or absence of the indicated compounds in vivo . An azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CRC mouse model was used to investigate the role of platelets in controlling CRC development. Multiplexed immunofluorescence staining, fluorescence-activated cell sorting (FACS), and RNA sequence analysis were used to examine the changes in TAMs. TAMs and bone marrow-derived macrophages (BMDMs) were treated with the indicated compounds or siRNA against specific targets, and the expression levels of signal transducer and activator of transcription 1 (STAT1), c-Jun N-terminal kinase (JNK), and P-selectin glycoprotein ligand-1 (PSGL-1) were measured by Western blotting. The mRNA expression levels of complement 5 ( C5 ), complement 5a receptor 1 ( C5ar1 ), Arginase 1 ( Arg1 ) and Il10 were measured by real-time RT-PCR, and the complement 5a (C5a) concentration was measured by ELISA. The dual-luciferase reporter assay and ChIP assay were performed to examine the potential regulatory mechanisms of platelet induction of C5 transcription in TAMs. Results: In our study, we found that an increase in platelets exacerbated CRC development, while inhibiting platelet adhesion attenuated tumor growth. Platelets signal TAMs through P-selectin (CD62P) binding to PSGL-1 expressed on TAMs and activating the JNK/STAT1 pathway to induce the transcription of C5 and the release of C5a, shifting TAMs toward a protumor phenotype. Inhibiting the C5a/C5aR1 axis or PSGL-1 significantly reduced CRC growth. Conclusions: An increase in intratumoral platelets promoted CRC growth and metastasis by CD62P binding to PSGL-1 expressed on TAMs, leading to JNK/STAT1 signaling activation, which promoted C5 transcription and activated the C5a/C5aR1 axis in TAMs. Our study examined the mechanism of the crosstalk between platelets and TAMs to exacerbate CRC development and proposed a potential therapeutic strategy for CRC patients.

Revealing profile of cancer-educated platelets and their factors to foster immunotherapy development

“…It has also been shown that intratumoral platelets promoted growth and progression of colorectal cancer leading to JNK/STAT1 signaling activation, which further promoted C5 transcription and activated the C5a/C5aR1 axis in tumor-associated macrophages (TAMs). Shifting TAMs toward M2 polarization and impairing the phagocytosis of TAMs was followed by the increased mRNA levels of Arg1 and IL-10 in sorted TAMs [ 64 , 65 ] ( Fig. 2 ).…”

Clinical application of liquid biopsy in colorectal cancer: detection, prediction, and treatment monitoring

“…Xueqin Li et al have found elevated TEPs can promote the growth and metastasis of CRC by binding CD62P to PSGL-1 expressed on tumor macrophages (TAMs), enhance the C5 transcription in TAMs and activate the C5a/C5aR1 axis via the JNK/STAT1 pathway. The study explored the mechanism by which the interaction between platelets and TAMs can aggravate the development of CRC and proposed a potential therapeutic strategy for CRC patients [ 125 ]. While previous research suggests that platelets can influence the course and outcome of CRC through interactions with TAMs, the precise mechanisms remain unclear.…”

Direct-Acting Oral Anticoagulant Therapy in Cancer Patients—A Review

“…This correlation can be explained mostly by elevation of prothrombotic factor expression by either cancer cells or cells forming the tumor microenvironment [2,3]. These mechanisms are self-reinforcing processes because platelets present the ability to promote progression of the cancer [4,5]. Among molecular mechanisms of tumor cell-induced platelet aggregation (TCIPA), scientists described production of tissue factor (TF) by cancer cells [6], production and regulation of thrombopoietin (TPO) [7], and granulocyte colony stimulating factor [8].…”