Tumour-associated macrophages mediate the invasion and metastasis of bladder cancer cells through CXCL8

Abstract

Tumour-associated macrophages (TAMs) are associated with both the progression and poor prognosis of a variety of solid tumours. This study aimed to investigate and clarify the tumour-promoting role of CXCL8 secreted by TAMs in the urothelial carcinoma microenvironment of the bladder. Immunohistochemistry (n = 55) was used to detect Chemokine (C-X-C motif) ligand 8 (CXCL8), CD163 (a TAM marker), Matrixmetalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF), and E-cadherin in cancerous and adjacent tissues of bladder cancer patients. TAMs-like PBM (peripheral blood mononuclear)-derived macrophages were developed using in vitro experiments. T24, 5637, and UM-UC-3 were treated with conditioned medium (CM) for the experimental intervention group, without CM for the blank control group, and with CM and an anti-CXCL8 neutralizing antibody for the experimental control group, respectively. The immunohistochemical study showed that the expression of CXCL8 was significantly upregulated as the number of infiltrating TAMs increased in the tumour tissues. A high expression of CXCL8 significantly correlated with an increase in the expression of MMP-9 and VEGF and a decrease in expression of E-cadherin in the microenvironment. This revealed that TAM-derived CXCL8 is highly associated with bladder cancer migration, invasion, and angiogenesis. The concentration of CXCL8 was significantly higher in CM collected from TAM-like PBM-derived macrophages than that from THP-1 cells. In subsequent in vitro experiments, we found that CM derived from TAM-like PBM-derived macrophages can also increase the migration rate, invasiveness, and pro-angiogenic properties of tumour cells. Additionally, the effect of CXCL8 was significantly diminished by the addition of an anti-CXCL8 neutralizing antibody to CM. The infiltration of TAMs in the tumour microenvironment leads to the elevation of CXCL8, which in turn promotes the secretion of MMP-9, VEGF, and E-cadherin by bladder cancer cells. This alters the migration, invasion, and pro-angiogenic capacity of bladder cancer cells and accelerates cancer progression.

The crosstalk between circular RNAs and the tumor microenvironment in cancer metastasis

“…Once in the TME, they are polarized to a tumor-associated macrophage (TAM) phenotype [28]. The infiltration of TAMs in the TME leads to the migration, invasion, and enhanced pro-angiogenic capacity of bladder cancer cells through CXCL8 secretion, which in turn regulates cadherin expression to accelerate cancer invasion [29]. Low expression of circ_0026344 was detected after CCL20 and CXCL8 synergized treatment in colorectal cancer (CRC) cell lines.…”

“…A small number of CTCs in the blood can resist anoikis in the bloodstream through increasing the expression of CXCL8, but it is still unclear how CXCL8 and its receptors regulate anoikis resistance [103]. Recently, one study revealed that TAM infiltration in the TME elevates CXCL8, promoting bladder cancer cell migration and invasion via the secretion of MMP9, VEGF, and E-cadherin [29]. Further, TAMs carried tumor cells into the bloodstream.…”

Redefining Tumor-Associated Macrophage Subpopulations and Functions in the Tumor Microenvironment

“…The role of TAMs in the TME, which is critical to current TAM-targeted strategies, remains to be uncovered due to the intricate heterogeneity of macrophages. Preclinical and clinical data show a close relationship between high infiltration of TAMs and a poor prognosis in most types of tumors (4), such as pancreatic ductal adenocarcinoma (PDAC) (5), glioblastoma (6), and bladder cancer (7). On the other hand, TAM infiltration has also been found to be associated with a favorable prognosis in some cases, such as in ovarian cancer (8) and colorectal cancer (9).…”

The Role of Rho GTPases in VEGF Signaling in Cancer Cells

“…By supplying oxygen and nutrients to the tumors, it is well established that VEGFA enhances tumor progression [36,37]. Specifically, cancer cell migration, invasion, and angiogenesis can also be linked to the increase in the expression levels of VEGF [38]. This has thus provided the basis for the development of therapies which target angiogenesis in cancer cells by downregulating or inhibiting VEGF and/or interfering with the corresponding (VEGFRs) receptors [1,39].…”