Crosstalk between tumor-associated macrophages and tumor cells promotes chemoresistance via CXCL5/PI3K/AKT/mTOR pathway in gastric cancer

Abstract

Background 5-fluorouracil (5-FU)-based chemotherapy regimen has been widely used for the treatment of gastric cancer, but meanwhile the development of chemotherapeutic resistance remains a major clinical challenge. Tumor microenvironment (TME) frequently correlates with the development of chemoresistance in human cancer. As a major component of TME, the role of tumor-associated macrophages (TAMs) in the chemoresistance of gastric cancer has not been fully elucidated. Methods Immunohistochemistry (IHC) was applied to detect the density of TAMs in clinical samples of 103 patients with gastric cancer who had undergone 5-FU-based neoadjuvant chemotherapy. 5-FU-resistant gastric cell lines MKN45-R and HGC27-R were established, macrophages were then separately co-cultured with MKN45-R, HGC27-R cells and their parental cells. The effect of gastric cancer cells on the polarization of macrophages, the biological function of M2-polaried macrophages and the mechanism for promoting 5-FU-resistance were investigated. Then the correlation between the expression of CXC motif chemokine ligand 5 (CXCL5) and the infiltration of hemoglobin scavenger receptor (CD163) positive and mannose receptor (CD206) positive macrophages was analyzed, the prognostic value of CXCL5 expression in clinical samples was further explored. Results The high infiltration of macrophages marked by CD68 in gastric cancer samples was significantly associated with the resistance of gastric cancer to chemotherapy. Gastric cancer cells could modulate macrophages to M2-like polarization through indirect co-culture, and chemoresistant cells were more efficient in inducing macrophages polarization to M2 phenotype. Co-culturing M2-polarized macrophages in turn enhanced 5-FU-resistance of gastric cancer cells, and it was further verified that CXCL5 derived from M2-polarized macrophages promoted chemoresistance through activing the PI3K/AKT/mTOR pathway. Besides, high level of CXCL5 could recruit monocytes to form more M2-polarized macrophages. Clinically, high expression of CXCL5 in gastric cancer samples was associated with the high infiltration of CD163 positive macrophages and CD206 positive macrophages, and patients with high expression of CXCL5 presented lower overall survival (OS) rates than those with low expression of CXCL5. Conclusion Interaction between TAMs and gastric cancer cells promoted chemoresistance in gastric cancer via CXCL5/PI3K/AKT/mTOR pathway. Thus, targeting TAMs and blocking the cell–cell crosstalk between TAMs and gastric cancer cells may represent prospective therapeutic strategies for patients with gastric cancer.

Lower SLC7A2 expression is associated with enhanced multidrug resistance, less immune infiltrates and worse prognosis of NSCLC

“…The activated M1 macrophage cell also secreted IL-1β [25]. CXCL5 could recruit monocytes to form M2-polarized macrophages, weaken the sensitivity of gastric cell line MNK-45 and HGC-27 to 5-FU [26]. With all these results, we could reasonably conclude that SLC7A2 was important in immune infiltration by regulating CXCL5 and IL-1β.…”

SPRR3 as a diagnostic and prognostic molecular marker for lung adenocarcinoma based on pan-cancer analysis

“…TIME contains different TIIC populations, which shows high relation to anticancer immune status within TME. Studies have shown that, as a kind of stroma cells, cancer-associated broblasts (CAFs) have the highest abundance in TME, and they are of cellular origin, phenotype and functional heterogeneities [28][29][30]. Shen [31]brie y summarize the roles of leukocytes and iron metabolism in tumorigenesis and their interaction in the tumor microenvironment.…”

Tumour‐associated macrophages in gastric cancer: From function and mechanism to application

“…Similarly, MSR1 facilitated the polarisation of M2 TAMs by enhancing arginine and proline metabolism in macrophages 46 . Meanwhile, increased levels of chemokines in the TME, CXCL5, CXCL12 and CCL5, can induce a higher proportion of M2 TAMs 41,83,85 . The results of flow cytometry and immunohistochemistry of a transplanted tumour model indicated that EZH2 induced the polarisation of M2 TAMs 86 .…”

“…162 Su et al found that patients with high infiltration of macrophages (CD68) were often related to poor response to neoadjuvant chemotherapy in a 103 sample cohort. 41 Meanwhile, high infiltration of M2 TAMs (CD206) was usually forecasted as resistant to trastuzumab therapy in patients with HER2-positive GC. 71 Sun et al reported that the high expression of total TAMs (CD68) or M2 TAMs (CD206) usually predicted a poor OS, while the high expression of M1 TAMs (CD86) indicated a better prognosis in HER2-positive patients with GC.…”