Intricate Macrophage-Colorectal Cancer Cell Communication in Response to Radiation

Abstract

Both cancer and tumour-associated host cells are exposed to ionizing radiation when a tumour is subjected to radiotherapy. Macrophages frequently constitute the most abundant tumour-associated immune population, playing a role in tumour progression and response to therapy. The present work aimed to evaluate the importance of macrophage-cancer cell communication in the cellular response to radiation. To address this question, we established monocultures and indirect co-cultures of human monocyte-derived macrophages with RKO or SW1463 colorectal cancer cells, which exhibit higher and lower radiation sensitivity, respectively. Mono- and co-cultures were then irradiated with 5 cumulative doses, in a similar fractionated scheme to that used during cancer patients’ treatment (2 Gy/fraction/day). Our results demonstrated that macrophages sensitize RKO to radiation-induced apoptosis, while protecting SW1463 cells. Additionally, the co-culture with macrophages increased the mRNA expression of metabolism- and survival-related genes more in SW1463 than in RKO. The presence of macrophages also upregulated glucose transporter 1 expression in irradiated SW1463, but not in RKO cells. In addition, the influence of cancer cells on the expression of pro- and anti-inflammatory macrophage markers, upon radiation exposure, was also evaluated. In the presence of RKO or SW1463, irradiated macrophages exhibit higher levels of pro-inflammatory TNF, IL6, CCL2 and CCR7, and of anti-inflammatory CCL18. However, RKO cells induce an increase of macrophage pro-inflammatory IL1B, while SW1463 cells promote higher pro-inflammatory CXCL8 and CD80, and also anti-inflammatory VCAN and IL10 levels. Thus, our data demonstrated that macrophages and cancer cells mutually influence their response to radiation. Notably, conditioned medium from irradiated co-cultures increased non-irradiated RKO cell migration and invasion and did not impact on angiogenesis in a chicken embryo chorioallantoic membrane assay. Overall, the establishment of primary human macrophage-cancer cell co-cultures revealed an intricate cell communication in response to ionizing radiation, which should be considered when developing therapies adjuvant to radiotherapy.

Tumor-Associated Macrophage Status in Cancer Treatment

“…The irradiation in the coculture with radiosensitive cells prompted the decrease of proinflammatory markers (CXCL8, CCR7, IL1β) while anti-inflammatory marker expression was not affected. In the coculture with radio-resistant cells, proinflammatory (CD80, CCR7) and anti-inflammatory (CCL18, IL10) markers were upregulated, these findings suggest that the interaction with different cancer cell types can affect the macrophage phenotype [103].…”

Immune targets in the tumor microenvironment treated by radiotherapy

“…Pinto et al investigated the relationship between TAMs and cancer cells in co-cultures of different cancer cell lines. Although their results showed different responses for different cancer cell lines, the overall output from their study was that TAMs were definitely in contact with cancer cells and they even might regulate metabolism, gene expression and cytokine production under IR and overall radiation response of cancer cells 230. Fortunately, IR shifts the pro-tumor effects predominance to anti-tumor side.…”

Predicting MicroRNA Target Genes and Identifying Hub Genes in IIA Stage Colon Cancer Patients Using Bioinformatics Analysis

“…Potential downregulated genes were involved in nervous system development, RNA polymerase II transcription factor activity, sequence-specific DNA binding, and nucleoplasm. Pinto et al [28] indicated that there is a complicated cell communication in response to ionizing radiation revealed by primary human macrophage-cancer cell culture. Kim et al [29] reported that IFITM1 expression was positively correlated with galectin-3 via receptor signaling protein activity in human colon cancer cells.…”