G-CSF and G-CSFR Induce a Pro-Tumorigenic Macrophage Phenotype to Promote Colon and Pancreas Tumor Growth

Abstract

Tumor-associated macrophages (TAMs) in the gastrointestinal tumor microenvironment (TME) are known to polarize into populations exhibiting pro- or anti-tumoral activity in response to stimuli such as growth factors and cytokines. Our previous work has recognized granulocyte colony-stimulating factor (G-CSF) as a cytokine capable of influencing immune cells of the TME exhibiting pro-tumoral activity. Here, we aimed to focus on how G-CSF regulates TAM phenotype and function and the effects on gastrointestinal (GI) tumor progression. Thus, wildtype (WT) and G-CSFR−/− macrophages were examined for cytokine production, gene expression, and transcription factor activity. Adoptive transfer of WT or G-CSFR−/− macrophages into tumor-bearing mice was performed to study their influence in the progression of colon (MC38) and pancreatic (PK5L1940) tumor mouse models. Finally, the difference in cytotoxic potential between WT and G-CSFR−/− macrophages was examined both in vitro and in vivo. Our results indicate that G-CSF promotes increased IL-10 production and decreased IL-12 production, which was reversed in G-CSFR−/− macrophages for a pro-inflammatory phenotype. Furthermore, G-CSFR−/− macrophages were characterized by higher levels of NOS2 expression and NO production, which led to greater tumor related cytotoxicity both in vitro and in vivo. Our results suggest that in the absence of G-CSFR, macrophage-related tumor cytotoxicity was amplified. These findings, along with our previous reports, pinpoint G-CSF /G-CSFR as a prominent target for possible clinical applications that aim to control the TME and the GI tumor progression.

TRIM37 Promotes Pancreatic Cancer Progression through Modulation of Cell Growth, Migration, Invasion, and Tumor Immune Microenvironment

“…Meanwhile, although the knockdown of TRIM37 did not significantly suppress the production of G-CSF, we observed a trend in downregulation. G-CSF/G-CSFR promoted the development of protumoral macrophages in colon and pancreatic cancer [41]. Patients with breast cancer have high levels of G-CSF, which supports M2-like macrophages, and anti-G-CSF treatment significantly reduced the proportion of MHCII low blood monocytes and TAM, as well as lung metastasis [42].…”

Neutrophilic leucocytosis induced by granulocyte colony‐stimulating factor and interleukin‐6 in canine primary lung adenocarcinoma

“…Recent studies have shown that G‐CSF has a pro‐tumourigenic function by promoting migration of breast cancer cells and an anti‐inflammatory macrophage phenotype (Hollmén et al., 2016 ). Furthermore, it has been reported that elevated expression of CSF3R promotes an overall pro‐tumourigenic immune phenotype (Karagiannidis et al., 2020 ). In both cases, the lung tumours were >100 cm 3 in size and the expression of CSF3R was increased.…”

Engineered endosymbionts capable of directing mammalian cell gene expression

“…For example, inflammation is an important hallmark of cancer, and the presence of immune cells known as tumor associated macrophages (TAM) is often conducive of tumor growth, metastases and poor outcomes (Gharib et al, 2019;Laoui et al, 2011). TAMs are broadly M2 polarized, and IL-10, IL-12p40 and G-CSF all have been shown to play important roles in impacting the tumor microenvironment through regulation of TAMs (Biswas et al, 2006;Kanemaru et al, 2017;Karagiannidis et al, 2020;Laoui et al, 2011) which could be targeted by the EES in cancer bacteriotherapy (Sawant et al, 2020;Yaghoubi et al, 2019Yaghoubi et al, , 2020bYaghoubi et al, , 2020aZhang et al, 2020). Arthritis represents the other side of immune polarization where homeostasis is driven to a proinflammatory condition (Georgopoulos et al, 1996;Henderson and Pettipher, 1989).…”