SCF and IL-33 regulate mouse mast cell phenotypic and functional plasticity supporting a pro-inflammatory microenvironment

Abstract

Mast cells (MCs) are multifaceted innate immune cells often present in the tumor microenvironment (TME). Several recent findings support their contribution to the transition from chronic inflammation to cancer. However, MC-derived mediators can either favor tumor progression, inducing the spread of the tumor, or exert anti-tumorigenic functions, limiting tumor growth. This apparent controversial role likely depends on the plastic nature of MCs that under different microenvironmental stimuli can rapidly change their phenotype and functions. Thus, the exact effect of unique MC subset(s) during tumor progression is far from being understood. Using a murine model of colitis-associated colorectal cancer, we initially characterized the MC population within the TME and in non-lesional colonic areas, by multicolor flow cytometry and confocal microscopy. Our results demonstrated that tumor-associated MCs harbor a main connective tissue phenotype and release high amounts of Interleukin (IL)-6 and Tumor Necrosis Factor (TNF)-α. This MC phenotype correlates with the presence of high levels of Stem Cell Factor (SCF) and IL-33 inside the tumor. Thus, we investigated the effect of SCF and IL-33 on primary MC cultures and underscored their ability to shape MC phenotype eliciting the production of pro-inflammatory cytokines. Our findings support the conclusion that during colonic transformation a sustained stimulation by SCF and IL-33 promotes the accumulation of a prevalent connective tissue-like MC subset that through the secretion of IL-6 and TNF-α maintains a pro-inflammatory microenvironment.

New Insight into Intestinal Mast Cells Revealed by Single-Cell RNA Sequencing

“…Moreover, genes associated with lymphocyte cytotoxicity were upregulated in the absence of MCs, suggesting that these cells promote immunosuppression [ 83 ]. These results support in vitro and in vivo evidence demonstrating a role for tumor-infiltrating MCs in favoring a suppressive microenvironment and/or in promoting tumor growth [ 69 , 84 , 85 , 86 , 87 ].…”

Unraveling the genetic basis of the causal association between inflammatory cytokines and osteonecrosis

“…Furthermore, it is worth noting that Molfetta et al. demonstrated that sustained stimulation of SCF promotes the proliferation of connective tissue-like mast cell subpopulations and maintains a pro-inflammatory microenvironment in the body, which may also be one of the potential factors contributing to the development of osteonecrosis lesions ( 63 ). Interestingly, however, the positive effects of SCF on osteogenesis, possibly through the c-Kit-Akt signaling pathway, have been recognized in recent years, which may also suggest that SCF may have beneficial effects on osteonecrosis repair ( 64 , 65 ).…”

“…Earlier studies have demonstrated the potent enhancing effect of SCF on osteoclast activity in vitro (61), and glucocorticoids, one of the causative agents of pharmacologic osteonecrosis, also increase the expression of SCF in various ways (62), which may reveal one of the key pathogenetic mechanisms of drug-induced osteonecrosis. Furthermore, it is worth noting that Molfetta et al demonstrated that sustained stimulation of SCF promotes the proliferation of connective tissue-like mast cell subpopulations and maintains a pro-inflammatory microenvironment in the body, which may also be one of the potential factors contributing to the development of osteonecrosis lesions (63). Interestingly, however, the positive effects of SCF on osteogenesis, possibly through the c-Kit-Akt signaling pathway, have been recognized in recent years, which may also suggest that SCF may have beneficial effects on osteonecrosis repair (64,65).…”

Halofuginone-guided nano-local therapy: Nano-thermosensitive hydrogels for postoperative metastatic canine mammary carcinoma with scar removal

“…These CSC are pivotal in tumor recurrence, occurrence, and metastasis ( Yao et al, 2023 ). Because of their limited number and location in oxygen-deprived tissue far from the blood vessels, it is difficult for drugs to kill CSCs ( Molfetta et al, 2023 ). The survival and stemness maintenance of CSCs depends on the TME.…”