SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment

Abstract

Despite the evidence for the role of inflammation in cancer initiation, promotion, and progression, the precise mechanism by which the inflammation within tumor is orchestrated by inflammatory cells remains to be determined. Here IntroductionChronic inflammation, a "promoting force" in the tumor microenvironment, has long been known to be commonly braided with the initiation, promotion, and progression of tumorigenesis. [1][2][3][4][5] To date, however, it is still incompletely understood how the inflammation in the tumor microenvironment is orchestrated by inflammatory cells. Recently, mast cells were highlighted as not only a major participator but also an important regulator of inflammation, 6,7 and their accumulation in tumors has also been well documented, [8][9][10][11][12][13] implying that mast cells may possibly play an important role in orchestrating the inflammation in tumors.The tumor microenvironment is regarded as a "smoldering" inflammation site in which a lot of cytokines, chemokines, and enzymes mediate the inflammatory process and drive malignant progression. 14,15 Among them, TNF-␣, IL-6, VEGF, iNOS, Cox-2, and MMP-9 are of particular interest. [15][16][17][18] Coincidentally, all of them can be produced by mast cells. However, the tumor microenvironment is also characterized by its immunoediting from immunosurveillance to immunosuppression. 19 Mast cells have been found to play a critical role in the suppression of immune reactions. 20 They not only produce inhibitory cytokine IL-10, 21 but they also are essential for the immune tolerance mediated by regulatory T (Treg) cells. 22 Thus, mast cell infiltration into tumor may possibly remodel tumor microenvironment and profoundly influence tumor behavior by participating and regulating inflammatory and immune reactions. However, although some studies have shown that mast cells promote tumor angiogenesis and tumor growth because of their properties as inflammatory cells, [23][24][25] the roles of mast cells in tumor progression have been incompletely understood so far. Several key questions remain unclear, especially how mast cells are recruited into the tumor site and whether they can remodel the tumor microenvironment.Mast cell migration to the tumor site and the following activation may be the prerequisite for their promoting effect on tumors. In this regard, stem cell factor (SCF) is possibly involved, because SCF triggers the c-Kit signaling pathway for the differentiation, migration, maturation, and survival of mast cells. 26 In the present study, we investigated the relation of mast cells and SCF in tumor progression and showed that SCF recruited and activated mast cells, the activated mast cells remodeled the tumor microenvironment by intensifying inflammation and immunosuppression, the tumor cell NF-B and AP-1 activities were augmented, and the suppression of T cells and natural killer (NK) cells was exacerbated in such remodeled microenvironments. These findings provide a new insight into the role of mast cells in tumors and the relati...

Human mast cells promote colon cancer growth via bidirectional crosstalk: studies in 2D and 3D coculture models

“…SCF is a well-known chemoattractant for MC migration in the context of cancer. 18 Therefore, we added various concentrations of SCF blocking antibody in the migration assay. Inhibition of SCF resulted in up to 65% reduction of MC recruitment to Caco2, but had no effect on that of HT29 (Figure 2(b)).…”

“…38 The importance of SCF in attracting MC into tumor environment was previously demonstrated by the migration of mouse primary MC toward mouse H22 hepatocarcinoma cells. 18 Surprisingly, HT29 colon cancer cells induced MC chemotaxis partly via the secretion of CCL15, while no SCF-induced migration was involved. This may reflect the intrinsic biological difference among individual colon cancers.…”

Mast Cells Boost Myeloid-Derived Suppressor Cell Activity and Contribute to the Development of Tumor-Favoring Microenvironment

“…Using a transplanted hepatocarcinoma model, Huang and colleagues (12) have recently demonstrated that mast cells can accumulate in the TME and exacerbate inflammation and immunosuppression via the SCF/c-kit signaling pathway. Moreover, they discuss a close loop between mast cells, MDSCs, and regulatory T cells (Treg) in creating a potent suppressive TME.…”

E-cadherin in canine mast cell tumors: Decreased expression and altered subcellular localization in Grade 3 tumors

“…Once mast cells are attracted to tumors by chemo-attractants, such as stem cell factor (SCF), they are triggered to secrete molecules that act as growth factors, stimulating tumor growth, angiogenesis, and metastasis. Mast cells thus promote the tumor microenvironment remodeling and tumor growth, increasing the secretion of inflammatory chemicals and the activity of NF-kappaB, which augments the suppression of Tcells and natural killer cells in tumors (Huang et al, 2008).…”