Mast cells are an essential hematopoietic component for polyp development

Abstract

It is generally agreed that most colon cancers develop from adenomatous polyps, and it is this fact on which screening strategies are based. Although there is overwhelming evidence to link intrinsic genetic lesions with the formation of these preneoplastic lesions, recent data suggest that the tumor stromal environment also plays an essential role in this disease. In particular, it has been suggested that CD34 ؉ immature myeloid precursor cells are required for tumor development and invasion. Here we have used mice conditional for the stabilization of ␤-catenin or defective for the adenomatous polyposis coli (APC) gene to reinvestigated the identity and importance of tumor-infiltrating hematopoietic cells in polyposis. We show that, from the onset, polyps are infiltrated with proinflammatory mast cells (MC) and their precursors. Depletion of MC either pharmacologically or through the generation of chimeric mice with genetic lesions in MC development leads to a profound remission of existing polyps. Our data suggest that MC are an essential hematopoietic component for preneoplastic polyp development and are a novel target for therapeutic intervention.cancer ͉ inflammation ͉ polyposis ͉ TNF␣

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

“…7 MC density in CRC tissues is positively associated with poor clinical outcomes in patients 10–13,15,17 and decreased intestinal tumor growth has been observed in MC-deficient mice. 28,29 Our study further provides experimental evidence that primary human MC promote colon cancer growth by stimulating production of pro-tumorigenic mediators in a bidirectional manner. Thus far, most studies in human MC-cancer interaction were using MC cell lines (LAD2 and HMC-1) 30–35 with specific limitations that these cell lines are leukemia-derived (e.g.…”

“…This notion is consistent with a study in APC ∆8,41 mouse model, where they suggest MC represent CCR1+ immature myeloid cells in the tumor invasive front. 28 Subsequent RNA sequence analysis revealed a less proliferative profile of MC when cocultured with colon cancer cells (Supplemental Figures. 4 and 5), implying the increased MC density in colorectal cancer tissues might be due to migration rather than local proliferation.…”

“…It has been shown that murine MC promote colon cancer growth, as illustrated by MC-deficient mouse models 28,29 and the coculture of primary murine MC and mouse colon cancer CT26. 17 We present for the first time that primary human MC can directly support human colon cancer proliferation.…”

SHIP1 Is a Repressor of Mast Cell Hyperplasia, Cytokine Production, and Allergic Inflammation In Vivo

“…TNF is required for mast cell development and stimulates mast cell colony formation in vitro (24,25). In addition, IL-6 promotes mast cell development from mixed cultures, likely via a secondary mediator such as PGE (24).…”

“…Our study suggests that SHIP1 agonists could reduce the severity of anaphylaxis, allergic asthma, and other mast cell-associated diseases in humans. Given that mast cells also have a role in such diverse diseases as rheumatoid arthritis, inflammatory bowel disease, and tumor progression and conversely aid in clearing peritoneal and helminth infections, modulators of SHIP1 function in mast cells may offer a variety of therapeutic strategies against key human diseases (25,38,39,42,43).…”