Mast Cell Targeting Hampers Prostate Adenocarcinoma Development but Promotes the Occurrence of Highly Malignant Neuroendocrine Cancers

Abstract

Mast cells (MC) are c-Kit-expressing cells, best known for their primary involvement in allergic reactions, but recently reappraised as important players in either cancer promotion or inhibition. Here, we assessed the role of MCs in prostate tumor development. In prostate tumors from both tumor-prone transgenic adenocarcinoma of the mouse prostate (TRAMP) mice and human patients, MCs are specifically enriched and degranulated in areas of well-differentiated (WD) adenocarcinoma but not around poorly differentiated (PD) foci that coexist in the same tumors. We derived novel TRAMP tumor cell lines, representative of WD and PD variants, and through pharmacologic stabilization or genetic ablation of MCs in recipients mice, we showed that MCs promote WD adenocarcinoma growth but are dispensable for PD tumors. WD tumors rely on MCs for matrix metalloprotease 9 (MMP-9) provision, as reconstitution of MC-deficient mice with wild-type but not MMP-9 À/À MCs was sufficient to promote their growth. In contrast, PD tumors are MMP-9 self-competent, consistently with epithelial-to-mesenchymal transition. Such a dual source of MMP-9 was confirmed in human tumors, suggesting that MCs could be a good target for early-stage prostate cancer. Interestingly, in testing whether MC targeting could block or delay tumorigenesis in tumor-prone TRAMP mice, we observed a high incidence of early and aggressive tumors, characterized by a neuroendocrine (NE) signature and c-Kit expression. Taken together, these data underscore the contribution of MCs in tumor progression and uncover a new, opposite role of MCs in protecting against the occurrence of aggressive NE variants in prostate cancer. Cancer Res; 71(18); 5987-97. Ó2011 AACR.

Mast cells influence neoangiogenesis in prostatic cancer independently of ERG status

“…In our study we observed a similar relationship with microvessel MC density, while the relationship between MCs and tumor grade was inverse and very weak. The inverse correlation between Gleason score and MC density could be expected from other studies [18,19], while others reported results similar to Stawerski et al [20].…”

Mast Cells Infiltrating Inflamed or Transformed Gut Alternatively Sustain Mucosal Healing or Tumor Growth

“…27). MC distribution and frequency in colon were assessed by toluidine blue stain, as previously reported (28). MCs were counted in five nonoverlapping high-power microscopic fields (Â400) and results were expressed as means.…”

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

“…In the context of the TME, mast cells are recognized as an early and persistent infiltrating cell type involved in angiogenesis, tissue remodeling, and immune modulation (9). Mast cells may have both antitumor and tumor-promoting roles, potentially also in the same context (10,11).…”