title: 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(-/-) 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.
authors: Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Paola
authors: P
authors: Pittoni
authors: Claudio
authors: C
authors: Tripodo
authors: Silvia
authors: S
authors: Piconese
authors: Giorgio
authors: G
authors: Mauri
authors: Mariella
authors: M
authors: Parenza
authors: Alice
authors: A
authors: Rigoni
authors: Sabina
authors: S
authors: Sangaletti
authors: Mario P
authors: MP
authors: Colombo
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology*; D000818:Animals; D018278:Carcinoma, Neuroendocrine / Q000201:enzymology / Q000473:pathology*; D015550:Cell Degranulation / Q000502:physiology; D045744:Cell Line, Tumor; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000201:enzymology / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis; D053219:Receptors, Tumor Necrosis Factor, Member 25; D059016:Tumor Microenvironment
chemical_list: D053219:Receptors, Tumor Necrosis Factor, Member 25; C506034:Tnfrsf25 protein, mouse; D019009:Proto-Oncogene Proteins c-kit; D020780:Matrix Metalloproteinase 9