title: Transient inflammatory response induced by apoptotic cells is an important mediator of melanoma cell engraftment and growth.
abstract: Two murine melanoma cell lines, Tm1 and Tm5, were derived from a nontumorigenic lineage of pigmented murine melanocytes, melan-a. Both Tm1 and Tm5 are invariably tumorigenic in syngeneic mice when inoculated s.c. in doses higher than 10(4) cells; 10(3) or fewer cells rarely give rise to tumors. We demonstrate that subtumorigenic inocula of Tm1 or Tm5 cells (10(3)) as well as of a known murine melanoma cell line (B16F10) develop as vigorously growing tumor grafts only when coinoculated with apoptotic, but not necrotic cells. The presence of apoptotic cells correlates with a transient inflammatory infiltrate, composed mainly of neutrophils and macrophages. Kinin B1 receptor-deficient mice, which have impaired transmigration of neutrophils to inflamed tissues, had significant growth inhibition of subtumorigenic doses of melanoma cells coinjected with apoptotic cells. Using the same model, tumor take in athymic mice was similar to that seen in wild-type mice, suggesting that a T cell-dependent inflammatory response is not necessary to promote the survival and growth of subtumorigenic doses of melanoma cells. Taken together, our results describe how tumor engraftment and growth can be profoundly affected by microenvironmental alterations in response to the presence of apoptotic cells. Disrupting the delicate balance between apoptotic cells and leukocyte infiltration may provide potentially important insights for understanding and interfering with tumor cell viability during treatment with either gamma-radiation or apoptosis-inducing drugs.
authors.affiliation: Disciplina de Imunologia, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Correa
authors.forename: Joel
authors.initials: J
authors.lastname: Machado
authors.forename: Célia R W
authors.initials: CR
authors.lastname: Carneiro
authors.forename: João Bosco
authors.initials: JB
authors.lastname: Pesquero
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.forename: Luiz R
authors.initials: LR
authors.lastname: Travassos
authors.forename: Roger
authors.initials: R
authors.lastname: Chammas
authors.forename: Miriam G
authors.initials: MG
authors.lastname: Jasiulionis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D005720:Gamma Rays; D007249:Inflammation; D007962:Leukocytes; D008544:Melanocytes; D008545:Melanoma / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009374:Neoplasms, Experimental; D020556:Neutrophil Infiltration; D012878:Skin Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured