title: Tyrosine isomers mediate the classical phenomenon of concomitant tumor resistance.
abstract: Concomitant tumor resistance (CR) is a phenomenon originally described in 1906 in which a tumor-bearing host is resistant to the growth of secondary tumor implants and metastasis. Although recent studies have indicated that T-cell-dependent processes mediate CR in hosts bearing immunogenic small tumors, manifestations of CR induced by immunogenic and nonimmunogenic large tumors have been associated with an elusive serum factor. In this study, we identify this serum factor as tyrosine in its meta and ortho isoforms. In three different murine models of cancer that generate CR, both meta-tyrosine and ortho-tyrosine inhibited tumor growth. In addition, we showed that both isoforms of tyrosine blocked metastasis in a fourth model that does not generate CR but is sensitive to CR induced by other tumors. Mechanistic studies showed that the antitumor effects of the tyrosine isoforms were mediated, in part, by early inhibition of mitogen-activated protein/extracellular signal-regulated kinase pathway and inactivation of STAT3, potentially driving tumor cells into a state of dormancy. By revealing a molecular basis for the classical phenomenon of CR, our findings may stimulate new generalized approaches to limit the development of metastases that arise after resection of primary tumors, an issue of pivotal importance to oncologists and their patients.
authors.affiliation: División Medicina Experimental, Academia Nacional de Medicina, Buenos Aires, Argentina. ruloruggiero@yahoo.com.ar
authors.forename: Raúl A
authors.initials: RA
authors.lastname: Ruggiero
authors.forename: Juan
authors.initials: J
authors.lastname: Bruzzo
authors.forename: Paula
authors.initials: P
authors.lastname: Chiarella
authors.forename: Pedro
authors.initials: P
authors.lastname: di Gianni
authors.forename: Martín A
authors.initials: MA
authors.lastname: Isturiz
authors.forename: Susana
authors.initials: S
authors.lastname: Linskens
authors.forename: Norma
authors.initials: N
authors.lastname: Speziale
authors.forename: Roberto P
authors.initials: RP
authors.lastname: Meiss
authors.forename: Oscar D
authors.initials: OD
authors.lastname: Bustuoabad
authors.forename: Christiane D
authors.initials: CD
authors.lastname: Pasqualini
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D060467:Disease Resistance; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005260:Female; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology; D010649:Phenylalanine / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000502:physiology; D014443:Tyrosine / Q000502:physiology*
chemical_list: D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014443:Tyrosine; D010649:Phenylalanine; C026741:2-tyrosine; C015566:3-tyrosine; D048049:Extracellular Signal-Regulated MAP Kinases