RESUMO
In some organs, adult stem cells are uniquely poised to serve as cancer cells of origin. It is unclear, however, whether tumorigenesis is influenced by the activation state of the adult stem cell. Hair follicle stem cells (HFSCs) act as cancer cells of origin for cutaneous squamous cell carcinoma and undergo defined cycles of quiescence and activation. The data presented here show that HFSCs are unable to initiate tumours during the quiescent phase of the hair cycle, indicating that the mechanisms that keep HFSCs dormant are dominant over the gain of oncogenes (such as Ras) or the loss of tumour suppressors (such as p53). Furthermore, Pten activity is necessary for quiescence-based tumour suppression, as its deletion alleviates tumour suppression without affecting proliferation. These data demonstrate that stem cell quiescence is a form of tumour suppression in HFSCs, and that Pten plays a role in maintaining quiescence in the presence of tumorigenic stimuli.
Assuntos
Carcinoma de Células Escamosas/patologia , Ciclo Celular , Neoplasias Cutâneas/patologia , Células-Tronco/patologia , Adulto , Animais , Carcinoma de Células Escamosas/genética , Ciclo Celular/genética , Proliferação de Células , Progressão da Doença , Citometria de Fluxo , Deleção de Genes , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Folículo Piloso/patologia , Humanos , Hiperplasia , Integrases/metabolismo , Camundongos , Proteínas Mutantes/metabolismo , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais/genética , Neoplasias Cutâneas/genética , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas ras/metabolismoRESUMO
Targeted expression of interleukin-10 (IL-10) has been proposed as a means to suppress acute and chronic inflammation. We explored the capacity of targeted adenoviral expression of human or viral IL-10 to improve outcome in a zymosan-induced model of acute lung injury and multisystem organ failure. Intratracheal administration of adenovirus expressing either human or viral IL-10 prior to zymosan administration significantly improved survival at a dose of 10(7) particles (P<0.01), whereas the same recombinant vectors were ineffective at 10(8) particles and increased mortality at 10(9) particles. Improved survival after administration of 10(7) particles of adenovirus expressing viral or human IL-10 was associated with local tissue expression of IL-10 (100-300 pg/g wet wt). In contrast, mortality after administration of 10(9) particles was associated with markedly elevated IL-10 expression, both in the lung (10000-70000 pg/g wet wt) and systemically (1000-3000 pg/ml plasma), with evidence of an exaggerated systemic inflammatory response (plasma IL-6 and TNFalpha). Targeted gene expression of IL-10 can be used to treat acute inflammatory processes, but increased doses resulting in its systemic release are not associated with improvements in outcome, and may actually exacerbate acute inflammatory processes.
