RESUMO
In microorganisms, evolutionarily conserved mechanisms facilitate adaptation to harsh conditions through stress-induced mutagenesis (SIM). Analogous processes may underpin progression and therapeutic failure in human cancer. We describe SIM in multiple in vitro and in vivo models of human cancers under nongenotoxic drug selection, paradoxically enhancing adaptation at a competing intrinsic fitness cost. A genome-wide approach identified the mechanistic target of rapamycin (MTOR) as a stress-sensing rheostat mediating SIM across multiple cancer types and conditions. These observations are consistent with a two-phase model for drug resistance, in which an initially rapid expansion of genetic diversity is counterbalanced by an intrinsic fitness penalty, subsequently normalizing to complete adaptation under the new conditions. This model suggests synthetic lethal strategies to minimize resistance to anticancer therapy.
Assuntos
Adaptação Fisiológica/genética , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Mutagênese , Neoplasias/tratamento farmacológico , Neoplasias/genética , Serina-Treonina Quinases TOR/metabolismo , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Reparo do DNA/genética , Aptidão Genética , Estudo de Associação Genômica Ampla , Humanos , Seleção Genética , Transdução de Sinais , Serina-Treonina Quinases TOR/genéticaRESUMO
Differentiation of stem cells into highly specialised cells requires gene expression changes brought about by remodelling of the chromatin architecture. During this lineage-commitment process, the majority of DNA needs to be packaged into inactive heterochromatin, allowing only a subset of regulatory elements to remain open and functionally required genes to be expressed. Epigenetic mechanisms such as DNA methylation, post-translational modifications to histone tails, and nucleosome positioning all potentially contribute to the changes in higher order chromatin structure during differentiation. The mammary gland is a particularly useful model to study these complex epigenetic processes since the majority of its development is postnatal, the gland is easily accessible, and development occurs in a highly reproducible manner. Inappropriate epigenetic remodelling can also drive tumourigenesis; thus, insights into epigenetic remodelling during mammary gland development advance our understanding of breast cancer aetiology. We review the current literature surrounding DNA methylation and histone modifications in the developing mammary gland and its implications for breast cancer.
Assuntos
Neoplasias da Mama/genética , Mama/crescimento & desenvolvimento , Carcinogênese/genética , Epigênese Genética/fisiologia , Animais , Mama/patologia , Neoplasias da Mama/patologia , Diferenciação Celular/genética , Cromatina/metabolismo , Metilação de DNA/fisiologia , Feminino , Código das Histonas/fisiologia , Histonas/metabolismo , Humanos , Glândulas Mamárias Animais/crescimento & desenvolvimento , Modelos Animais , Células-Tronco/fisiologiaRESUMO
We have recently been the first to demonstrate that interleukin (IL)-27 protects against the emergence and progression of autochthonous tumors. Accumulating evidence suggests that IL-27 might be uniquely well positioned to amplify beneficial TH1 anticancer immune responses while suppressing the unwanted accumulation of regulatory T cells.
RESUMO
Interleukin-27 (IL-27) is a pleiotropic cytokine but its immunosuppressive effects predominate during many in vivo immunological challenges. Despite this, evidence from tumor cell line transfer models suggested that IL-27 could promote immune responses in the tumor context. However, the role of IL-27 in immunity against tumors that develop in situ and in tumor immunosurveillance remain undefined. In this study, we demonstrate that tumor development and growth are accelerated in IL-27 receptor α (Il27ra)-deficient mice. Enhanced tumor growth in both carcinogen-induced fibrosarcoma and oncogene-driven mammary carcinoma was associated with decreased interferon-γ production by CD4 and CD8 T cells and increased numbers of regulatory T-cells (Treg). This is the first study to show that IL-27 promotes protective immune responses against endogenous tumors, which is critical as the basis for future development of an IL-27 based therapeutic agent.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Interleucinas/imunologia , Neoplasias Experimentais/imunologia , Receptores de Citocinas/imunologia , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , Tolerância Imunológica/genética , Interferon gama/genética , Interferon gama/imunologia , Interleucinas/genética , Masculino , Camundongos , Camundongos Knockout , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Receptores de Citocinas/genética , Receptores de Interleucina , Transdução de Sinais/genética , Linfócitos T Reguladores/patologiaRESUMO
Infiltration of leukocytes into tissue is a common feature of many physiological and pathological conditions. Histopathologically, the diversity of leukocytes that infiltrate a tissue associated with a pathophysiologic response cannot be appreciated and/or examined unless highly selective immunologic detection methods are utilized. Specific populations of infiltrating leukocytes into squamous tissues harboring pre-malignant and/or malignant keratinocytes have recently been demonstrated to play a functionally significant role in the pathogenesis of squamous carcinomas. To evaluate immune cell types and quantify changes in their relative presence and localization during multi-stage neoplastic progression, we performed flow cytometry and histochemical detection using lineage-selective markers. Herein, we provide detailed methodology facilitating these analyses.
