RESUMO
Aberrant activation of oncogenes or loss of tumour suppressor genes opposes malignant transformation by triggering a stable arrest in cell growth, which is termed cellular senescence. This process is finely tuned by both cell-autonomous and non-cell-autonomous mechanisms that regulate the entry of tumour cells to senescence. Whether tumour-infiltrating immune cells can oppose senescence is unknown. Here we show that at the onset of senescence, PTEN null prostate tumours in mice are massively infiltrated by a population of CD11b(+)Gr-1(+) myeloid cells that protect a fraction of proliferating tumour cells from senescence, thus sustaining tumour growth. Mechanistically, we found that Gr-1(+) cells antagonize senescence in a paracrine manner by interfering with the senescence-associated secretory phenotype of the tumour through the secretion of interleukin-1 receptor antagonist (IL-1RA). Strikingly, Pten-loss-induced cellular senescence was enhanced in vivo when Il1ra knockout myeloid cells were adoptively transferred to PTEN null mice. Therapeutically, docetaxel-induced senescence and efficacy were higher in PTEN null tumours when the percentage of tumour-infiltrating CD11b(+)Gr-1(+) myeloid cells was reduced using an antagonist of CXC chemokine receptor 2 (CXCR2). Taken together, our findings identify a novel non-cell-autonomous network, established by innate immunity, that controls senescence evasion and chemoresistance. Targeting this network provides novel opportunities for cancer therapy.
Assuntos
Movimento Celular , Senescência Celular , Células Mieloides/citologia , Células Mieloides/metabolismo , Neoplasias da Próstata/patologia , Receptores de Quimiocinas/metabolismo , Animais , Senescência Celular/efeitos dos fármacos , Progressão da Doença , Docetaxel , Resistencia a Medicamentos Antineoplásicos , Humanos , Imunidade Inata , Proteína Antagonista do Receptor de Interleucina 1/deficiência , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1alfa/imunologia , Interleucina-1alfa/metabolismo , Masculino , Camundongos , Células Mieloides/transplante , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/metabolismo , Receptores de Interleucina-8B/antagonistas & inibidores , Taxoides/farmacologia , Evasão Tumoral , Microambiente TumoralRESUMO
Infiltration of the central nervous system is a severe trait of T cell acute lymphoblastic leukemia. Inhibition of CXC chemokine receptor 4 significantly ameliorates T cell acute lymphoblastic leukemia in murine models of the disease; however, signaling by CXC chemokine receptor 4 is important in limiting the divagation of peripheral blood mononuclear cells out of the perivascular space into the central nervous system parenchyma. Therefore, Inhibition of CXC chemokine receptor 4 potentially may untangle T cell acute lymphoblastic leukemia cells from retention outside the brain. Here, we show that leukemic lymphoblasts massively infiltrate cranial bone marrow, with diffusion to the meninges without invasion of the brain parenchyma, in mice that underwent xenotransplantation with human T cell acute lymphoblastic leukemia cells or that developed leukemia from transformed hematopoietic progenitors. We tested the hypothesis that T cell acute lymphoblastic leukemia neuropathology results from meningeal infiltration through CXC chemokine receptor 4-mediated bone marrow colonization. Inhibition of leukemia engraftment in the bone marrow by pharmacologic CXC chemokine receptor 4 antagonism significantly ameliorated neuropathologic aspects of the disease. Genetic deletion of CXCR4 in murine hematopoietic progenitors abrogated leukemogenesis induced by constitutively active Notch1, whereas lack of CCR6 and CCR7, which have been shown to be involved in T cell and leukemia extravasation into the central nervous system, respectively, did not influence T cell acute lymphoblastic leukemia development. We hypothesize that lymphoblastic meningeal infiltration as a result of bone marrow colonization is responsible for the degenerative alterations of the neuroparenchyma as well as the alteration of cerebrospinal fluid drainage in T cell acute lymphoblastic leukemia xenografts. Therefore, CXC chemokine receptor 4 may constitute a pharmacologic target for T cell acute lymphoblastic leukemia neuropathology.
Assuntos
Medula Óssea/patologia , Sistema Nervoso Central/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptores CXCR4/metabolismo , Adolescente , Animais , Benzilaminas , Medula Óssea/efeitos dos fármacos , Linhagem Celular Transformada , Linhagem Celular Tumoral , Sistema Nervoso Central/efeitos dos fármacos , Criança , Pré-Escolar , Ciclamos , Feminino , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Compostos Heterocíclicos/farmacologia , Humanos , Fígado/citologia , Fígado/embriologia , Masculino , Meninges/efeitos dos fármacos , Meninges/patologia , Camundongos , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CXCR4/antagonistas & inibidores , Receptores de Quimiocinas/metabolismo , Receptores Notch/metabolismo , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In this work, we show the realization of a fully-implantable device for monitoring free-moving small animals. The device integrates a microfabricated sensing platform, a coil for power and data transmission and two custom designed integrated circuits. The device is intended to be implanted in mice, free to move in a cage, to monitor the concentration of metabolites. We show the system level design of each block of the device, and we present the fabrication of the passive sensing platform and its employment for the electrochemical detection of endogenous and exogenous metabolites. Moreover, we describe the assembly of the device to test the biocompatibility of the materials used for the microfabrication. To ensure biocompatibility, an epoxy enhanced polyurethane membrane was used to cover the device. We proved through an in-vitro characterization that the membrane was capable to retain enzyme activity up to 35 days. After 30 days of implant in mice, in-vivo experiments proved that the membrane promotes the integration of the sensor with the surrounding tissue, as demonstrated by the low inflammation level at the implant site.