RESUMEN
Angiopoietin 2 (ANGPT2) is a proangiogenic cytokine whose expression is often upregulated by endothelial cells in tumors. Expression of its receptor, TIE2, defines a highly proangiogenic subpopulation of myeloid cells in circulation and tumors called TIE2-expressing monocytes/macrophages (TEMs). Genetic depletion of TEMs markedly reduces tumor angiogenesis in various tumor models, emphasizing their essential role in driving tumor progression. Previously, we demonstrated that ANGPT2 augments the expression of various proangiogenic genes, the potent immunosuppressive cytokine, IL-10, and a chemokine for regulatory T cells (Tregs), CCL17 by TEMs in vitro. We now show that TEMs also express higher levels of IL-10 than TIE2(-) macrophages in tumors and that ANGPT2-stimulated release of IL-10 by TEMs suppresses T cell proliferation, increases the ratio of CD4(+) T cells to CD8(+) T cells, and promotes the expansion of CD4(+)CD25(high)FOXP3(+) Tregs. Furthermore, syngeneic murine tumors expressing high levels of ANGPT2 contained not only high numbers of TEMs but also increased numbers of Tregs, whereas genetic depletion of tumor TEMs resulted in a marked reduction in the frequency of Tregs in tumors. Taken together, our data suggest that ANGPT2-stimulated TEMs represent a novel, potent immunosuppressive force in tumors.
Asunto(s)
Angiopoyetina 2/fisiología , Proteínas de Ciclo Celular/fisiología , Diferenciación Celular/inmunología , Proteínas de Unión al ADN/fisiología , Activación de Linfocitos/inmunología , Monocitos/inmunología , Neovascularización Patológica/inmunología , Proteínas Represoras/fisiología , Linfocitos T Reguladores/inmunología , Factores de Transcripción/fisiología , Animales , Proteínas Reguladoras de la Apoptosis , Carcinoma Pulmonar de Lewis/inmunología , Carcinoma Pulmonar de Lewis/patología , Proteínas de Ciclo Celular/biosíntesis , Línea Celular Tumoral , Técnicas de Cocultivo , Proteínas de Unión al ADN/biosíntesis , Inhibidores de Crecimiento/biosíntesis , Inhibidores de Crecimiento/fisiología , Humanos , Interleucina-10/biosíntesis , Interleucina-10/metabolismo , Interleucina-10/fisiología , Macrófagos/inmunología , Macrófagos/metabolismo , Neoplasias Mamarias Experimentales/inmunología , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Monocitos/metabolismo , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Proteínas Represoras/biosíntesis , Linfocitos T Reguladores/citología , Factores de Transcripción/biosíntesisRESUMEN
Sustained growth of solid tumours can rely on both the formation of new and the co-option of existing blood vessels. Current models suggest that binding of angiopoietin-2 (Ang-2) to its endothelial Tie2 receptor prevents receptor phosphorylation, destabilizes blood vessels, and promotes vascular permeability. In contrast, binding of angiopoietin-1 (Ang-1) induces Tie2 receptor activation and supports the formation of mature blood vessels covered by pericytes. Despite the intense research to decipher the role of angiopoietins during physiological neovascularization and tumour angiogenesis, a mechanistic understanding of angiopoietin function on vascular integrity and remodelling is still incomplete. We therefore assessed the vascular morphology of two mouse mammary carcinoma xenotransplants (M6378 and M6363) which differ in their natural angiopoietin expression. M6378 displayed Ang-1 in tumour cells but no Ang-2 in tumour endothelial cells in vivo. In contrast, M6363 tumours expressed Ang-2 in the tumour vasculature, whereas no Ang-1 expression was present in tumour cells. We stably transfected M6378 mouse mammary carcinoma cells with human Ang-1 or Ang-2 and investigated the consequences on the host vasculature, including ultrastructural morphology. Interestingly, M6378/Ang-2 and M6363 tumours displayed a similar vascular morphology, with intratumoural haemorrhage and non-functional and abnormal blood vessels. Pericyte loss was prominent in these tumours and was accompanied by increased endothelial cell apoptosis. Thus, overexpression of Ang-2 converted the vascular phenotype of M6378 tumours into a phenotype similar to M6363 tumours. Our results support the hypothesis that Ang-1/Tie2 signalling is essential for vessel stabilization and endothelial cell/pericyte interaction, and suggest that Ang-2 is able to induce a switch of vascular phenotypes within tumours.
Asunto(s)
Angiopoyetina 1/metabolismo , Angiopoyetina 2/farmacología , Neoplasias Mamarias Experimentales/irrigación sanguínea , Neovascularización Patológica/patología , Angiopoyetina 1/análisis , Angiopoyetina 2/metabolismo , Animales , Línea Celular Tumoral , Células Endoteliales/patología , Neoplasias Mamarias Experimentales/metabolismo , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Neovascularización Patológica/metabolismo , Pericitos/patología , Fenotipo , Receptor TIE-2/metabolismo , Trasplante HeterólogoRESUMEN
Colon capsule endoscopy (CCE; PillCam Colon; Given Imaging; Yoqneam, Israel) is a minimally invasive wireless technique for the visualization of the colon. With the recent introduction of the second generation colon capsule the diagnostic accuracy of CCE for polyp detection has significantly improved and preliminary data suggest it may be useful to monitor mucosal inflammation in patients with inflammatory bowel disease. Limitations include the inability to take biopsies and the procedural costs. However, given the potentially higher acceptance within an average risk colorectal cancer (CRC) screening population, its usefulness as a screening tool with regard to CRC prevention should be further evaluated.
Asunto(s)
Endoscopía Capsular/tendencias , Colon/patología , Enfermedades del Colon/patología , Colonoscopía/tendencias , Endoscopios en Cápsulas/tendencias , Endoscopía Capsular/instrumentación , Colonoscopía/instrumentación , Contraindicaciones , Difusión de Innovaciones , Diseño de Equipo , Historia del Siglo XXI , Humanos , Selección de Paciente , Valor Predictivo de las Pruebas , PronósticoRESUMEN
TIE2-expressing monocytes/macrophages (TEM) are a highly proangiogenic subset of myeloid cells in tumors. Here, we show that circulating human TEMs are already preprogrammed in the circulation to be more angiogenic and express higher levels of such proangiogenic genes as matrix metalloproteinase-9 (MMP-9), VEGFA, COX-2, and WNT5A than TIE2(-) monocytes. Additionally, angiopoietin-2 (ANG-2) markedly enhanced the proangiogenic activity of TEMs and increased their expression of two proangiogenic enzymes: thymidine phosphorylase (TP) and cathepsin B (CTSB). Three "alternatively activated" (or M2-like) macrophage markers were also upregulated by ANG-2 in TEMs: interleukin-10, mannose receptor (MRC1), and CCL17. To investigate the effects of ANG-2 on the phenotype and function of TEMs in tumors, we used a double-transgenic (DT) mouse model in which ANG-2 was specifically overexpressed by endothelial cells. Syngeneic tumors grown in these ANG-2 DT mice were more vascularized and contained greater numbers of TEMs than those in wild-type (WT) mice. In both tumor types, expression of MMP-9 and MRC1 was mainly restricted to tumor TEMs rather than TIE2(-) macrophages. Furthermore, tumor TEMs expressed higher levels of MRC1, TP, and CTSB in ANG-2 DT tumors than WT tumors. Taken together, our data show that although circulating TEMs are innately proangiogenic, exposure to tumor-derived ANG-2 stimulates these cells to exhibit a broader, tumor-promoting phenotype. As such, the ANG-2-TEM axis may represent a new target for antiangiogenic cancer therapies.