RESUMO
The recent landmark Phase III clinical trial with a VEGF-specific antibody suggests that antiangiogenic therapy must be combined with cytotoxic therapy for the treatment of solid tumors. However, there are no guidelines for optimal scheduling of these therapies. Here we show that VEGFR2 blockade creates a "normalization window"--a period during which combined radiation therapy gives the best outcome. This window is characterized by an increase in tumor oxygenation, which is known to enhance radiation response. During the normalization window, but not before or after it, VEGFR2 blockade increases pericyte coverage of brain tumor vessels via upregulation of Ang1 and degrades their pathologically thick basement membrane via MMP activation.
Assuntos
Vasos Sanguíneos/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/uso terapêutico , Angiopoietina-1/fisiologia , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antígenos/análise , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Membrana Basal/efeitos dos fármacos , Membrana Basal/metabolismo , Membrana Basal/patologia , Vasos Sanguíneos/química , Vasos Sanguíneos/efeitos da radiação , Western Blotting , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/radioterapia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Colágeno Tipo IV/análise , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Terapia Combinada/métodos , Dipeptídeos/farmacologia , Efrina-B2/genética , Angiofluoresceinografia , Raios gama/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/metabolismo , Glioma/radioterapia , Humanos , Imuno-Histoquímica , Masculino , Inibidores de Metaloproteinases de Matriz , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Nus , Modelos Biológicos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/radioterapia , Análise de Sequência com Séries de Oligonucleotídeos , Oxigênio/metabolismo , Pericitos/química , Pericitos/citologia , Pericitos/fisiologia , Proteoglicanas/análise , Receptor TIE-2/antagonistas & inibidores , Receptor TIE-2/imunologia , Fatores de Tempo , Transfecção , Regulação para Cima/genéticaRESUMO
At the time of transplantation, tumor fragments contain "passenger" cells: endothelial cells and other stromal cells from the original host. Here, we investigated the fate of genetically labeled endothelial and nonendothelial stromal cells after transplantation in syngeneic mice. We report that angiogenic stroma associated with tumor or adipose tissue persists when transplanted, remains functional, and governs the initial neovascularization of grafted tissue fragments for more than 4 weeks after implantation. Surprisingly, the passenger endothelial cells survive longer than other stromal cells, which are replaced by host-activated fibroblasts after 3 weeks. The transplantability of tumor stroma suggests that the angiogenic potential of a tumor xenograft, which determines its viability, depends on the presence of passenger endothelial cells and other stromal cells within the xenograft. These studies of tumor tissue transplantation provide a platform for exploring the role of epithelial-stromal interactions in studies of tumor heterogeneity and drug resistance.
Assuntos
Endotélio Vascular/patologia , Neoplasias Mamárias Experimentais/irrigação sanguínea , Neoplasias Mamárias Experimentais/patologia , Transplante de Neoplasias , Neovascularização Patológica/patologia , Animais , Divisão Celular/fisiologia , Sobrevivência Celular/fisiologia , Endotélio Vascular/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Camundongos Transgênicos , Neovascularização Patológica/metabolismo , Células Estromais/metabolismo , Células Estromais/patologia , Fator A de Crescimento do Endotélio Vascular/biossínteseRESUMO
Paracrine signaling via platelet-derived growth factor B (PDGFB), expressed by endothelial cells, and its receptor PDGFR-beta, expressed by pericytes, plays a central role in blood vessel maturation. A new study (see the related article beginning on page 1142) reveals that it is not just the presence of PDGFB, but how it is presented to pericytes, that determines the quality of the endothelium-pericyte interaction.
