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1.
J Clin Invest ; 126(11): 4187-4204, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27721236

RESUMO

Different tumor microenvironments (TMEs) induce stromal cell plasticity that affects tumorigenesis. The impact of TME-dependent heterogeneity of tumor endothelial cells (TECs) on tumorigenesis is unclear. Here, we isolated pure TECs from human colorectal carcinomas (CRCs) that exhibited TMEs with either improved (Th1-TME CRCs) or worse clinical prognosis (control-TME CRCs). Transcriptome analyses identified markedly different gene clusters that reflected the tumorigenic and angiogenic activities of the respective TMEs. The gene encoding the matricellular protein SPARCL1 was most strongly upregulated in Th1-TME TECs. It was also highly expressed in ECs in healthy colon tissues and Th1-TME CRCs but low in control-TME CRCs. In vitro, SPARCL1 expression was induced in confluent, quiescent ECs and functionally contributed to EC quiescence by inhibiting proliferation, migration, and sprouting, whereas siRNA-mediated knockdown increased sprouting. In human CRC tissues and mouse models, vessels with SPARCL1 expression were larger and more densely covered by mural cells. SPARCL1 secretion from quiescent ECs inhibited mural cell migration, which likely led to stabilized mural cell coverage of mature vessels. Together, these findings demonstrate TME-dependent intertumoral TEC heterogeneity in CRC. They further indicate that TEC heterogeneity is regulated by SPARCL1, which promotes the cell quiescence and vessel homeostasis contributing to the favorable prognoses associated with Th1-TME CRCs.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Proteínas de Neoplasias/metabolismo , Neovascularização Patológica/metabolismo , Microambiente Tumoral , Animais , Neoplasias Colorretais/patologia , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Células Jurkat , Camundongos , Neovascularização Patológica/patologia
2.
Inflamm Bowel Dis ; 21(10): 2360-71, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26164664

RESUMO

BACKGROUND: Interferon (IFN)-γ is a central pathogenesis factor in inflammatory bowel disease (IBD) with pleiotropic effects on many different cell types. However, as yet, the immune modulatory functions of IFN-γ in IBD have been predominantly investigated. Based on previous studies showing that IFN-γ acts antiangiogenic in colorectal carcinoma, we investigated the effects of IFN-γ on the vascular system in IBD. METHODS: Colon tissues of patients with IBD and dextran sulfate sodium-induced colitis in mice were subjected to immunohistochemistry, quantitative real-time polymerase chain reactions, and in situ hybridization to quantify cell activation, angiogenesis, and immune responses. Vascular structure and permeability in mice were analyzed by ultramicroscopy and in vivo confocal laser endomicroscopy. RESULTS: We showed a significantly increased blood vessel density in IBD and dextran sulfate sodium colitis. In mice, this was associated with a disorganized blood vessel structure and profound vascular leakage. As compared with genes associated with angiogenesis, genes associated with inflammatory cell activation including IFN-γ were more strongly upregulated in colitis tissues. IFN-γ exerted direct effects on endothelial cells in IBD tissues in vivo, as indicated by the expression of IFN-γ-induced guanylate binding protein 1 (GBP-1). Neutralization of IFN-γ in the acute dextran sulfate sodium colitis model demonstrated that this cytokine exerts endogenous angiostatic activity in IBD and contributes to increased vascular permeability. CONCLUSIONS: The dissection of the pleiotropic activities of IFN-γ in IBD provides new insights to the pathological functions of this cytokine and may be of high relevance for the optimization of combination therapy approaches.


Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Colite/patologia , Colo/irrigação sanguínea , Doenças Inflamatórias Intestinais/patologia , Interferon gama/metabolismo , Neovascularização Patológica , Animais , Biópsia , Vasos Sanguíneos/patologia , Colite/induzido quimicamente , Colo/patologia , Sulfato de Dextrana , Modelos Animais de Doenças , Proteínas de Ligação ao GTP/metabolismo , Voluntários Saudáveis , Humanos , Imuno-Histoquímica , Hibridização In Situ , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real , Remodelação Vascular
3.
Gastroenterology ; 149(1): 177-189.e10, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25797700

RESUMO

BACKGROUND & AIMS: Senescence prevents cellular transformation. We investigated whether vascular endothelial growth factor (VEGF) signaling via its receptor, VEGFR2, regulates senescence and proliferation of tumor cells in mice with colitis-associated cancer (CAC). METHODS: CAC was induced in VEGFR2(ΔIEC) mice, which do not express VEGFR2 in the intestinal epithelium, and VEGFR2(fl/fl) mice (controls) by administration of azoxymethane followed by dextran sodium sulfate. Tumor development and inflammation were determined by endoscopy. Colorectal tissues were collected for immunoblot, immunohistochemical, and quantitative polymerase chain reaction analyses. Findings from mouse tissues were confirmed in human HCT116 colorectal cancer cells. We analyzed colorectal tumor samples from patients before and after treatment with bevacizumab. RESULTS: After colitis induction, VEGFR2(ΔIEC) mice developed significantly fewer tumors than control mice. A greater number of intestinal tumor cells from VEGFR2(ΔIEC) mice were in senescence than tumor cells from control mice. We found VEGFR2 to activate phosphatidylinositol-4,5-bisphosphate-3-kinase and AKT, resulting in inactivation of p21 in HCT116 cells. Inhibitors of VEGFR2 and AKT induced senescence in HCT116 cells. Tumor cell senescence promoted an anti-tumor immune response by CD8(+) T cells in mice. Patients whose tumor samples showed an increase in the proportion of senescent cells after treatment with bevacizumab had longer progression-free survival than patients in which the proportion of senescent tumor cells did not change before and after treatment. CONCLUSIONS: Inhibition of VEGFR2 signaling leads to senescence of human and mouse colorectal cancer cells. VEGFR2 interacts with phosphatidylinositol-4,5-bisphosphate-3-kinase and AKT to inactivate p21. Colorectal tumor senescence and p21 level correlate with patient survival during treatment with bevacizumab.


Assuntos
Proliferação de Células/genética , Senescência Celular/genética , Colite/genética , Neoplasias Colorretais/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Bevacizumab , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Colite/complicações , Colite/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Intervalo Livre de Doença , Feminino , Células HCT116 , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-akt/metabolismo
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