RESUMEN
The overexpression of the protein tyrosine kinase, Focal adhesion kinase (FAK), in endothelial cells has implicated its requirement in angiogenesis and tumour growth, but how pericyte FAK regulates tumour angiogenesis is unknown. We show that pericyte FAK regulates tumour growth and angiogenesis in multiple mouse models of melanoma, lung carcinoma and pancreatic B-cell insulinoma and provide evidence that loss of pericyte FAK enhances Gas6-stimulated phosphorylation of the receptor tyrosine kinase, Axl with an upregulation of Cyr61, driving enhanced tumour growth. We further show that pericyte derived Cyr61 instructs tumour cells to elevate expression of the proangiogenic/protumourigenic transmembrane receptor Tissue Factor. Finally, in human melanoma we show that when 50% or more tumour blood vessels are pericyte-FAK negative, melanoma patients are stratified into those with increased tumour size, enhanced blood vessel density and metastasis. Overall our data uncover a previously unknown mechanism of tumour growth by pericytes that is controlled by pericyte FAK.
Asunto(s)
Proteína 61 Rica en Cisteína/metabolismo , Quinasa 1 de Adhesión Focal/metabolismo , Regulación Neoplásica de la Expresión Génica , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Neovascularización Patológica , Pericitos/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Animales , Aorta Torácica/patología , Carcinoma Pulmonar de Lewis/metabolismo , Adhesión Celular , Proliferación Celular , Femenino , Quinasa 1 de Adhesión Focal/genética , Humanos , Linfocinas/metabolismo , Masculino , Melanoma/irrigación sanguínea , Melanoma/metabolismo , Melanoma Experimental , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias/patología , Factor de Crecimiento Placentario/metabolismo , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Proteínas Proto-Oncogénicas c-sis/metabolismo , Transducción de Señal , Microambiente Tumoral , Factor A de Crecimiento Endotelial Vascular/metabolismo , Tirosina Quinasa del Receptor AxlRESUMEN
Emerging evidence suggests that cancer cell metabolism can be regulated by cancer-associated fibroblasts (CAFs), but the mechanisms are poorly defined. Here we show that CAFs regulate malignant cell metabolism through pathways under the control of FAK. In breast and pancreatic cancer patients we find that low FAK expression, specifically in the stromal compartment, predicts reduced overall survival. In mice, depletion of FAK in a subpopulation of CAFs regulates paracrine signals that increase malignant cell glycolysis and tumour growth. Proteomic and phosphoproteomic analysis in our mouse model identifies metabolic alterations which are reflected at the transcriptomic level in patients with low stromal FAK. Mechanistically we demonstrate that FAK-depletion in CAFs increases chemokine production, which via CCR1/CCR2 on cancer cells, activate protein kinase A, leading to enhanced malignant cell glycolysis. Our data uncover mechanisms whereby stromal fibroblasts regulate cancer cell metabolism independent of genetic mutations in cancer cells.
Asunto(s)
Fibroblastos Asociados al Cáncer/enzimología , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Animales , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular , Quimiocinas/metabolismo , Femenino , Glucólisis , Humanos , Masculino , Redes y Vías Metabólicas , Ratones Endogámicos C57BL , Neoplasias/irrigación sanguínea , Neoplasias Pancreáticas/irrigación sanguínea , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Fosfoproteínas/metabolismo , Células del Estroma/metabolismo , Análisis de Supervivencia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Angiogenesis, the formation of new blood vessels from pre-existing ones, is thought to enhance tumour growth and these blood vessels can act as conduits of tumour cell metastasis. Integrins, the family of cell surface extracellular matrix receptors, can promote endothelial cell migration and survival, both essential features of angiogenesis, and were thus considered good targets for anti-angiogenic therapy. This sparked the development of agents to block integrin function as new cancer therapies. Here, we review the current status of αvß3-integrin in tumour angiogenesis. Learning from what we now know about integrin conformational changes and endocytosis, we discuss the possible future of targeting blood vessel αvß3-integrin in the control of cancer.
Asunto(s)
Integrina alfaVbeta3/metabolismo , Neoplasias/irrigación sanguínea , Neoplasias/metabolismo , Neovascularización Patológica/metabolismo , Animales , Humanos , Modelos Biológicos , Terapia Molecular Dirigida , Transducción de SeñalRESUMEN
Increasing chemotherapy delivery to tumors, while enhancing drug uptake and reducing side effects, is a primary goal of cancer research. In mouse and human cancer models in vivo, we show that coadministration of low-dose Cilengitide and Verapamil increases tumor angiogenesis, leakiness, blood flow, and Gemcitabine delivery. This approach reduces tumor growth, metastasis, and minimizes side effects while extending survival. At a molecular level, this strategy alters Gemcitabine transporter and metabolizing enzyme expression levels, enhancing the potency of Gemcitabine within tumor cells in vivo and in vitro. Thus, the dual action of low-dose Cilengitide, in vessels and tumor cells, improves chemotherapy efficacy. Overall, our data demonstrate that vascular promotion therapy is a means to improve cancer treatment.
Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Carcinoma Pulmonar de Lewis/patología , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamiento farmacológico , Venenos de Serpiente/administración & dosificación , Verapamilo/administración & dosificación , Animales , Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica , Línea Celular Tumoral , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Sinergismo Farmacológico , Humanos , Pulmón/irrigación sanguínea , Pulmón/patología , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Neovascularización Patológica/tratamiento farmacológico , Páncreas/irrigación sanguínea , Páncreas/patología , Neoplasias Pancreáticas/patología , Venenos de Serpiente/uso terapéutico , Verapamilo/uso terapéutico , GemcitabinaRESUMEN
Chemoresistance is a serious limitation of cancer treatment. Until recently, almost all the work done to study this limitation has been restricted to tumour cells. Here we identify a novel molecular mechanism by which endothelial cells regulate chemosensitivity. We establish that specific targeting of focal adhesion kinase (FAK; also known as PTK2) in endothelial cells is sufficient to induce tumour-cell sensitization to DNA-damaging therapies and thus inhibit tumour growth in mice. The clinical relevance of this work is supported by our observations that low blood vessel FAK expression is associated with complete remission in human lymphoma. Our study shows that deletion of FAK in endothelial cells has no apparent effect on blood vessel function per se, but induces increased apoptosis and decreased proliferation within perivascular tumour-cell compartments of doxorubicin- and radiotherapy-treated mice. Mechanistically, we demonstrate that endothelial-cell FAK is required for DNA-damage-induced NF-κB activation in vivo and in vitro, and the production of cytokines from endothelial cells. Moreover, loss of endothelial-cell FAK reduces DNA-damage-induced cytokine production, thus enhancing chemosensitization of tumour cells to DNA-damaging therapies in vitro and in vivo. Overall, our data identify endothelial-cell FAK as a regulator of tumour chemosensitivity. Furthermore, we anticipate that this proof-of-principle data will be a starting point for the development of new possible strategies to regulate chemosensitization by targeting endothelial-cell FAK specifically.