Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 6 de 6
Filter
Add more filters










Database
Language
Publication year range
2.
Nat Commun ; 11(1): 2810, 2020 06 04.
Article in English | MEDLINE | ID: mdl-32499572

ABSTRACT

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.


Subject(s)
Cysteine-Rich Protein 61/metabolism , Focal Adhesion Kinase 1/metabolism , Gene Expression Regulation, Neoplastic , Intercellular Signaling Peptides and Proteins/metabolism , Neovascularization, Pathologic , Pericytes/metabolism , Proto-Oncogene Proteins/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Animals , Aorta, Thoracic/pathology , Carcinoma, Lewis Lung/metabolism , Cell Adhesion , Cell Proliferation , Female , Focal Adhesion Kinase 1/genetics , Humans , Lymphokines/metabolism , Male , Melanoma/blood supply , Melanoma/metabolism , Melanoma, Experimental , Mice , Mice, Inbred C57BL , Mice, Knockout , Neoplasms/pathology , Placenta Growth Factor/metabolism , Platelet-Derived Growth Factor/metabolism , Proto-Oncogene Proteins c-sis/metabolism , Signal Transduction , Tumor Microenvironment , Vascular Endothelial Growth Factor A/metabolism , Axl Receptor Tyrosine Kinase
3.
Nat Commun ; 11(1): 1290, 2020 03 10.
Article in English | MEDLINE | ID: mdl-32157087

ABSTRACT

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.


Subject(s)
Cancer-Associated Fibroblasts/enzymology , Focal Adhesion Protein-Tyrosine Kinases/metabolism , Neoplasms/metabolism , Neoplasms/pathology , Animals , Breast Neoplasms/blood supply , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation , Chemokines/metabolism , Female , Glycolysis , Humans , Male , Metabolic Networks and Pathways , Mice, Inbred C57BL , Neoplasms/blood supply , Pancreatic Neoplasms/blood supply , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Phosphoproteins/metabolism , Stromal Cells/metabolism , Survival Analysis , Xenograft Model Antitumor Assays
4.
Curr Opin Cell Biol ; 42: 121-127, 2016 10.
Article in English | MEDLINE | ID: mdl-27474973

ABSTRACT

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.


Subject(s)
Integrin alphaVbeta3/metabolism , Neoplasms/blood supply , Neoplasms/metabolism , Neovascularization, Pathologic/metabolism , Animals , Humans , Models, Biological , Molecular Targeted Therapy , Signal Transduction
5.
Cancer Cell ; 27(1): 123-37, 2015 Jan 12.
Article in English | MEDLINE | ID: mdl-25584895

ABSTRACT

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.


Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Carcinoma, Lewis Lung/drug therapy , Carcinoma, Lewis Lung/pathology , Deoxycytidine/analogs & derivatives , Pancreatic Neoplasms/drug therapy , Snake Venoms/administration & dosage , Verapamil/administration & dosage , Animals , Antimetabolites, Antineoplastic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols , Cell Line, Tumor , Deoxycytidine/administration & dosage , Deoxycytidine/therapeutic use , Drug Synergism , Humans , Lung/blood supply , Lung/pathology , Mice , Mice, Inbred C57BL , Neoplasm Transplantation , Neovascularization, Pathologic/drug therapy , Pancreas/blood supply , Pancreas/pathology , Pancreatic Neoplasms/pathology , Snake Venoms/therapeutic use , Verapamil/therapeutic use , Gemcitabine
6.
Nature ; 514(7520): 112-6, 2014 Oct 02.
Article in English | MEDLINE | ID: mdl-25079333

ABSTRACT

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.


Subject(s)
DNA Damage , Drug Resistance, Neoplasm/drug effects , Endothelial Cells/drug effects , Endothelial Cells/enzymology , Focal Adhesion Protein-Tyrosine Kinases/metabolism , Active Transport, Cell Nucleus/drug effects , Animals , Apoptosis/drug effects , Apoptosis/radiation effects , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Cell Proliferation/drug effects , Cell Proliferation/radiation effects , Cytokines/biosynthesis , DNA Damage/drug effects , DNA Damage/genetics , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Drug Resistance, Neoplasm/genetics , Endothelial Cells/metabolism , Focal Adhesion Protein-Tyrosine Kinases/deficiency , Focal Adhesion Protein-Tyrosine Kinases/genetics , Humans , Mice , NF-kappa B/metabolism , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/pathology , Neoplasms/radiotherapy , Phosphorylation/drug effects
SELECTION OF CITATIONS
SEARCH DETAIL
...