title: Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination.
abstract: Therapy-induced resistance remains a significant hurdle to achieve long-lasting responses and cures in cancer patients. We investigated the long-term consequences of genetically impaired angiogenesis by engineering multiple tumor models deprived of endoglin, a co-receptor for TGF-β in endothelial cells actively engaged in angiogenesis. Tumors from endoglin-deficient mice adapted to the weakened angiogenic response, and refractoriness to diminished endoglin signaling was accompanied by increased metastatic capability. Mechanistic studies in multiple mouse models of cancer revealed that deficiency for endoglin resulted in a tumor vasculature that displayed hallmarks of endothelial-to-mesenchymal transition, a process of previously unknown significance in cancer biology, but shown by us to be associated with a reduced capacity of the vasculature to avert tumor cell intra- and extravasation. Nevertheless, tumors deprived of endoglin exhibited a delayed onset of resistance to anti-VEGF (vascular endothelial growth factor) agents, illustrating the therapeutic utility of combinatorial targeting of multiple angiogenic pathways for the treatment of cancer.
authors: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors: Charlotte
authors: C
authors: Anderberg
authors: Sara I
authors: SI
authors: Cunha
authors: Zhenhua
authors: Z
authors: Zhai
authors: Eliane
authors: E
authors: Cortez
authors: Evangelia
authors: E
authors: Pardali
authors: Jill R
authors: JR
authors: Johnson
authors: Marcela
authors: M
authors: Franco
authors: Marta
authors: M
authors: Páez-Ribes
authors: Ross
authors: R
authors: Cordiner
authors: Jonas
authors: J
authors: Fuxe
authors: Bengt R
authors: BR
authors: Johansson
authors: Marie-José
authors: MJ
authors: Goumans
authors: Oriol
authors: O
authors: Casanovas
authors: Peter
authors: P
authors: ten Dijke
authors: Helen M
authors: HM
authors: Arthur
authors: Kristian
authors: K
authors: Pietras
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000071063:Endoglin; D004730:Endothelium, Vascular / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D020690:GTPase-Activating Proteins / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000502:physiology*; D008114:Liver Neoplasms, Experimental / Q000556:secondary; D051379:Mice; D018919:Neovascularization, Physiologic; D018358:Neuroendocrine Tumors / Q000098:blood supply*; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000473:pathology; D051879:Twist-Related Protein 1 / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D000071063:Endoglin; C502004:Eng protein, mouse; D020690:GTPase-Activating Proteins; D047908:Intracellular Signaling Peptides and Proteins; C490620:Ralbp1 protein, mouse; D051879:Twist-Related Protein 1; D042461:Vascular Endothelial Growth Factor A
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