Reinforcing endothelial junctions prevents microvessel permeability increase and tumor cell adhesion in microvessels in vivo.
Tumor cell adhesion to the microvessel wall is a critical step during tumor metastasis. Vascular endothelial growth factor (VEGF), a secretion of tumor cells, can increase microvessel permeability and tumor cell adhesion in the microvessel. To test the hypothesis that inhibiting permeability increase can reduce tumor cell adhesion, we used in vivo fluorescence microscopy to measure both microvessel permeability and adhesion rates of human mammary carcinoma MDA-MB-231 cells in post-capillary venules of rat mesentery under the treatment of VEGF and a cAMP analog, 8-bromo-cAMP, which can decrease microvessel permeability. By immunostaining adherens junction proteins between endothelial cells forming the microvessel wall, we further investigated the structural mechanism by which cAMP abolishes VEGF-induced increase in microvessel permeability and tumor cell adhesion. Our results demonstrate that 1) Pretreatment of microvessels with cAMP can abolish VEGF-enhanced microvessel permeability and tumor cell adhesion; 2) Tumor cells prefer to adhere to the endothelial cell junctions instead of cell bodies; 3) VEGF increases microvessel permeability and tumor cell adhesion by compromising endothelial junctions while cAMP abolishes these effects of VEGF by reinforcing the junctions. These results suggest that strengthening the microvessel wall integrity can be a potential approach to inhibiting hematogenous tumor metastasis.
Department of Biomedical Engineering, The City College of the City University of New York, 160 Convent Ave, New York, NY 10031.
Bingmei M
BM
Fu
Department of Biomedical Engineering, The City College of the City University of New York, 160 Convent Ave, New York, NY 10031.
Jinlin
J
Yang
Department of Biomedical Engineering, The City College of the City University of New York, 160 Convent Ave, New York, NY 10031.
Bin
B
Cai
Department of Biomedical Engineering, The City College of the City University of New York, 160 Convent Ave, New York, NY 10031.
Jie
J
Fan
Department of Biomedical Engineering, The City College of the City University of New York, 160 Convent Ave, New York, NY 10031.
Lin
L
Zhang
Department of Biomedical Engineering, The City College of the City University of New York, 160 Convent Ave, New York, NY 10031.
Min
M
Zeng
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002196:Capillaries / Q000378:metabolism / Q000502:physiology*; D002199:Capillary Permeability / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology*; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D008643:Mesentery / Q000098:blood supply / Q000378:metabolism / Q000502:physiology; D055806:Microvessels / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014699:Venules / Q000378:metabolism / Q000502:physiology
D042461:Vascular Endothelial Growth Factor A; D015124:8-Bromo Cyclic Adenosine Monophosphate; C044258:8-chloro-cyclic adenosine monophosphate; D000242:Cyclic AMP