Endothelial Cells Require CD98 for Efficient Angiogenesis-Brief Report.
CD98 regulates integrin signaling and is critical for tumor cell proliferation. It is also expressed on endothelial cells (EC), but its role in angiogenesis is unclear.



We used specific genetic targeting and antibody blockade approaches to examine the function of CD98 in EC proliferation, blood vessel growth, and tumor angiogenesis. It is upregulated on angiogenic ECs, and EC-specific deletion of CD98 in mice inhibited tumor growth, retinal angiogenesis, and EC proliferation. Reconstitution with CD98 mutants showed that integrin and CD98 interaction is necessary for EC survival and growth. Moreover, anti-CD98 treatment inhibited vessel formation and reversed EC-assisted tumor growth.



Our findings demonstrate a requirement for CD98 in EC growth and suggest that CD98-specific reagents could have a dual anticancer effect: directly by inhibiting tumor cell proliferation and indirectly by preventing tumor angiogenesis.
From the Department of Medicine, University of California San Diego, La Jolla.
Zhongji
Z
Liao
From the Department of Medicine, University of California San Diego, La Jolla. jmcantor@ucsd.edu.
Joseph M
JM
Cantor
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005838:Genotype; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010641:Phenotype; D010766:Phosphorylation; D015861:Retinal Neovascularization / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013997:Time Factors; D047368:Tumor Burden; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000906:Antibodies; D027282:Fusion Regulatory Protein 1, Heavy Chain; D016023:Integrins; C523212:Slc3A2 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2
angiogenesis inhibitors; cell proliferation; endothelial cell; integrins
Science. 1994 Apr 22;264(5158):569-71
7512751
Nat Immunol. 2009 Apr;10(4):412-9
19270713
J Exp Med. 2009 Oct 26;206(11):2397-406
19841087
Eur J Immunol. 2014 Dec;44(12):3484-99
25251823
Proc Natl Acad Sci U S A. 2005 Jan 11;102(2):355-60
15625115
Nat Rev Cancer. 2008 Aug;8(8):604-17
18497750
Am J Physiol Cell Physiol. 2001 Oct;281(4):C1077-93
11546643
Cancer Lett. 2005 Nov 8;229(1):13-23
16157214
J Immunol. 2011 Jul 15;187(2):851-60
21670318
Mol Immunol. 2003 Jan;39(12):739-51
12531285
Int J Oncol. 2006 Feb;28(2):457-62
16391801
Int J Cancer. 2015 Aug 1;137(3):710-20
25556716
Circ Res. 2002 Jun 28;90(12):1243-50
12089061
Mol Endocrinol. 2008 Mar;22(3):707-15
18032696
Curr Top Dev Biol. 2004;64:207-38
15563949
Angiogenesis. 2009;12(2):177-85
19267251
Exp Cell Res. 2006 Mar 10;312(5):676-83
16337189
J Biol Chem. 2001 Mar 23;276(12):8746-52
11121428