Stromal endothelial cells directly influence cancer progression.
Cancer growth and metastasis are regulated in part by stromal cells such as fibroblasts and immune cells within the tumor microenvironment. Endothelial cells (ECs) are also ubiquitous within tumors because tumors are vascular, and yet, the impact of tumor-resident ECs is less well understood. Through paracrine regulation, ECs modulate a diverse spectrum of pathophysiologic processes in normal and hyperplastic tissues. We hypothesized that ECs offer similar paracrine regulatory control of cancer biology. Indeed, secretions from quiescent ECs muted the proliferative and invasive phenotype of lung and breast cancer cells in vitro and reduced cancer cell protumorigenic and proinflammatory signaling. EC perlecan silencing significantly changed this regulatory relationship, eliminating the ability of ECs to inhibit cancer cell invasiveness via increased interleukin-6 secretion. Moreover, implanting ECs embedded within porous matrices slowed adjacent xenograft tumor growth and prevented architectural degeneration, with a concomitant reduction in proliferative and tumorigenic markers. Finally, lung carcinoma cells pretreated with intact EC-conditioned media, but not media conditioned with perlecan-silenced ECs, exhibited reduced micrometastatic burden after tail vein injection. These findings add to an emerging appreciation of EC-regulatory effects that transcend their structural roles and pave the way for improved characterization and control of EC-cancer cross-talk interactions for diagnosis, prognosis, and treatment of cancer.
Biomedical Engineering Center, Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, E25-438, Cambridge, MA 02139, USA.
Joseph W
JW
Franses
Aaron B
AB
Baker
Vipul C
VC
Chitalia
Elazer R
ER
Edelman
D000818:Animals; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000378:metabolism; D018450:Disease Progression; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D017154:Stromal Cells / Q000378:metabolism*
D017077:Culture Media, Conditioned; D019812:Heparan Sulfate Proteoglycans; D015850:Interleukin-6; C071927:perlecan
Cancer Cell. 2009 Mar 3;15(3):232-9
19249681
Circ Res. 1993 Dec;73(6):1051-60
8222077
Eur J Gynaecol Oncol. 2005;26(4):403-6
16122188
Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6722-7
10841569
Nat Genet. 2008 May;40(5):494-5
18443582
Transplant Proc. 2006 Dec;38(10):3293-9
17175253
J Clin Invest. 2007 Dec;117(12):3846-56
18060032
Circ Res. 2007 Feb 2;100(2):174-90
17272819
Nat Protoc. 2008;3(6):1085-91
18546599
Cell. 2000 Jan 7;100(1):57-70
10647931
Annu Rev Med. 2006;57:1-18
16409133
Thromb Haemost. 2007 Aug;98(2):278-82
17721607
Blood. 2006 Oct 1;108(7):2339-48
16794251
Cell. 2010 Oct 29;143(3):355-66
21029859
Science. 2000 Aug 18;289(5482):1197-202
10947988
Circulation. 1996 Dec 1;94(11):2909-14
8941120
Circ Res. 2007 Feb 2;100(2):158-73
17272818
J Clin Invest. 2007 Dec;117(12):3660-3
18060028
Circulation. 2005 Aug 30;112(9 Suppl):I89-95
16159871
Clin Lung Cancer. 2008 Nov;9(6):340-5
19073516
Trends Genet. 2009 Jan;25(1):30-8
19054589
J Mol Cell Cardiol. 2009 May;46(5):682-94
19302827
Nat Rev Cancer. 2008 Apr;8(4):309-16
18337733
Nat Rev Cancer. 2009 Nov;9(11):798-809
19851315
Cancer Cell. 2007 Jan;11(1):69-82
17222791
Nat Protoc. 2007;2(3):504-11
17406614
Nature. 2004 Nov 18;432(7015):332-7
15549095
Science. 2005 Jan 7;307(5706):58-62
15637262
Cell. 2006 Jan 27;124(2):263-6
16439202
Nat Med. 2006 Aug;12(8):933-8
16862154
Nat Rev Immunol. 2007 Jan;7(1):41-51
17186030
J Clin Invest. 2007 Dec;117(12):3988-4002
18060036
Cancer Cell. 2009 Mar 3;15(3):220-31
19249680
J Vasc Res. 2002 Nov-Dec;39(6):524-33
12566978
Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8130-4
7667257
J Vasc Surg. 2009 Dec;50(6):1359-68.e1
19958986
Blood. 2003 May 15;101(10):3765-77
12543869
Oncol Rep. 2009 Mar;21(3):821-6
19212645
Proc Natl Acad Sci U S A. 2008 May 13;105(19):7046-51
18458330
Nat Rev Cancer. 2010 Feb;10(2):138-46
20094048
Cell Tissue Res. 2009 Jan;335(1):271-81
18726119
J Cell Biochem. 1993 Sep;53(1):21-31
8227180
Ann Med. 1999 Feb;31(1):34-45
10219712
Microvasc Res. 2007 Sep-Nov;74(2-3):72-84
17560615
Biochemistry. 2008 Oct 28;47(43):11174-83
18826258
N Engl J Med. 1971 Nov 18;285(21):1182-6
4938153
Nature. 2002 Dec 19-26;420(6917):860-7
12490959
Nat Rev Cancer. 2001 Oct;1(1):46-54
11900251
Pharmacol Rep. 2008 Jan-Feb;60(1):139-43
18276995
Oncol Rep. 2005 Jul;14(1):89-92
15944773
Curr Cancer Drug Targets. 2008 Sep;8(6):447-53
18781891
Exp Cell Res. 2006 Mar 10;312(5):594-607
16376330
J Clin Invest. 1998 Oct 15;102(8):1599-608
9788974
Curr Protoc Cell Biol. 2001 Nov;Chapter 19:19.2.1-19.2.7
18228345
Differentiation. 2004 Apr;72(4):162-70
15157239
Semin Immunol. 2008 Apr;20(2):117-22
18243732