title: Targeting the tumor microenvironment: from understanding pathways to effective clinical trials.
abstract: It is clear that tumor cells do not act alone but in close interaction with the extracellular matrix and with stromal cells in the tumor microenvironment (TME). As our understanding of tumor cell-stroma interactions increased over the last two decades, significant efforts have been made to develop agents that interfere with these interactions. Here, we discuss four different therapeutic strategies that target the TME, focusing on agents that are at the most advanced stage of preclinical or clinical development. We end this review by outlining some of the lessons we have learned so far from the development of TME-targeting agents.
authors.affiliation: Division of Hematology-Oncology, University of Southern California, Los Angeles, Los Angeles, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Fang
authors.forename: Yves A
authors.initials: YA
authors.lastname: Declerck
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002450:Cell Communication / Q000187:drug effects*; D002986:Clinical Trials as Topic; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents
references.citation: J Clin Oncol. 2008 Dec 1;26(34):5610-7
references.pmid: 18981465
references.citation: Annu Rev Biochem. 1987;56:881-914
references.pmid: 3039909
references.citation: Int J Cancer. 2000 May 20;89(3):251-8
references.pmid: 10861501
references.citation: Lancet Oncol. 2009 Oct;10(10):992-1000
references.pmid: 19796751
references.citation: Nature. 2005 Dec 15;438(7070):967-74
references.pmid: 16355214
references.citation: Clin Cancer Res. 2004 Oct 1;10(19):6528-34
references.pmid: 15475440
references.citation: J Clin Oncol. 2010 Feb 10;28(5):780-7
references.pmid: 20048182
references.citation: Oligonucleotides. 2007 Summer;17(2):201-12
references.pmid: 17638524
references.citation: J Pathol. 2006 Feb;208(3):356-63
references.pmid: 16353170
references.citation: Nat Rev Cancer. 2008 Mar;8(3):180-92
references.pmid: 18273037
references.citation: Nat Rev Cancer. 2004 Nov;4(11):839-49
references.pmid: 15516957
references.citation: Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7220-5
references.pmid: 10377395
references.citation: Leukemia. 2006 Aug;20(8):1341-52
references.pmid: 16810203
references.citation: Lancet Oncol. 2012 May;13(5):549-58
references.pmid: 22452894
references.citation: Cell. 2010 Apr 2;141(1):39-51
references.pmid: 20371344
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: Leukemia. 2009 May;23(5):912-8
references.pmid: 19225537
references.citation: Clin Cancer Res. 2011 Aug 1;17(15):5132-9
references.pmid: 21558407
references.citation: Cell. 1998 May 29;93(5):705-16
references.pmid: 9630216
references.citation: J Clin Oncol. 2012 Aug 10;30(23):2815-6
references.pmid: 22753919
references.citation: Clin Cancer Res. 2003 Jul;9(7):2394-9
references.pmid: 12855610
references.citation: Cancer Cell. 2012 Jul 10;22(1):21-35
references.pmid: 22789536
references.citation: Clin Cancer Res. 2005 Jan 1;11(1):28-40
references.pmid: 15671525
references.citation: Prog Mol Biol Transl Sci. 2012;109:161-226
references.pmid: 22727422
references.citation: Science. 2013 Jan 18;339(6117):286-91
references.pmid: 23329041
references.citation: Nat Rev Cancer. 2011 Dec 15;12(1):9-22
references.pmid: 22169972
references.citation: Clin Cancer Res. 2012 Apr 1;18(7):2090-8
references.pmid: 22238246
references.citation: Nat Rev Cancer. 2012 Jan 19;12(2):121-32
references.pmid: 22257950
references.citation: J Clin Oncol. 2005 Sep 1;23(25):5950-9
references.pmid: 16135466
references.citation: Invest New Drugs. 2004 Nov;22(4):459-66
references.pmid: 15292716
references.citation: J Clin Oncol. 2007 Oct 10;25(29):4542-9
references.pmid: 17925549
references.citation: Cancer Discov. 2011 Dec;1(7):OF1-2
references.pmid: 22586694
references.citation: Expert Opin Investig Drugs. 2009 Jan;18(1):77-87
references.pmid: 19053884
references.citation: Science. 2002 Mar 29;295(5564):2387-92
references.pmid: 11923519
references.citation: Hematology Am Soc Hematol Educ Program. 2009;:636-42
references.pmid: 20008249
references.citation: Cancer Cell. 2012 Mar 20;21(3):309-22
references.pmid: 22439926
references.citation: Cancer Cell. 2007 Jan;11(1):83-95
references.pmid: 17222792
references.citation: Nat Rev Cancer. 2009 Nov;9(11):798-809
references.pmid: 19851315
references.citation: Science. 2005 Jan 7;307(5706):58-62
references.pmid: 15637262
references.citation: Neuro Oncol. 2011 Jan;13(1):132-42
references.pmid: 20980335
references.citation: Nat Rev Immunol. 2005 Oct;5(10):749-59
references.pmid: 16175180
references.citation: Nat Rev Cancer. 2006 Jul;6(7):506-20
references.pmid: 16794634
references.citation: Cancer Prev Res (Phila). 2009 Apr;2(4):285-7
references.pmid: 19336723
references.citation: Nat Rev Cancer. 2008 Aug;8(8):592-603
references.pmid: 18650835
references.citation: Crit Rev Clin Lab Sci. 2000 Oct;37(5):431-502
references.pmid: 11078056
references.citation: Gastroenterology. 2011 Oct;141(4):1167-78
references.pmid: 21839702
references.citation: J Exp Ther Oncol. 2007;6(3):183-92
references.pmid: 17552358
references.citation: Adv Exp Med Biol. 2013;986:171-87
references.pmid: 22879069
references.citation: BMC Cancer. 2011 Oct 07;11:432
references.pmid: 21982454
references.citation: Endocr Rev. 1997 Feb;18(1):4-25
references.pmid: 9034784
references.citation: Nat Rev Drug Discov. 2004 Jan;3(1):17-26
references.pmid: 14708018
references.citation: J Clin Oncol. 2011 Nov 10;29(32):4320-6
references.pmid: 21990410
references.citation: Br J Cancer. 2010 Oct 12;103(8):1154-62
references.pmid: 20808314
references.citation: Cell. 2008 Jul 25;134(2):215-30
references.pmid: 18662538
references.citation: Nature. 2009 Apr 9;458(7239):719-24
references.pmid: 19360079
references.citation: Cell. 2002 Sep 20;110(6):673-87
references.pmid: 12297042
references.citation: Clin Exp Metastasis. 2012 Aug;29(6):585-601
references.pmid: 22484917
references.citation: Eur J Med Chem. 2012 Mar;49:24-40
references.pmid: 22305612
references.citation: Eur J Cancer. 2012 Jan;48(1):85-93
references.pmid: 22129890
references.citation: Clin Cancer Res. 2011 Sep 15;17(18):6083-96
references.pmid: 21795409
references.citation: Clin Cancer Res. 2008 Oct 15;14(20):6371-5
references.pmid: 18927275
references.citation: J Cancer Res Ther. 2011 Oct-Dec;7(4):442-7
references.pmid: 22269407
references.citation: Cancer Res. 2007 Oct 1;67(19):9417-24
references.pmid: 17909051
references.citation: Science. 1994 Apr 22;264(5158):569-71
references.pmid: 7512751
references.citation: Drug Resist Updat. 2010 Feb-Apr;13(1-2):16-28
references.pmid: 20061178
references.citation: Nat Rev Cancer. 2006 Jan;6(1):24-37
references.pmid: 16397525
references.citation: Nat Rev Cancer. 2009 Sep;9(9):665-74
references.pmid: 19693095
references.citation: Clin Cancer Res. 2005 Mar 1;11(5):2089-96
references.pmid: 15756036
references.citation: Nature. 2011 Dec 21;480(7378):480-9
references.pmid: 22193102
references.citation: Pharmacol Ther. 2011 Jul;131(1):80-90
references.pmid: 21439312
references.citation: Urology. 2011 Sep;78(3):626-30
references.pmid: 21762967
references.citation: Cancer Metastasis Rev. 2006 Sep;25(3):409-16
references.pmid: 16951987
references.citation: Ann N Y Acad Sci. 2012 Aug;1263:29-40
references.pmid: 22831177
references.citation: Nat Rev Cancer. 2011 Jun;11(6):393-410
references.pmid: 21606941
references.citation: Drug Saf. 2012 Jan 1;35(1):15-25
references.pmid: 22136182
references.citation: Nat Rev Cancer. 2008 Nov;8(11):851-64
references.pmid: 18846101
references.citation: J Clin Invest. 2012 Mar;122(3):787-95
references.pmid: 22378047
references.citation: Cell. 2001 Feb 23;104(4):487-501
references.pmid: 11239407
references.citation: Clin Cancer Res. 2008 Nov 1;14(21):7110-5
references.pmid: 18981010
references.citation: Cancer Discov. 2012 Aug;2(8):694-705
references.pmid: 22719020
references.citation: Br J Cancer. 2010 Oct 12;103(8):1149-53
references.pmid: 20842130
references.citation: Nat Rev Cancer. 2002 Aug;2(8):584-93
references.pmid: 12154351
references.citation: Mol Cancer Ther. 2007 Oct;6(10):2609-17
references.pmid: 17938257
references.citation: Cancer Res. 2002 Sep 15;62(18):5317-24
references.pmid: 12235002
references.citation: Cancer Res. 2004 Aug 1;64(15):5378-84
references.pmid: 15289345
references.citation: Cancer Res. 1997 Mar 1;57(5):963-9
references.pmid: 9041202
references.citation: Br J Cancer. 2011 Jul 26;105(3):346-52
references.pmid: 21750555
references.citation: Nat Immunol. 2010 Oct;11(10):889-96
references.pmid: 20856220
references.citation: Nat Rev Cancer. 2003 Jun;3(6):401-10
references.pmid: 12778130
references.citation: Nature. 2004 Sep 23;431(7007):461-6
references.pmid: 15329734
references.citation: Clin Cancer Res. 2011 Oct 1;17(19):6130-9
references.pmid: 21953501
references.citation: Mol Cancer Ther. 2009 Nov;8(11):3151-61
references.pmid: 19887542
references.citation: J Med Chem. 1999 Aug 12;42(16):3033-40
references.pmid: 10447947
references.citation: Hematol Oncol Clin North Am. 2004 Oct;18(5):1007-21, viii
references.pmid: 15474332
references.citation: Clin Cancer Res. 2011 May 1;17(9):2997-3004
references.pmid: 21415214
references.citation: Mol Cancer Ther. 2006 Nov;5(11):2634-43
references.pmid: 17121910
references.citation: Cancer. 2010 Mar 15;116(6):1526-34
references.pmid: 20108344
references.citation: Nat Rev Cancer. 2002 Nov;2(11):826-35
references.pmid: 12415253
references.citation: Recent Results Cancer Res. 2010;180:103-14
references.pmid: 20033380
references.citation: Genes Dev. 2008 May 15;22(10):1276-312
references.pmid: 18483217
references.citation: Nat Rev Clin Oncol. 2010 Nov;7(11):641-51
references.pmid: 20808302