title: Influence of tumour micro-environment heterogeneity on therapeutic response.
abstract: Tumour formation involves the co-evolution of neoplastic cells together with extracellular matrix, tumour vasculature and immune cells. Successful outgrowth of tumours and eventual metastasis is not determined solely by genetic alterations in tumour cells, but also by the fitness advantage such mutations confer in a given environment. As fitness is context dependent, evaluating tumours as complete organs, and not simply as masses of transformed epithelial cells, becomes paramount. The dynamic tumour topography varies drastically even throughout the same lesion. Heterologous cell types within tumours can actively influence therapeutic response and shape resistance.
authors.affiliation: Department of Molecular Biology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Junttila
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D018450:Disease Progression; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000502:physiology
references.citation: Br J Cancer. 2006 Jun 19;94(12):1823-32
references.pmid: 16773076
references.citation: Br J Cancer. 2011 Jun 7;104(12):1877-81
references.pmid: 21540863
references.citation: Nature. 2011 Dec 21;480(7378):480-9
references.pmid: 22193102
references.citation: PLoS One. 2011;6(9):e24605
references.pmid: 21957456
references.citation: J Pathol. 2012 Aug;227(4):404-16
references.pmid: 22611017
references.citation: Dev Cell. 2010 Jun 15;18(6):884-901
references.pmid: 20627072
references.citation: Nat Rev Immunol. 2008 Jan;8(1):59-73
references.pmid: 18097448
references.citation: J Clin Oncol. 2009 Oct 1;27(28):4733-40
references.pmid: 19720927
references.citation: Cancer Cell. 2005 May;7(5):411-23
references.pmid: 15894262
references.citation: Cancer Cell. 2009 Mar 3;15(3):232-9
references.pmid: 19249681
references.citation: Science. 2011 Mar 25;331(6024):1612-6
references.pmid: 21436454
references.citation: J Clin Oncol. 2007 Oct 20;25(30):4722-9
references.pmid: 17947719
references.citation: Cancer Res. 2004 May 1;64(9):3215-22
references.pmid: 15126362
references.citation: Nature. 2008 May 15;453(7193):410-4
references.pmid: 18418378
references.citation: Nat Cell Biol. 2000 Oct;2(10):737-44
references.pmid: 11025665
references.citation: Cancer Cell. 2013 Feb 11;23(2):171-85
references.pmid: 23375636
references.citation: N Engl J Med. 2007 Dec 20;357(25):2543-51
references.pmid: 18094375
references.citation: Proc Natl Acad Sci U S A. 2012 May 15;109(20):7841-6
references.pmid: 22547817
references.citation: Cell. 2005 May 6;121(3):335-48
references.pmid: 15882617
references.citation: N Engl J Med. 2006 Dec 14;355(24):2542-50
references.pmid: 17167137
references.citation: Int J Cancer. 2002 May 10;99(2):157-66
references.pmid: 11979428
references.citation: Nat Med. 2012 Sep;18(9):1359-68
references.pmid: 22863786
references.citation: J Pathol. 2012 Aug;227(4):417-30
references.pmid: 22611036
references.citation: J Clin Oncol. 2007 Apr 20;25(12):1539-44
references.pmid: 17442997
references.citation: J Clin Oncol. 2011 Jan 1;29(1):83-8
references.pmid: 21098326
references.citation: N Engl J Med. 2010 Aug 19;363(8):711-23
references.pmid: 20525992
references.citation: Clin Cancer Res. 2006 Feb 15;12(4):1260-9
references.pmid: 16489082
references.citation: Science. 2009 Jun 12;324(5933):1457-61
references.pmid: 19460966
references.citation: J Immunother. 2007 Nov-Dec;30(8):798-807
references.pmid: 18049331
references.citation: Cancer Cell. 2012 Jul 10;22(1):21-35
references.pmid: 22789536
references.citation: Nat Genet. 2005 Aug;37(8):899-905
references.pmid: 16007089
references.citation: J Cell Physiol. 2013 Aug;228(8):1651-7
references.pmid: 23460038
references.citation: Nature. 2012 Oct 18;490(7420):412-6
references.pmid: 23051752
references.citation: Genes Dev. 1999 Jun 1;13(11):1382-97
references.pmid: 10364156
references.citation: Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):6079-84
references.pmid: 23530240
references.citation: Nat Biotechnol. 2007 Aug;25(8):911-20
references.pmid: 17664940
references.citation: J Clin Oncol. 2005 May 20;23(15):3502-8
references.pmid: 15908660
references.citation: Nat Biotechnol. 2012 Jul 10;30(7):648-57
references.pmid: 22781694
references.citation: Cancer Res. 2010 Dec 1;70(23):9969-78
references.pmid: 21098716
references.citation: Clin Cancer Res. 2008 Sep 15;14(18):5692-9
references.pmid: 18794077
references.citation: Clin Cancer Res. 2013 Feb 15;19(4):929-37
references.pmid: 23169435
references.citation: Cancer Res. 2006 Jan 1;66(1):29-33
references.pmid: 16397211
references.citation: Clin Cancer Res. 2008 Sep 15;14(18):5893-9
references.pmid: 18794102
references.citation: Cell Rep. 2013 Feb 21;3(2):277-81
references.pmid: 23395639
references.citation: Nature. 2010 Dec 16;468(7326):973-7
references.pmid: 21107323
references.citation: Nat Rev Cancer. 2008 Apr;8(4):299-308
references.pmid: 18354418
references.citation: Pancreas. 2010 May 7;39(8):1254-1262
references.pmid: 20467342
references.citation: Clin Cancer Res. 1999 Oct;5(10):2963-70
references.pmid: 10537366
references.citation: J Clin Oncol. 2011 Aug 1;29(22):3085-96
references.pmid: 21383288
references.citation: Nat Med. 2008 May;14(5):518-27
references.pmid: 18438415
references.citation: Science. 2002 Mar 29;295(5564):2387-92
references.pmid: 11923519
references.citation: Cancer Cell. 2012 Jun 12;21(6):822-35
references.pmid: 22698406
references.citation: Cancer Cell. 2012 Mar 20;21(3):309-22
references.pmid: 22439926
references.citation: Cancer Res. 2010 Aug 1;70(15):6171-80
references.pmid: 20631075
references.citation: Nat Rev Cancer. 2004 Aug;4(8):579-91
references.pmid: 15286738
references.citation: Science. 2005 Jan 7;307(5706):58-62
references.pmid: 15637262
references.citation: Breast Cancer. 2012 Apr;19(2):170-6
references.pmid: 20978953
references.citation: Cancer Cell. 2007 Jan;11(1):69-82
references.pmid: 17222791
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6742-7
references.pmid: 19346489
references.citation: N Engl J Med. 2011 Jun 30;364(26):2507-16
references.pmid: 21639808
references.citation: Cancer Discov. 2011 Jun;1(1):54-67
references.pmid: 22039576
references.citation: Science. 2008 Aug 15;321(5891):974-7
references.pmid: 18703743
references.citation: Cancer Cell. 2009 Mar 3;15(3):220-31
references.pmid: 19249680
references.citation: Chin Clin Oncol. 2014 Mar;3(1):6
references.pmid: 25842084
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12072-7
references.pmid: 11593017
references.citation: Nat Rev Immunol. 2011 Sep 23;11(10):702-11
references.pmid: 21941296
references.citation: J Immunol. 1998 May 1;160(9):4175-81
references.pmid: 9574517
references.citation: Science. 1996 Dec 20;274(5295):2057-9
references.pmid: 8953032
references.citation: J Immunol. 2010 Nov 1;185(9):4977-82
references.pmid: 20962266
references.citation: Nat Rev Cancer. 2005 May;5(5):397-405
references.pmid: 15864281
references.citation: J Clin Oncol. 2013 Mar 20;31(9):1219-30
references.pmid: 23401453
references.citation: Nat Med. 2012 Mar 06;18(3):344-6; author reply 346
references.pmid: 22395693
references.citation: Cancer Res. 2010 Jul 1;70(13):5213-9
references.pmid: 20551059
references.citation: Cancer Cell. 2012 Mar 20;21(3):418-29
references.pmid: 22439937
references.citation: N Engl J Med. 2011 Dec 29;365(26):2484-96
references.pmid: 22204725
references.citation: Cell. 2008 Oct 31;135(3):437-48
references.pmid: 18984156
references.citation: N Engl J Med. 2005 Feb 24;352(8):786-92
references.pmid: 15728811
references.citation: N Engl J Med. 2003 Jul 31;349(5):427-34
references.pmid: 12890841
references.citation: Cancer Res. 2009 Aug 1;69(15):6007-10
references.pmid: 19638582
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20932-7
references.pmid: 18093943
references.citation: Cancer Cell. 2009 Jan 6;15(1):21-34
references.pmid: 19111878
references.citation: Neuro Oncol. 2010 Mar;12(3):233-42
references.pmid: 20167811
references.citation: PLoS Genet. 2006 Jul;2(7):e119
references.pmid: 16895450
references.citation: J Cancer Res Clin Oncol. 2013 Feb;139(2):211-22
references.pmid: 23052691
references.citation: Cancer Cell. 2004 Oct;6(4):409-21
references.pmid: 15488763
references.citation: Cancer Cell. 2012 Jun 12;21(6):836-47
references.pmid: 22698407
references.citation: J Natl Cancer Inst. 2007 Oct 3;99(19):1441-54
references.pmid: 17895480
references.citation: Cancer Res. 2011 Feb 15;71(4):1263-71
references.pmid: 21303976
references.citation: Nat Med. 2008 Jan;14(1):28-36
references.pmid: 18157142
references.citation: Nat Rev Cancer. 2012 Mar 15;12(4):298-306
references.pmid: 22419253
references.citation: Nat Rev Cancer. 2009 Sep;9(9):665-74
references.pmid: 19693095
references.citation: Cancer Cell. 2012 Jan 17;21(1):82-91
references.pmid: 22264790
references.citation: N Engl J Med. 2011 Jun 30;364(26):2517-26
references.pmid: 21639810
references.citation: J Clin Oncol. 1999 Jun;17(6):1802-8
references.pmid: 10561218
references.citation: Sci Transl Med. 2011 Mar 23;3(75):75ra26
references.pmid: 21430269
references.citation: J Clin Oncol. 2005 Nov 1;23(31):8033-40
references.pmid: 16258101
references.citation: Nature. 2010 Mar 11;464(7286):302-5
references.pmid: 20220849
references.citation: Cancer Res. 2004 May 1;64(9):2941-55
references.pmid: 15126324
references.citation: Proc Natl Acad Sci U S A. 1988 Sep;85(17):6389-93
references.pmid: 2457913
references.citation: Nat Rev Cancer. 2012 Mar 22;12(4):252-64
references.pmid: 22437870
references.citation: N Engl J Med. 2010 Jul 29;363(5):411-22
references.pmid: 20818862
references.citation: Science. 2007 May 18;316(5827):1039-43
references.pmid: 17463250
references.citation: Lancet Oncol. 2013 Jan;14(1):29-37
references.pmid: 23168366
references.citation: Br J Cancer. 2002 Sep 23;87(7):694-701
references.pmid: 12232748
references.citation: Cancer Cell. 2011 Feb 15;19(2):257-72
references.pmid: 21316604
references.citation: Cancer Res. 2013 May 1;73(9):2782-94
references.pmid: 23418320
references.citation: Nature. 2005 Dec 15;438(7070):967-74
references.pmid: 16355214
references.citation: N Engl J Med. 1999 May 20;340(20):1555-64
references.pmid: 10332019
references.citation: Nat Rev Drug Discov. 2004 May;3(5):391-400
references.pmid: 15136787
references.citation: Cancer Res. 2008 Jul 1;68(13):5405-13
references.pmid: 18593943
references.citation: Curr Opin Immunol. 2010 Apr;22(2):231-7
references.pmid: 20144856
references.citation: Clin Cancer Res. 2012 Dec 1;18(23):6509-18
references.pmid: 23032746
references.citation: Clin Cancer Res. 2013 Jan 1;19(1):258-67
references.pmid: 23082002
references.citation: Clin Cancer Res. 2012 Jun 15;18(12):3281-92
references.pmid: 22553348
references.citation: Nat Genet. 2008 May;40(5):650-5
references.pmid: 18408720
references.citation: Cancer Res. 2000 Mar 1;60(5):1254-60
references.pmid: 10728684
references.citation: Nat Rev Cancer. 2003 Jun;3(6):422-33
references.pmid: 12778132
references.citation: Nat Rev Immunol. 2012 Mar 22;12(4):253-68
references.pmid: 22437938
references.citation: Clin Cancer Res. 2013 Mar 1;19(5):1225-31
references.pmid: 23307859