title: Obesity and Cancer: An Angiogenic and Inflammatory Link.
abstract: With the current epidemic of obesity, a large number of patients diagnosed with cancer are overweight or obese. Importantly, this excess body weight is associated with tumor progression and poor prognosis. The mechanisms for this worse outcome, however, remain poorly understood. We review here the epidemiological evidence for the association between obesity and cancer, and discuss potential mechanisms focusing on angiogenesis and inflammation. In particular, we will discuss how the dysfunctional angiogenesis and inflammation occurring in adipose tissue in obesity may promote tumor progression, resistance to chemotherapy, and targeted therapies such as anti-angiogenic and immune therapies. Better understanding of how obesity fuels tumor progression and therapy resistance is essential to improve the current standard of care and the clinical outcome of cancer patients. To this end, we will discuss how an anti-diabetic drug such as metformin can overcome these adverse effects of obesity on the progression and treatment resistance of tumors.
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Dai
authors.initials: D
authors.lastname: Fukumura
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.|I3S, Institute for Innovation and Research in Heath, Metabolism, Nutrition and Endocrinology Group, Biochemistry Department, Faculty of Medicine, Porto University, Porto, Portugal.|Department of Internal Medicine, Hospital S. João, Porto, Portugal.
authors.forename: Joao
authors.initials: J
authors.lastname: Incio
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Morphology, Surgery and Experimental Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Ram C
authors.initials: RC
authors.lastname: Shankaraiah
authors.affiliation: Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D000818:Animals; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008687:Metformin / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D008687:Metformin
keywords: IL-1β; IL-6; VEGFR-1; cytokines; desmoplasia; hypoxia; immune environment; metformin; obesity
references.citation: Am J Clin Nutr. 2007 Sep;86(3):s858-66
references.pmid: 18265479
references.citation: Cancer Cell. 2005 Oct;8(4):299-309
references.pmid: 16226705
references.citation: Free Radic Res. 2010 Feb;44(2):128-34
references.pmid: 19886750
references.citation: Breast Cancer Res Treat. 2007 Apr;102(2):129-35
references.pmid: 16927176
references.citation: Br J Cancer. 2013 Aug 20;109(4):926-33
references.pmid: 23907428
references.citation: Int J Cancer. 2009 Sep 1;125(5):1054-64
references.pmid: 19431143
references.citation: Proc Natl Acad Sci U S A. 2011 Jan 4;108(1):302-7
references.pmid: 21173223
references.citation: ISRN Oncol. 2013 May 30;2013:697521
references.pmid: 23819063
references.citation: Breast Cancer Res. 2007;9(6):R91
references.pmid: 18162139
references.citation: BMC Cancer. 2013;13:392
references.pmid: 23962053
references.citation: N Engl J Med. 2003 Apr 24;348(17):1625-38
references.pmid: 12711737
references.citation: Metabolism. 2014 Jun;63(6):860-73
references.pmid: 24684825
references.citation: Clin Cancer Res. 2011 Oct 1;17(19):6130-9
references.pmid: 21953501
references.citation: BMC Cancer. 2015;15:51
references.pmid: 25885700
references.citation: Nutr Cancer. 2008;60(4):534-41
references.pmid: 18584488
references.citation: FASEB J. 2006 Jul;20(9):1495-7
references.pmid: 16754748
references.citation: J Biomed Biotechnol. 2011;2011:197636
references.pmid: 21274264
references.citation: Breast Cancer Res. 2013;15(4):R59
references.pmid: 23880059
references.citation: Blood. 2006 Sep 15;108(6):1849-56
references.pmid: 16709927
references.citation: Gastroenterology. 2009 Aug;137(2):482-8
references.pmid: 19375425
references.citation: Tissue Eng Part A. 2013 Jun;19(11-12):1327-35
references.pmid: 23394225
references.citation: Front Biosci (Landmark Ed). 2012;17:2550-8
references.pmid: 22652797
references.citation: Gut. 2014 Mar;63(3):385-94
references.pmid: 23729675
references.citation: Front Endocrinol (Lausanne). 2015 May 15;6:77
references.pmid: 26029167
references.citation: Surg Oncol. 2014 Jun;23(2):61-71
references.pmid: 24746917
references.citation: Carcinogenesis. 2014 May;35(5):1055-66
references.pmid: 24419232
references.citation: J Natl Cancer Inst. 1991 Oct 16;83(20):1491-5
references.pmid: 1920496
references.citation: Cancer Prev Res (Phila). 2013 Oct;6(10):1046-55
references.pmid: 23980075
references.citation: Mol Endocrinol. 2012 Dec;26(12):1961-6
references.pmid: 23051592
references.citation: Hypertens Res. 2014 Jun;37(6):513-8
references.pmid: 24572913
references.citation: Mol Cancer Ther. 2012 Oct;11(10):2212-21
references.pmid: 22826466
references.citation: Biochem Biophys Res Commun. 2012 Aug 31;425(3):560-4
references.pmid: 22925674
references.citation: Nat Rev Clin Oncol. 2009 Jun;6(6):327-38
references.pmid: 19483739
references.citation: Cancer Biol Ther. 2015;16(3):484-92
references.pmid: 25701261
references.citation: Oncologist. 2011;16(1):71-81
references.pmid: 21212435
references.citation: Ann N Y Acad Sci. 2012 Oct;1271:82-7
references.pmid: 23050968
references.citation: Br J Pharmacol. 2011 May;163(2):424-37
references.pmid: 21250975
references.citation: Ann Intern Med. 2003 Jan 7;138(1):24-32
references.pmid: 12513041
references.citation: Pharmacol Ther. 2013 May;138(2):197-210
references.pmid: 23353703
references.citation: Breast Cancer Res Treat. 2008 Sep;111(2):329-42
references.pmid: 17939036
references.citation: Gastroenterology. 2004 Nov;127(5 Suppl 1):S97-103
references.pmid: 15508109
references.citation: J Immunol. 2005 Mar 15;174(6):3137-42
references.pmid: 15749839
references.citation: Oncol Lett. 2014 Nov;8(5):1993-1999
references.pmid: 25289085
references.citation: JOP. 2009;10(2):82-7
references.pmid: 19287098
references.citation: Obes Res. 2001 Oct;9(10):631-6
references.pmid: 11595780
references.citation: Nat Commun. 2013;4:2516
references.pmid: 24084631
references.citation: Clin Cancer Res. 2012 May 15;18(10):2905-12
references.pmid: 22465831
references.citation: Vitam Horm. 2009;80:613-33
references.pmid: 19251052
references.citation: Iran J Basic Med Sci. 2012 Nov;15(6):1202-9
references.pmid: 23653852
references.citation: Diabetes. 2012 Apr;61(4):944-53
references.pmid: 22344560
references.citation: Arterioscler Thromb Vasc Biol. 2008 Apr;28(4):658-64
references.pmid: 18174461
references.citation: Physiol Rev. 2013 Jan;93(1):1-21
references.pmid: 23303904
references.citation: Oncogene. 2009 Aug 20;28(33):2940-7
references.pmid: 19581928
references.citation: Cancer Res. 2010 Jan 1;70(1):57-67
references.pmid: 20048072
references.citation: Pancreas. 2015 May;44(4):636-47
references.pmid: 25875801
references.citation: Mol Med Rep. 2012 Apr;5(4):1068-74
references.pmid: 22246099
references.citation: Oncogene. 2004 Aug 23;23(38):6365-78
references.pmid: 15322511
references.citation: Nutr Cancer. 2007;59(2):207-16
references.pmid: 18001216
references.citation: Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):2909-14
references.pmid: 21282607
references.citation: Front Physiol. 2014 Nov 07;5:426
references.pmid: 25426078
references.citation: Cancer Res. 2012 Jan 1;72(1):325-34
references.pmid: 22052460
references.citation: Curr Drug Targets. 2016;17(4):439-46
references.pmid: 25738299
references.citation: J Cell Biochem. 2016 Jan;117(1):180-96
references.pmid: 26096299
references.citation: J Natl Cancer Inst. 2013 Jul 17;105(14):1027-35
references.pmid: 23847240
references.citation: Surgery. 2009 Aug;146(2):258-63
references.pmid: 19628082
references.citation: Eur J Pharmacol. 2008 May 6;585(1):38-49
references.pmid: 18407262
references.citation: JAMA. 2004 Mar 10;291(10):1238-45
references.pmid: 15010446
references.citation: Circ Res. 2003 Oct 31;93(9):e88-97
references.pmid: 14525808
references.citation: Cancer Treat Res. 2014;159:355-76
references.pmid: 24114491
references.citation: J Clin Invest. 2003 Dec;112(12):1821-30
references.pmid: 14679177
references.citation: J Clin Endocrinol Metab. 2007 Apr;92(4):1510-6
references.pmid: 17213279
references.citation: Endocrinology. 2005 Oct;146(10):4545-54
references.pmid: 16020476
references.citation: Oncoimmunology. 2014 Jan 1;3(1):e27810
references.pmid: 24804162
references.citation: Am J Pathol. 2014 Jul;184(7):2099-110
references.pmid: 24952430
references.citation: Mol Cells. 2013 Oct;36(4):279-87
references.pmid: 23794020
references.citation: Cancer Cell Int. 2014 Jun 16;14:53
references.pmid: 24966801
references.citation: Cancer Epidemiol Biomarkers Prev. 2013 Mar;22(3):337-47
references.pmid: 23300021
references.citation: Eur J Obstet Gynecol Reprod Biol. 2008 Jan;136(1):74-7
references.pmid: 17007993
references.citation: Diabetes. 2015 May;64(5):1632-42
references.pmid: 25576058
references.citation: J Lipid Res. 2008 Jul;49(7):1562-8
references.pmid: 18390487
references.citation: Hormones (Athens). 2014 Jul-Sep;13(3):369-74
references.pmid: 25079461
references.citation: Diab Vasc Dis Res. 2014 Nov;11(6):371-89
references.pmid: 25231191
references.citation: Cancer Res. 2013 Oct 1;73(19):5880-91
references.pmid: 23918796
references.citation: N Engl J Med. 2005 Mar 17;352(11):1138-45
references.pmid: 15784668
references.citation: Nat Rev Cancer. 2004 Aug;4(8):579-91
references.pmid: 15286738
references.citation: Diabetes Res Clin Pract. 2005 Jul;69(1):29-35
references.pmid: 15955385
references.citation: Angiogenesis. 2007;10(3):149-66
references.pmid: 17457680
references.citation: Nat Rev Cancer. 2012 Mar;12(3):159-69
references.pmid: 22337149
references.citation: Nat Rev Gastroenterol Hepatol. 2011 Mar;8(3):169-77
references.pmid: 21304475
references.citation: Crit Rev Oncol Hematol. 2013 Sep;87(3):201-23
references.pmid: 23434537
references.citation: Biochem Biophys Res Commun. 1996 Apr 16;221(2):286-9
references.pmid: 8619847
references.citation: Cancer Prev Res (Phila). 2014 Jan;7(1):54-64
references.pmid: 24196830
references.citation: Curr Opin Urol. 2011 Sep;21(5):356-61
references.pmid: 21730854
references.citation: Curr Opin Mol Ther. 2007 Dec;9(6):563-71
references.pmid: 18041667
references.citation: Nat Rev Cancer. 2006 Jul;6(7):521-34
references.pmid: 16794635
references.citation: Proc Jpn Acad Ser B Phys Biol Sci. 2011;87(4):167-78
references.pmid: 21558755
references.citation: J Mol Med (Berl). 2010 Jul;88(7):677-86
references.pmid: 20339829
references.citation: Crit Care Med. 2005 Dec;33(12 Suppl):S466-7
references.pmid: 16340423
references.citation: Microvasc Res. 2007 Sep-Nov;74(2-3):72-84
references.pmid: 17560615
references.citation: Curr Cancer Drug Targets. 2014;14(8):727-36
references.pmid: 25329671
references.citation: J Clin Invest. 2003 Dec;112(12):1796-808
references.pmid: 14679176
references.citation: Am J Epidemiol. 2008 Nov 1;168(9):1047-55
references.pmid: 18801887
references.citation: Clin Cancer Res. 2016 Mar 1;22(5):1076-85
references.pmid: 26459175
references.citation: J Nutr Biochem. 2012 Oct;23(10):1207-13
references.pmid: 22209007
references.citation: Eur J Neurosci. 2014 Jun;39(12):2129-38
references.pmid: 24649970
references.citation: Cancer Invest. 2010 Dec;28(10):1063-9
references.pmid: 21077757
references.citation: Ann N Y Acad Sci. 1999 Nov 18;892:146-54
references.pmid: 10842660
references.citation: Clin Cancer Res. 2012 Aug 15;18(16):4249-56
references.pmid: 22896691
references.citation: Biochim Biophys Acta. 2011 Apr;1815(2):135-46
references.pmid: 21129444
references.citation: Breast. 2011 Oct;20 Suppl 3:S31-5
references.pmid: 22015290
references.citation: Transl Oncol. 2013 Dec 01;6(6):649-59
references.pmid: 24466367
references.citation: Diabetes. 2006 Oct;55(10):2698-704
references.pmid: 17003333
references.citation: Breast Cancer Res Treat. 2010 Aug;122(3):647-59
references.pmid: 19851863
references.citation: Carcinogenesis. 2013 Dec;34(12):2870-9
references.pmid: 23803693
references.citation: PLoS One. 2015;10(12):e0141392
references.pmid: 26641266
references.citation: Nat Rev Cancer. 2008 Dec;8(12):942-56
references.pmid: 19029957
references.citation: JAMA. 2014 Feb 26;311(8):806-14
references.pmid: 24570244
references.citation: Cancers (Basel). 2013 Sep 06;5(3):1140-62
references.pmid: 24202338
references.citation: Clin Cancer Res. 2009 Sep 1;15(17):5511-7
references.pmid: 19706808
references.citation: Nature. 2000 Sep 14;407(6801):249-57
references.pmid: 11001068
references.citation: Biochem Biophys Res Commun. 2011 Jul 22;411(1):102-6
references.pmid: 21712027
references.citation: Cancer Res Treat. 2016 Jan;48(1):171-9
references.pmid: 25779362
references.citation: Endocr Relat Cancer. 2008 Sep;15(3):833-9
references.pmid: 18469156
references.citation: J Steroid Biochem Mol Biol. 2015 Sep;153:35-44
references.pmid: 26209254
references.citation: Nat Rev Drug Discov. 2011 Jun;10(6):417-27
references.pmid: 21629292
references.citation: Clin Transl Gastroenterol. 2014 Mar 13;5:e53
references.pmid: 24622469
references.citation: J Clin Oncol. 2013 Jun 10;31(17):2205-18
references.pmid: 23669226
references.citation: Biochem Biophys Res Commun. 1988 May 31;153(1):347-52
references.pmid: 2454107
references.citation: Pancreas. 2013 Jul;42(5):781-5
references.pmid: 23462329
references.citation: AJR Am J Roentgenol. 1983 May;140(5):959-65
references.pmid: 6601441
references.citation: Arch Physiol Biochem. 2008 Oct;114(4):267-76
references.pmid: 18946787
references.citation: Endocrinology. 2008 May;149(5):2176-83
references.pmid: 18258676
references.citation: Arterioscler Thromb Vasc Biol. 2006 Mar;26(3):611-7
references.pmid: 16385087
references.citation: Science. 2009 Jun 12;324(5933):1457-61
references.pmid: 19460966
references.citation: Cancer Lett. 2012 Nov 28;324(2):142-51
references.pmid: 22643115
references.citation: Diabetes Care. 2003 Aug;26(8):2442-50
references.pmid: 12882876
references.citation: Gut. 2010 Mar;59(3):341-7
references.pmid: 19837679
references.citation: J Clin Endocrinol Metab. 1994 Oct;79(4):1173-6
references.pmid: 7962291
references.citation: Diabetes. 2007 Apr;56(4):901-11
references.pmid: 17395738
references.citation: Ann Transl Med. 2014 Jun;2(6):57
references.pmid: 25333032
references.citation: Breast Cancer Res Treat. 2012 Feb;132(1):131-42
references.pmid: 21574055
references.citation: Cancer Res. 2011 Apr 1;71(7):2455-65
references.pmid: 21459803
references.citation: Oncology. 2005;68(4-6):454-61
references.pmid: 16020976
references.citation: JAMA. 2009 Jun 24;301(24):2553-62
references.pmid: 19549972
references.citation: Nature. 2011 May 19;473(7347):298-307
references.pmid: 21593862
references.citation: Lancet Oncol. 2015 Jul;16(7):839-47
references.pmid: 26067687
references.citation: Int J Cancer. 2015 Mar 15;136(6):E534-44
references.pmid: 25196138
references.citation: J Natl Cancer Inst. 2013 Jun 5;105(11):762-5
references.pmid: 23670727
references.citation: BMJ. 2005 Jun 4;330(7503):1304-5
references.pmid: 15849206
references.citation: Cancer Epidemiol Biomarkers Prev. 2006 Nov;15(11):2285-91
references.pmid: 17119059
references.citation: PLoS One. 2009;4(3):e4974
references.pmid: 19333381
references.citation: Endocr Rev. 2007 Dec;28(7):763-77
references.pmid: 17981890
references.citation: Proc Natl Acad Sci U S A. 1976 Dec;73(12):4536-40
references.pmid: 1070004
references.citation: Gynecol Oncol. 2012 Jun;125(3):751-7
references.pmid: 22449736
references.citation: Proc Natl Acad Sci U S A. 2013 Jul 23;110(30):12325-30
references.pmid: 23836645
references.citation: Nat Mater. 2013 Nov;12(11):958-62
references.pmid: 24150413
references.citation: Mamm Genome. 2008 Mar;19(3):163-78
references.pmid: 18286334
references.citation: Cancer Prev Res (Phila). 2011 Dec;4(12):2002-14
references.pmid: 21952584
references.citation: Ann N Y Acad Sci. 2014 Apr;1311:57-76
references.pmid: 24725147
references.citation: Am J Cancer Res. 2013;3(1):21-33
references.pmid: 23359288
references.citation: Proc Natl Acad Sci U S A. 2012 Apr 10;109(15):5874-9
references.pmid: 22451920
references.citation: Mol Cancer Res. 2013 Dec;11(12):1585-96
references.pmid: 24092775
references.citation: J Biol Chem. 2014 Oct 3;289(40):27692-701
references.pmid: 25143389
references.citation: J Mol Endocrinol. 2012 Jun;48(3):R31-43
references.pmid: 22355097
references.citation: Microcirculation. 2016 Apr;23(3):173-82
references.pmid: 26237291
references.citation: J Clin Oncol. 2010 Jan 10;28(2):183-5
references.pmid: 19949009
references.citation: Mol Cell Biol. 2009 Aug;29(16):4467-83
references.pmid: 19546236
references.citation: Novartis Found Symp. 2004;262:84-98; discussion 98-107, 265-8
references.pmid: 15562824
references.citation: Infect Immun. 2005 May;73(5):2751-7
references.pmid: 15845478
references.citation: JAMA. 2006 Jul 12;296(2):193-201
references.pmid: 16835425
references.citation: Annu Rev Med. 2003;54:131-52
references.pmid: 12525670
references.citation: Am J Pathol. 2003 Jun;162(6):1913-26
references.pmid: 12759248
references.citation: Annu Rev Chem Biomol Eng. 2011;2:281-98
references.pmid: 22432620
references.citation: Endocr Relat Cancer. 2011 Aug;18(4):491-503
references.pmid: 21636700
references.citation: Am J Gastroenterol. 2012 Feb;107(2):196-204
references.pmid: 22146489
references.citation: Cell Metab. 2009 Jan 7;9(1):52-63
references.pmid: 19117546
references.citation: Cardiovasc Res. 2008 May 1;78(2):286-93
references.pmid: 18006485
references.citation: J Anim Sci. 2004 Mar;82(3):925-34
references.pmid: 15032451
references.citation: Cancer Prev Res (Phila). 2011 Mar;4(3):329-46
references.pmid: 21372033