Obesity, inflammation and cancerRole of tumour-surrounding adipocytes in cancer progressionGroup “Microenvironnement, Cancer and Adipocytes”Department of Cancer BiologyInstitute of Pharmacology and Structural BiologyPr Catherine MULLER-STAUMONT
Overweight, obesity and cancer : a complex situationBreast CancerDecreased overall survivalDecreased disease free survival (DFS)Increased MetastasisMajed B et al., Breast Cancer Res Treat. 2007Ewertz et al, J Clin Oncol, 2011Parek et al, Ann Rev Nutr 2012Prostate Cancer✓ Advanced tumors at diagnosis✓ Decreased overall survival✓ Increased relapse post-prostatectomyAmling et al, J. Clin. Oncol (2004)Freedland et al, J. Clin. Oncol (2004)Parek et al, Ann Rev Nutr 2012Overweight and obesity can affect different steps of carcinogenesis :From initiation (occurrence) to tumor progression (prognosis)There are probably more than one mechanism involved
Poor prognosisDelay in diagnosisInappropriate therapyLimit in surgery, increase in surgery morbidity and mortalityInadequate doses of radiotherapyInadequate doses of chemotherapy (under-dosage +++++)Tumor with aggressive featuresOverweight, obesity and cancer prognosis : the current hypotheses
Paracrine role of adipose tissue in cancer progression :Breast cancer as a paradigmVargo-Gogola et al, Nature Reviews Cancer, 2007Adipose tissue is also present in breast cancer stromaAdipose tissueTumour
A role for mature adipocytes in cancer progression ?Adipocytes store lipids and alsosecrete a large panel of adipokineswomen and are characterized by frequent tumours at diagnosis (positive lymphnodes involvement ) and propensity to metastasise.Nature of the cross-talk between tumour cells and mature adipocytes ?Amplification in obesity conditions ?Adipose tissue is also presentin breast cancer stromaAdipose tissueTumour
0 ou 10% sérummatrigelSUM 159PT cell lineZR 75.1 cell lineNC C Ad-cm CAA-cm05101520numberofcellsperfield** ***nc c cm020406080numberofcellsperfield*Ad-Tumor cellswith adipocytesMurine adipocytesHuman mammary adipocytesTumor cells aloneCooperation of breast tumor cells with adipocytes promotes an invasive phenotypeIn vivoTail Vein MetastasisAssay (4T1)In vitroNCC***** ** *** *NC C0204060*Numberofnodulesinlungs
MMP-11 PAI-1 MMP-90.00.51.01.5mRNArelativeexpression*****IL-6 IL-1b TNF-a0.00.51.01.52.0mRNArelativeexpression*** *** ***nc c0.02.55.07.510.0IL-6secretion(ng/ml)*nc c02505007501000IL-1bsecretion(pg/ml)***resistin adiponectin leptin01234mRNArelativeexpression* ** PPARg2 CEBPa aP20.00.51.01.52.0mRNArelativeexpression*** *NC CDelipidation Decrease in late adipose markersInflammatory phenotypenc c0.00.51.01.52.0TG(g/L)**Adipocytes co-cultivated with tumor cells exhibit a reorientated phenotypeIL-6 IL-1b
« Cancer-Associated adipocytes »are also observed in human breast tumors
IL-6 plays a key role in the adipocyte driven pro-invasive effectRecombinant IL-6 induces EMTand increases invasivenessDramatic effect of blocking mIL-6 AbCoculture tumour cells /adipocytesTumor cells in the presence of CAA-CM
The Cancer-Associated Adipocytes (CAAs) contribute to breast cancer progression throughsecretion of inflammatory moleculesDirat B et al, Endocrine Dev 2010 (review)Dirat B et al, Cancer Research, 2011Bochet et al, BBRC 2011Wang et al, Cancer Letters, 2012 (review)MatureAdipocytesTumour cellsCAAs increaseTumour growthTumour invasion (EMT)RadioresistanceCancer-Associated Adipocytes Delipidation Decrease in late adipose markers includingleptin Over-expression of pro-inflammatory molecules(IL-6, IL-1β) Over-expression of ECM and ECM-relatedmoleculesFound in other cancers !ReorientationAutocrine secreted factors CCL20 MIC-1 IL-6IL-6,COLVI, MMP-11
Adipose progenitors also contribute to breast cancer progression through secretion ofinflammatory moleculesAdapted from Wang et al, Cancer Letters, 2012 (review)
Involvement of peri-tumoral adipose tissue into tumour progression through pro-inflammatory molecules is not limited to breast cancer : tumor type specificitiesProstate cancerNo infiltration by inflammatory cellsNo increase in circulating levels of IL-6Reference : Finley et al, J Urol, 2009MelanomaMassive infiltration by inflammatory cellsMouse modelsReference :Wagner et al, Angiogenesis, 2012Remaining questions :Infiltration or not of adipose tissue by immune cells ?Major inflammatory cytokine(s) or chemokine(s) secreted ?
Normalmature AdipocytesCancer-AssociatedAdipocytesTumour cellsThe Cancer-Associated Adipocytes (CAAs) contribute to tumour progression :amplification in a context of obesity ?Tumour cellswomen and are characterized by frequent tumours at diagnosis(positive lymph nodes involvement ) andObeseMature Adipocytes
Presence of a sub-inflammatory state in visceral adipose tissue in obese conditionsIs this sub-inflammatory state observed in mammary adipose tissue ?
Obesity Is Associated with Inflammation in the Mouse Mammary GlandSubbaramaiah et al. Cancer Prev Res 2011 : 329-346Presence of CLS in MAT of obese mice Inflammatory state of the MAT of obese miceAre these modifications found in the mammary gland of obese patients ????Expression of inflammatory cytokinesNFkB activity
A first step in favor of this hypothesis : inflammatory mammary adipose tissue inobese patientsMorris P G et al. Cancer Prev Res 2011;4:1021-1029Presence of CLS in MAT of obese patients Hypertrophy of adipocytes in MAT from obese patientsHuman tumours (modifications in tumour-surrounding adipocytes in obese patients)Original 3D coculture system with primary isolated adipocytes from lean and obese patientsXenografts in immunocompetent obese and lean mice
Obesity increases aggressivity of xenografted tumors in miceCell lines derived from MMTV-Wnt-1 mammary tumorsDunlap S M et al. Cancer Prev Res 2012;5:930-942
Inflammation of adipose tissue could also affect tumour progression throughendocrine mechanismsDoyle et al, Proc Nutrition Soc, 2012
Intimate cross-talk between adipose tissue and breast cancer through“soluble” molecules : inflammatory cytokines (IL-6) and FFAs✔ Characterize the inflammatory response in tumour-surrounding adipose tissue ofobese versus lean patients [circulating inflammatory molecules /signalling signatures]Validate the role of inflammation in pre-clinical models of lean and obese mice bythe use of blocking antibodies or drugs that inhibit signalling pathways✔ Include the metabolic status of the patients in ongoing clinical trials targeting inflammationIn cancers✔ Develop more specific approaches targeting adipocytes/cancer cell cross-talk :inhibition of lipid transfer ????
Group « Microenvironment, Cancer and Adipocytes »IPBS, ToulouseLudivine BochetStéphanie DauvillierBéatrice DiratFrédérique FalloneVictor LaurentIkram LazareCamille LehuédéLaurence NietoYuan Yuan WangGroup of Pathology (CHU Rangueil)Ghislaine EscourrouAdipÔKGroup « Adipocyte secretions, Obesities and associated pathologies»I2MC, ToulouseCamille AttanéDanièle DaviaudCédric DraySophie Le GonidecPhilippe ValetAcknowledgementsIbOXFondationDe France