Obesity, inflammation and cancerRole of tumour-surrounding adipocytes in cancer progression                           Grou...
Overweight, obesity and cancer : a complex situation Overweight and obesity can affect different steps of carcinogenesis :...
Overweight, obesity and cancer prognosis : the current hypotheses                                   Poor prognosis        ...
Paracrine role of adipose tissue in cancer progression :                                        Breast cancer as a paradig...
A role for mature adipocytes in cancer progression ?  Adipose tissue is also present               Adipocytes store lipids...
Cooperation of breast tumor cells with adipocytes promotes an invasive phenotype                    In vitro              ...
Cocultivated tumor cells exhibit incomplete epithelial-mesenchymal transition (EMT)                                       ...
Adipocytes co-cultivated with tumor cells exhibit a reorientated phenotype           Delipidation                         ...
« Cancer-Associated adipocytes »are also observed in human breast tumors                                                  ...
IL-6 plays a key role in the adipocyte driven pro-invasive effect           Recombinant IL-6 induces EMT                  ...
The Cancer-Associated Adipocytes (CAAs) contribute to breast cancer progression throughsecretion of inflammatory molecules...
The Cancer-Associated Adipocytes (CAAs) contribute to breast cancer progression throughtransfer of lipids between the two ...
Adipose progenitors also contribute to breast cancer progression through secretion ofinflammatory molecules Adapted from W...
Both progenitors and mature adipose cells contribute to create an inflammatorymicroenvironment in breast cancers      Adap...
Involvement of peri-tumoral adipose tissue into tumour progression through pro-inflammatory molecules is not limited to br...
The Cancer-Associated Adipocytes (CAAs) contribute to tumour progression :amplification in a context of obesity ?         ...
Presence of a sub-inflammatory state in visceral adipose tissue in obese conditions                   Is this sub-inflamma...
Obesity Is Associated with Inflammation in the Mouse Mammary Gland  Presence of CLS in MAT of obese mice                  ...
A first step in favor of this hypothesis : inflammatory mammary adipose tissue inobese patients      Presence of CLS in MA...
Obesity increases aggressivity of xenografted tumors in mice                                            Cell lines derived...
Inflammation of adipose tissue could also affect tumour progression throughendocrine mechanisms  Doyle et al, Proc Nutriti...
Intimate cross-talk between adipose tissue and breast cancer through          “soluble” molecules : inflammatory cytokines...
Acknowledgements                                                                       Group « Microenvironment, Cancer an...
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Muller staumont opac2013

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Muller staumont opac2013

  1. 1. Obesity, inflammation and cancerRole of tumour-surrounding adipocytes in cancer progression Group “Microenvironnement, Cancer and Adipocytes” Department of Cancer Biology Institute of Pharmacology and Structural Biology Pr Catherine MULLER-STAUMONT IASO Meeting, London, April 2013
  2. 2. Overweight, obesity and cancer : a complex situation Overweight and obesity can affect different steps of carcinogenesis :From initiation (occurrence) to tumor progression (prognosis) There are probably more than one mechanism involved Breast Cancer Breast Cancer Prostate Cancer Prostate Cancer Decreased overall survival Decreased overall survival ✓ Advanced tumors at diagnosis ✓ Advanced tumors at diagnosis Decreased disease free survival (DFS) Decreased disease free survival (DFS) ✓ Decreased overall survival ✓ Decreased overall survival Increased Metastasis Increased Metastasis ✓ Increased relapse post-prostatectomy ✓ Increased relapse post-prostatectomyMajed B et al., Breast Cancer Res Treat. 2007Majed B et al., Breast Cancer Res Treat. 2007 Amling et al, J. Clin. Oncol (2004) Amling et al, J. Clin. Oncol (2004)Ewertz et al, JJClin Oncol, 2011Ewertz et al, Clin Oncol, 2011 Freedland et al, J. Clin. Oncol (2004) Freedland et al, J. Clin. Oncol (2004) Parek et al, Ann Rev Nutr 2012 Parek et al, Ann Rev Nutr 2012Parek et al, Ann Rev Nutr 2012Parek et al, Ann Rev Nutr 2012 IASO Meeting, London, April 2013
  3. 3. Overweight, obesity and cancer prognosis : the current hypotheses Poor prognosis Tumor with aggressive featuresDelay in diagnosis Inappropriate therapy Limit in surgery, increase in surgery morbidity and mortality Inadequate doses of radiotherapy Inadequate doses of chemotherapy (under-dosage +++++) IASO Meeting, London, April 2013
  4. 4. Paracrine role of adipose tissue in cancer progression : Breast cancer as a paradigm Adipose tissue is also present in breast cancer stroma Adipose tissue TumourVargo-Gogola et al, Nature Reviews Cancer, 2007 IASO Meeting, London, April 2013
  5. 5. A role for mature adipocytes in cancer progression ? Adipose tissue is also present Adipocytes store lipids and also in breast cancer stroma secrete a large panel of adipokines Adipose tissue Tumour Nature of the cross-talk between tumour cells and mature adipocytes ? Amplification in obesity conditions ? IASO Meeting, London, April 2013
  6. 6. Cooperation of breast tumor cells with adipocytes promotes an invasive phenotype In vitro ZR 75.1 cell line SUM 159PT cell line 20 80 * matrigel 15 ** *** 60 0 ou 10% sérum Tumor cells 10 40 with adipocytes 5 20 number of cells per field number of cells per field 0 0 NC C Ad-cm CAA-cm nc c Ad- cm Murine adipocytes Human mammary adipocytes NC 60 * Tumor cells alone Tail Vein Metastasis 40 Assay (4T1) in 20 lungs ** * 0 Number of nodules NC C C 0.3 * In vivo * 0.2 * ** * * 0.1 ** 0.0 Nodule Area Index NC C IASO Meeting, London, April 2013
  7. 7. Cocultivated tumor cells exhibit incomplete epithelial-mesenchymal transition (EMT) IASO Meeting, London, April 2013
  8. 8. Adipocytes co-cultivated with tumor cells exhibit a reorientated phenotype Delipidation Decrease in late adipose markers 4 2.0 3 1.5 2 1.0 NC C 0.5 * 1 2.0 mRNA relative expression * µΡΝΑ ρελατιϖε εξπρεσσιον *** * 1.5 0 * resistin adiponectin leptin 0.0 PPAR γ 2 ΧΕΒΠα αΠ2 1.0 ** TG (g/L) 0.5 0.0 nc c Inflammatory phenotype 1.5 2.0 *** *** *** ** 1.5 1.0 *** 1.0 0.5 0.5 mRNA relative expression µΡΝΑ ρελατιϖε εξπρεσσιον 0.0 0.0 MMP-11 PAI-1 MMP-9 IL-6 IL-1 β ΤΝΦ−α IL-6 IL-1β 1000 10.0 * *** 750 7.5 500 5.0 250 σεχρετιον (πγ/µλ) 2.5 β IL-6 secretion (ng/ml) IL-1 0 0.0 nc c nc c IASO Meeting, London, April 2013
  9. 9. « Cancer-Associated adipocytes »are also observed in human breast tumors IASO Meeting, London, April 2013
  10. 10. IL-6 plays a key role in the adipocyte driven pro-invasive effect Recombinant IL-6 induces EMT Dramatic effect of blocking mIL-6 Ab and increases invasiveness Coculture tumour cells /adipocytes Tumor cells in the presence of CAA-CM IASO Meeting, London, April 2013
  11. 11. The Cancer-Associated Adipocytes (CAAs) contribute to breast cancer progression throughsecretion of inflammatory molecules Autocrine secreted factors CAAs increase CCL20 Tumour growth MIC-1 Tumour invasion IL-6 (EMT) Radioresistance IL-6, COLVI, MMP-11 Tumour cells Reorientation Cancer-Associated Adipocytes  Delipidation  Decrease in late adipose markers including leptin  Over-expression of pro-inflammatory molecules (IL-6, IL-1β)  Over-expression of ECM and ECM-related molecules Found in other cancers ! Mature Adipocytes Dirat B et al, Endocrine Dev 2010 (review) Dirat B et al, Cancer Research, 2011 Bochet et al, BBRC 2011 Wang et al, Cancer Letters, 2012 (review) IASO Meeting, London, April 2013
  12. 12. The Cancer-Associated Adipocytes (CAAs) contribute to breast cancer progression throughtransfer of lipids between the two populations Lipid transfer : Increase inflammatory Mediators ? Tumour cells IL-6, FFAs Tumour cells COLVI, MMP-11 Reorientation Cancer-Associated Adipocytes  Delipidation  Decrease in late adipose markers including leptin  Over-expression of pro-inflammatory molecules (IL-6, IL-1β)  Over-expression of ECM and ECM-related molecules Mature Adipocytes Niemann et al, Nature Medecine, 2011 Wang et al (in prep) IASO Meeting, London, April 2013
  13. 13. Adipose progenitors also contribute to breast cancer progression through secretion ofinflammatory molecules Adapted from Wang et al, Cancer Letters, 2012 (review) IASO Meeting, London, April 2013
  14. 14. Both progenitors and mature adipose cells contribute to create an inflammatorymicroenvironment in breast cancers Adapted from Muller et al, in press IASO Meeting, London, April 2013
  15. 15. Involvement of peri-tumoral adipose tissue into tumour progression through pro-inflammatory molecules is not limited to breast cancer : tumor type specificities Prostate cancer Melanoma No infiltration by inflammatory cells No increase in circulating levels of IL-6 Reference : Finley et al, J Urol, 2009 Massive infiltration by inflammatory cells Mouse models Reference :Wagner et al, Angiogenesis, 2012 Remaining questions : Infiltration or not of adipose tissue by immune cells ? Major inflammatory cytokine(s) or chemokine(s) secreted ? IASO Meeting, London, April 2013
  16. 16. The Cancer-Associated Adipocytes (CAAs) contribute to tumour progression :amplification in a context of obesity ? Tumour cells Tumour cells sion I nva sion Inva -6 d IL-6 rive ECM IL -d e ECM s and ecules FFA rs ? n tatio ECM mol rien e Réo FFA s OthCancer-Associated Adipocytes Obese Normal mature Adipocytes Mature Adipocytes IASO Meeting, London, April 2013
  17. 17. Presence of a sub-inflammatory state in visceral adipose tissue in obese conditions Is this sub-inflammatory state observed in mammary adipose tissue ? IASO Meeting, London, April 2013
  18. 18. Obesity Is Associated with Inflammation in the Mouse Mammary Gland Presence of CLS in MAT of obese mice Inflammatory state of the MAT of obese mice Expression of inflammatory cytokines NFκB activity Subbaramaiah et al. Cancer Prev Res 2011 : 329-346 Are these modifications found in the mammary gland of obese patients ???? IASO Meeting, London, April 2013
  19. 19. A first step in favor of this hypothesis : inflammatory mammary adipose tissue inobese patients Presence of CLS in MAT of obese patients Hypertrophy of adipocytes in MAT from obese patientsMorris P G et al. Cancer Prev Res 2011;4:1021-1029 Human tumours (modifications in tumour-surrounding adipocytes in obese patients) Original 3D coculture system with primary isolated adipocytes from lean and obese patients Xenografts in immunocompetent obese and lean mice IASO Meeting, London, April 2013
  20. 20. Obesity increases aggressivity of xenografted tumors in mice Cell lines derived from MMTV-Wnt-1 mammary tumors Dunlap S M et al. Cancer Prev Res 2012;5:930-942 IASO Meeting, London, April 2013
  21. 21. Inflammation of adipose tissue could also affect tumour progression throughendocrine mechanisms Doyle et al, Proc Nutrition Soc, 2012 IASO Meeting, London, April 2013
  22. 22. 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 ???? IASO Meeting, London, April 2013
  23. 23. Acknowledgements Group « Microenvironment, Cancer and Adipocytes » IPBS, Toulouse Ludivine Bochet Stéphanie Dauvillier Béatrice Dirat Frédérique Fallone Victor Laurent Ikram Lazare Camille Lehuédé Laurence Nieto Yuan Yuan Wang Group « Adipocyte secretions, Obesities and associated pathologies» I2MC, Toulouse Camille Attané Danièle Daviaud Cédric Dray Sophie Le Gonidec Philippe Valet Group of Pathology (CHU Rangueil) Ghislaine Escourrou Fondation De France IβOX AdipÔK IASO Meeting, London, April 2013

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