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Muller staumont opac2013
1. Obesity, inflammation and cancer
Role 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. 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-prostatectomy
Majed B et al., Breast Cancer Res Treat. 2007
Majed 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, 2011
Ewertz 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 2012
Parek et al, Ann Rev Nutr 2012
Parek et al, Ann Rev Nutr 2012
IASO Meeting, London, April 2013
3. Overweight, obesity and cancer prognosis : the current hypotheses
Poor prognosis
Tumor with aggressive features
Delay 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. Paracrine role of adipose tissue in cancer progression :
Breast cancer as a paradigm
Adipose tissue is also present in breast cancer stroma
Adipose tissue
Tumour
Vargo-Gogola et al, Nature Reviews Cancer, 2007
IASO Meeting, London, April 2013
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. 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
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. The Cancer-Associated Adipocytes (CAAs) contribute to breast cancer progression through
secretion 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. The Cancer-Associated Adipocytes (CAAs) contribute to breast cancer progression through
transfer 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. Adipose progenitors also contribute to breast cancer progression through secretion of
inflammatory molecules
Adapted from Wang et al, Cancer Letters, 2012 (review)
IASO Meeting, London, April 2013
14. Both progenitors and mature adipose cells contribute to create an inflammatory
microenvironment in breast cancers
Adapted from Muller et al, in press
IASO Meeting, London, April 2013
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. 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
Oth
Cancer-Associated
Adipocytes
Obese
Normal
mature Adipocytes
Mature Adipocytes
IASO Meeting, London, April 2013
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. 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. A first step in favor of this hypothesis : inflammatory mammary adipose tissue in
obese patients
Presence of CLS in MAT of obese patients Hypertrophy of adipocytes in MAT from obese patients
Morris 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. 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. Inflammation of adipose tissue could also affect tumour progression through
endocrine mechanisms
Doyle et al, Proc Nutrition Soc, 2012
IASO Meeting, London, April 2013
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 of
obese versus lean patients [circulating inflammatory molecules /signalling signatures]
Validate the role of inflammation in pre-clinical models of lean and obese mice by
the use of blocking antibodies or drugs that inhibit signalling pathways
✔ Include the metabolic status of the patients in ongoing clinical trials targeting inflammation
In cancers
✔ Develop more specific approaches targeting adipocytes/cancer cell cross-talk :
inhibition of lipid transfer ????
IASO Meeting, London, April 2013
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
