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

2. Overweight, obesity and cancer : a complex situation
Breast Cancer
Decreased overall survival
Decreased disease free survival (DFS)
Increased Metastasis
Majed B et al., Breast Cancer Res Treat. 2007
Ewertz et al, J Clin Oncol, 2011
Parek et al, Ann Rev Nutr 2012
Prostate Cancer
✓ Advanced tumors at diagnosis
✓ Decreased overall survival
✓ Increased relapse post-prostatectomy
Amling et al, J. Clin. Oncol (2004)
Freedland et al, J. Clin. Oncol (2004)
Parek et al, Ann Rev Nutr 2012
Overweight and obesity can affect different steps of carcinogenesis :
From initiation (occurrence) to tumor progression (prognosis)
There are probably more than one mechanism involved

3. Poor prognosis
Delay in diagnosis
Inappropriate therapy
Limit in surgery, increase in surgery morbidity and mortality
Inadequate doses of radiotherapy
Inadequate doses of chemotherapy (under-dosage +++++)
Tumor with aggressive features
Overweight, obesity and cancer prognosis : the current hypotheses

4. Paracrine role of adipose tissue in cancer progression :
Breast cancer as a paradigm
Vargo-Gogola et al, Nature Reviews Cancer, 2007
Adipose tissue is also present in breast cancer stroma
Adipose tissue
Tumour

5. A role for mature adipocytes in cancer progression ?
Adipocytes store lipids and also
secrete a large panel of adipokines
women and are characterized by frequent tumours at diagnosis (positive lymph
nodes involvement ) and propensity to metastasise.
Nature of the cross-talk between tumour cells and mature adipocytes ?
Amplification in obesity conditions ?
Adipose tissue is also present
in breast cancer stroma
Adipose tissue
Tumour

6. 0 ou 10% sérum
matrigel
SUM 159PT cell lineZR 75.1 cell line
NC C Ad-cm CAA-cm
0
5
10
15
20
numberofcellsperfield
** ***
nc c cm
0
20
40
60
80
numberofcellsperfield
*
Ad-
Tumor cells
with adipocytes
Murine adipocytes
Human mammary adipocytes
Tumor cells alone
Cooperation of breast tumor cells with adipocytes promotes an invasive phenotype
In vivo
Tail Vein Metastasis
Assay (4T1)
In vitro
NC
C
***
*
* ** *
** *
NC C
0
20
40
60
*
Numberofnodules
inlungs

7. Cocultivated tumor cells exhibit incomplete epithelial-mesenchymal transition (EMT)

8. MMP-11 PAI-1 MMP-9
0.0
0.5
1.0
1.5
mRNArelativeexpression
***
**
IL-6 IL-1b TNF-a
0.0
0.5
1.0
1.5
2.0
mRNArelativeexpression
*** *** ***
nc c
0.0
2.5
5.0
7.5
10.0
IL-6secretion(ng/ml)
*
nc c
0
250
500
750
1000
IL-1bsecretion(pg/ml)
***
resistin adiponectin leptin
0
1
2
3
4
mRNArelativeexpression
* ** PPARg2 CEBPa aP2
0.0
0.5
1.0
1.5
2.0
mRNArelativeexpression
*** *
NC C
Delipidation Decrease in late adipose markers
Inflammatory phenotype
nc c
0.0
0.5
1.0
1.5
2.0
TG(g/L)
**
Adipocytes co-cultivated with tumor cells exhibit a reorientated phenotype
IL-6 IL-1b

9. « Cancer-Associated adipocytes »are also observed in human breast tumors

10. IL-6 plays a key role in the adipocyte driven pro-invasive effect
Recombinant IL-6 induces EMT
and increases invasiveness
Dramatic effect of blocking mIL-6 Ab
Coculture tumour cells /adipocytes
Tumor cells in the presence of CAA-CM

11. The Cancer-Associated Adipocytes (CAAs) contribute to breast cancer progression through
secretion of inflammatory molecules
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)
Mature
Adipocytes
Tumour cells
CAAs increase
Tumour growth
Tumour invasion (EMT)
Radioresistance
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 !
Reorientation
Autocrine secreted factors
 CCL20
 MIC-1
 IL-6
IL-6,
COLVI, MMP-11

12. Adipose progenitors also contribute to breast cancer progression through secretion of
inflammatory molecules
Adapted from Wang et al, Cancer Letters, 2012 (review)

13. Involvement of peri-tumoral adipose tissue into tumour progression through pro-
inflammatory molecules is not limited to breast cancer : tumor type specificities
Prostate cancer
No infiltration by inflammatory cells
No increase in circulating levels of IL-6
Reference : Finley et al, J Urol, 2009
Melanoma
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 ?

14. Normal
mature Adipocytes
Cancer-Associated
Adipocytes
Tumour cells
The Cancer-Associated Adipocytes (CAAs) contribute to tumour progression :
amplification in a context of obesity ?
Tumour cells
women and are characterized by frequent tumours at diagnosis
(positive lymph nodes involvement ) and
Obese
Mature Adipocytes

15. Presence of a sub-inflammatory state in visceral adipose tissue in obese conditions
Is this sub-inflammatory state observed in mammary adipose tissue ?

16. Obesity Is Associated with Inflammation in the Mouse Mammary Gland
Subbaramaiah et al. Cancer Prev Res 2011 : 329-346
Presence of CLS in MAT of obese mice Inflammatory state of the MAT of obese mice
Are these modifications found in the mammary gland of obese patients ????
Expression of inflammatory cytokines
NFkB activity

17. A first step in favor of this hypothesis : inflammatory mammary adipose tissue in
obese patients
Morris P G et al. Cancer Prev Res 2011;4:1021-1029
Presence of CLS in MAT of obese patients Hypertrophy of adipocytes in MAT from obese patients
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

18. 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

19. Inflammation of adipose tissue could also affect tumour progression through
endocrine mechanisms
Doyle et al, Proc Nutrition Soc, 2012

20. 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 ????

21. 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 of Pathology (CHU Rangueil)
Ghislaine Escourrou
AdipÔK
Group « Adipocyte secretions, Obesities and associated pathologies»
I2MC, Toulouse
Camille Attané
Danièle Daviaud
Cédric Dray
Sophie Le Gonidec
Philippe Valet
Acknowledgements
IbOX
Fondation
De France