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Role of tumor surrounding adipocytes in breast cancer progression: new links between obesity and cancer

 

Growing evidence indicates that obesity is associated with increased breast cancer risk after menopause and may act as a negative prognostic factor influencing breast cancer recurrence and survival independently of menopausal status. Our studies point to a role for the mammary adipose tissue (MAT) adjacent to tumors in breast cancer development and progression.

Using in vitro coculture and in vivo approaches, we have shown that invasive cancer cells dramatically impact surrounding adipocytes that exhibit loss of differentiation markers, delipidation and an activated phenotype marked by the overexpression of pro-inflammatory cytokines, extracellular matrix proteins and proteases. We named these adipocytes «Cancer-Associated Adipocytes (CAA) », a term that is now used by the scientific community (Dirat et al, Cancer research 2011, Top 1% Web of science).

muller_topic01.pngModification of size and lipid content of adipocytes at the invasive front of a human breast cancer (HE staining) © Ghislaine Escourrou

Muller Topic 1,2.pngTwo representative cases of MAT from obese patients showing the IL6 positive expression of macrophages surrounding necrotic adipocytes (x200 magnification (A-B) and x400 zoom (A’-B’) © Charlotte Vaysse

Upon prolonged exposure to tumor secretions, more dramatic phenotypical changes occur to generate fibroblast-like cells termed ‘adipocyte-derived fibroblasts’ (ADF), showing that adipocytes contribute to a sub-population of Cancer Associated Fibroblasts (Bochet et al, Cancer Research, 2011). In turn, CAAs and ADFs modify cancer cell characteristics/phenotype, leading to increased cell invasiveness, the pro-inflammatory cytokine, interleukin 6, being involved in this effect. Our latest results demonstrate that free fatty acids (FFAs) released by adipocytes are uptaken by tumor cells and modulate tumor metabolism in favor of fatty acid oxidation, a metabolic shift that also stimulates tumor invasion (Wang et al, JCI Insight, 2017). Therefore, our results support the innovative concept that adipocytes participate in a highly complex vicious cycle orchestrated by cancer cells to support tumor progression, which might be amplified in obese patients. In contrast to other adipose depots, the changes induced by obesity in MAT are not well known. In collaboration with the Cancer centre of the Oslo University hospital, we recently demonstrated that, like for sub-cutaneous and visceral AT, overweight and obesity are associated with the occurrence of a sub-inflammatory state in MAT marked by the appearance of Crown-Like Structures (pro-inflammatory macrophages surrounding necrotic adipocytes) (Vaysse et al, NPG Breast Cancer, 2017). We plan to perform an extensive characterization of MAT in obese versus lean patients (infiltration by other immune cells, secretome of adipocytes) that will, in addition to a novel 3D coculture system with primary adipocytes, allow us to identify the key molecular events characterizing the adipocyte/tumor crosstalk in obesity.

Principal investigators

Frederique Fallone, Charlotte Vaysse, and Catherine Muller

Other staff involved:

Xia Li, Stéphanie Dauvillier

Selected publications

Vaysse C, Lomo J, Garred O, Fjeldheim, Lofteroed T, Schlichting E, McTiernan A, Frydenberg H, Husoy A, Lundgren S, Fagerlang MW, Wist EA, Muller C, Thune I. Inflammation of mammary adipose tissue occurs in overweight and obese patients exhibiting early-stage breast cancer. NPG Breast Cancer (in press). 

Wang YY, Attané C, Milhas D, Dirat D, Dauvillier S, Guerard A, Gilhodes J, Lazar I, Alet N, Laurent V, Le Gonidec S, Biard D, Hervé C, Bost F, Ren GS, Bono F, Escourrou G, Prentki M, Nieto L, Valet P, Muller C (2017). Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells. JCI Insight 2: e87489. doi :10.1172

Laurent V, Nieto L, Valet P, Muller C (2014). Adipose tissue and cancer: a high risk tandem. Med Sci (Paris) 30:398-404 (review upon invitation, in french)

Bochet L, Lehuede C, Dauvillier S, Wang YY, Dirat B, Laurent V, Dray C, Guiet R, Maridonneau-Parini I, Le Gonidec S, Couderc B, Escourrou G, Valet P, Muller C (2013). Adipocyte-Derived Fibroblasts promote tumor progression and contribute to desmoplastic reaction in breast cancer. Cancer Research, 73:5657-68

Wang YY., Lehuédé C., Laurent V., Dauvillier S., Dirat B., Bochet L., Escourrou G., Valet P., Muller C. (2012). Adipose tissue and epithelial cancer cells: a dangerous dynamic duo in breast cancer. Cancer Letters, 324:142-51 (invited review)

Dirat B., Bochet L., Dabek M., Daviaud D., Dauvillier S., Majed B., Wang YY, Meulle A., Salles B., Le Gonidec S., Garrido I., Escourrou G., Valet P., Muller C. (2011), Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion, Cancer Research, 71: 2455-2465 (Top 1 % Web of science).

 

Collaborators

Pr Philippe Valet’s group at the Institute of Metabolic and Cardiovascular diseases (I2MC), Toulouse (see Adipolab web page http://adipolab.weebly.com/)

Pathology Department of the University Toulouse Cancer center (headed by Pr P. Brousset)

Dr Inger Thune, Cancer Centre, Oslo University Hospital, Oslo.