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Role of Cancer-Associated Adipocytes (CAAs) in cancer progression: a new link between obesity and cancer

Emerging evidences suggest that host factors contribute to the occurrence in obese women of tumors exhibiting aggressive biology defined by advanced stage and high grade and propensity to metastasis (for review, see Dirat et al. Endocrine Dev, 2010 ; Wang et al. Cancer Lett, 2012). Obesity is also associated with an increased risk of aggressive, widespread prostate cancers. This association is poorly understood but a paracrine role of adipocytes in stimulating tumour progression is an attractive hypothesis.

Tumor-surrounding adipocytes exhibit a specific and activated phenotype. We named these cells “Cancer-Associated Adipocytes”. CAAs contribute to breast tumor progression by stimulating local and distant invasion (Dirat et al. Endocrine Dev, 2010; Dirat et al. Cancer Res, 2011; Wang et al. Cancer Lett, 2012.)

 

Using an original 2D co-culture system, we have demonstrated that murine and human tumor cells co-cultivated with mature adipocytes exhibit increased invasive capacities in vitro and in vivo.

Adipocytes cultivated with cancer cells exhibit an altered phenotype in terms of delipidation and decreased adipocyte markers associated with the occurrence of an activated state characterized by over-expression of proteases, including MMP-11, and pro-inflammatory cytokines (IL-6, IL-1β). In the case of IL-6, we show that it plays a key role in the acquired pro-invasive effect by tumor cells. Equally important, we confirm the presence of these modified adipocytes in human breast tumors using immunohistochemistry and qPCR. Interestingly, the tumors of larger size and/or with lymph nodes involvement exhibit the higher levels of IL-6 in tumor surrounding adipocytes.

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Collectively, all our data bring in vitro and in vivo evidences that: i) invasive cancer cells dramatically impact surrounding adipocytes; ii) peri-tumoral adipocytes exhibit a modified phenotype and specific biological features sufficient to be named «Cancer-Associated Adipocytes (CAAs)», iii) CAAs modify the cancer cell characteristics/phenotype leading to a more aggressive behavior. Our team has been among the first to highlight the key role of mature adipocytes on cancer progression. As we reviewed recently (Wang et al. Cancer Letters, 2012), both components of adipose tissue (mature adipocytes and stem cells stimulate by different means tumor progression including stimulation of cancer local and distant invasion and resistance to chemotherapy and radiotherapy

 

Ongoing projects

  • Demonstrate the role of mature adipocytes in the desmoplastic reaction in breast cancers (Bochet, Lehuédé et al. submitted) 
  • Characterize the metabolic crosstalk between CAAs and cancer cells (Wang et al. in preparation) 
  • Evaluate if the bidirectional crosstalk between CAAs and breast cancer cells is amplified in obesity conditions using both in vitro 3D coculture systems, murine models and human tumours. 
  • Investigate the adipocyte/tumour cross-talk in prostate cancer and melanoma.
 

Publications

  • C. Muller, L. Nieto, P. Valet. (2013). Unraveling the local influence of tumor-surrounding adipose tissue on tumor progression: cellular and molecular actors involved. In “Obesity and Cancer” (Editor M. Kolonin, Springer edition (invited contribution) 
  • YY. Wang, C. Lehuédé, V. Laurent, S. Dauvillier, B. Dirat, L. Bochet, G. Escourrou, P. Valet, C. Muller. (2012). Adipose tissue and epithelial cancer cells: a dangerous dynamic duo in breast cancer. Cancer Letters 324:142-51 (invited review) 
  • L. Bochet, A. Meulle, S. Imbert, B. Salles, P. Valet, C. Muller. (2011). Cancer-associated adipocytes promote breast tumor radioresistance. Biochem Biophys Res Commun 411:102-6 
  • B. Dirat, L. Bochet, M. Dabek, D. Daviaud, S. Dauvillier, B. Majed, YY Wang, A. Meulle, B. Salles, S. Le Gonidec, I. Garrido, G. Escourrou , P. Valet, C. Muller, Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res 71:2455-2465 
  • B. Dirat, L. Bochet, G. Escourrou, P. Valet, C. Muller (2010). Unraveling the obesity and breast cancer links : a role for cancer-Associated Adipocytes ? Endocr Dev 19:45-52 (invited review). 
  • O. Masson, C. Chavey, C. Dray, A. Meulle, D. Daviaud, D. Quilliot, C. Muller, P. Valet, E. Liaudet-Coopman. (2009). LRP1 Receptor Controls Adipogenesis and Is Up-Regulated In Human and Mouse Obese Adipose Tissue. PLos One 4(10):e7422 
  • A. Meulle, B. Salles, D. Daviaud, P. Valet, C. Muller (2008). Positive regulation of DNA double strand break repair activity during adipogenesis: implication of the DNA dependent protein kinase. PLos One 3(10):e334