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Dissemination of prostate cancer: a way paved of fat

After lung cancer, prostate cancer is the second leading cause of death by cancer in men. Although the incidence of this cancer is increasing, relatively little is known about the molecular mechanisms involved in the development and progression of the disease. Of note, obesity is associated with aggressive diseases with increased local and distant dissemination.
The prostate is surrounded by a fat depot named periprostatic adipose tissue (PPAT) that is, like other fat depots, an active endocrine organ. Clinically, PPAT infiltration by tumor cells is a major histological criterion of poor prognosis in prostate cancer. During local dissemination, this adipose depot appears to be a key emerging actor, although limited data are currently available. We have shown that PPAT, through an original CCR3/CCL7 axis, favors the homing of cancer cells outside of the prostate gland. This effect is amplified in obesity and controls the local dissemination of prostate cancer in vivo (as shown using animal models and annotated collections of human cancers) (Laurent et al, Nature Comm, 2016). We recently showed that the CCR3/CCL7 axis is also involved in bone metastasis as bone-marrow adipocytes secrete CCL7, which increases prostate cancer directed migration in a CCR3 dependent-manner, and this effect is amplified with ageing and obesity. Human bone metastasis are enriched in CCR3 expressing cells as compared to primary or other metastatic sites. (Guerard et al, Intern J Mol Sci, 2021). These results underline the clinical importance of CCR3 in the progression of prostate cancer.

 

 

 Once tumor cells have invaded the PPAT, a bidirectional crosstalk is established between cancer cells and adipocytes. We reported that tumor cells induce lipolysis in adipocytes and the liberated free fatty acids (FFAs) are taken up and stored in tumor cells. Indeed, accumulated FFAs stimulate the expression of pro-oxidant enzymes contributing to increased intra-cellular reactive oxygen species that in turns increases the invasive potential of tumor cells. In obese conditions, tumor-surrounding adipocytes activate this signaling pathway to a higher extent and induce further increased tumor invasion in vitro and in vivo. Of importance, human tumor analysis revealed that pro-oxidant enzymes expression is highly upregulated at the tumor invasive front where cancer cells are in close proximity to adipocytes and, this process is exacerbated by obesity, highlighting the clinical relevance of our results (Laurent et al, Mol Cancer Res. 2019). Our work emphasizes the key role of adipocytes in prostate cancer local dissemination and proposes new molecular targets for the treatment of obese patients exhibiting aggressive diseases.  We have recently reviewed the role of PPAT in prostate cancer dissemination (Estève et al, Curr Opin Endocr Met Res, 2020)

Moreover, abnormal accumulation of periprostatic adipose tissue (PPAT) is an emerging risk factor of aggressive prostate cancer. The link between these two events being only correlative we are currently performing the biological characterization of these abundant PPAT in patients undergoing prostatectomy for prostate cancer.  This project has been funded by the French National Cancer Institute (INCA), ARC and the Ligue Nationale contre le Cancer.

 

Principal investigators:

Delphine Milhas and Catherine Muller


Other staff involved:

David Estève (post-doc fellow of the Fondation pour la Recherche Médicale), Yiyue Jia (PhD student fellow of the Chinese Research Council), Mathieu Roumiguié (PhD student, clinical Urologist), Stéphanie Dauvillier (Engineer), Cynthia Houel (Engineer Fellow of the National Cancer Institute),

 

Selected publications:

  • Laurent V et al, 2016. Dissemination of prostate cancer: a way paved of fat. Med Sci (Paris) (invited review)
  • Laurent V et al, 2016. Periprostatic adipose tissue acts as a driving force for the local invasion of prostate cancer in obesity: role of the CCR3/CCL7 axis. Nature Comm (Highlights in Nature Reviews Cancer and Nature Reviews Urology, Top 1% Web of Science)
  • Laurent V*, Toulet A* et al, 2019. Periprostatic adipose tissue favors prostate cancer cell invasion in an obesity-dependent manner: role of oxidative stress. Mol Cancer Res.
  • Estève et al, 2020. Periprostatic adipose tissue a heavy player in prostate cancer progression. Curr Opin Endocr Met Res (invited review)

 

Collaborators:

Pr Philippe Valet’s group at the Institute RESTORE, Toulouse
Dr Anne Bouloumié’s group at the Institute of Metabolic and Cardiovascular diseases (I2MC), Toulouse
Dr Sarah Pericart, Pathology Department of the University Toulouse Cancer Center (headed by Pr P. Brousset)
Surgeons (Dr Mathieu Roumiguié and Pr Bernard Malavaud) and radiologists (Dr Daniel Portalez) of the University Toulouse Cancer Center