Human periprostatic adipose tissue promotes prostate cancer aggressiveness in vitro

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Background

Obesity is associated with prostate cancer aggressiveness and mortality. The contribution of periprostatic adipose tissue, which is often infiltrated by malignant cells, to cancer progression is largely unknown. Thus, this study aimed to determine if periprostatic adipose tissue is linked with aggressive tumor biology in prostate cancer.

Methods

Supernatants of whole adipose tissue (explants) or stromal vascular fraction (SVF) from paired fat samples of periprostatic (PP) and pre-peritoneal visceral (VIS) anatomic origin from different donors were prepared and analyzed for matrix metalloproteinases (MMPs) 2 and 9 activity. The effects of those conditioned media (CM) on growth and migration of hormone-refractory (PC-3) and hormone-sensitive (LNCaP) prostate cancer cells were measured.

Results

We show here that PP adipose tissue of overweight men has higher MMP9 activity in comparison with normal subjects. The observed increased activities of both MMP2 and MMP9 in PP whole adipose tissue explants, likely reveal the contribution of adipocytes plus stromal-vascular fraction (SVF) as opposed to SVF alone. MMP2 activity was higher for PP when compared to VIS adipose tissue. When PC-3 cells were stimulated with CM from PP adipose tissue explants, increased proliferative and migratory capacities were observed, but not in the presence of SVF. Conversely, when LNCaP cells were stimulated with PP explants CM, we found enhanced motility despite the inhibition of proliferation, whereas CM derived from SVF increased both cell proliferation and motility. Explants culture and using adipose tissue of PP origin are most effective in promoting proliferation and migration of PC-3 cells, as respectively compared with SVF culture and using adipose tissue of VIS origin. In LNCaP cells, while explants CM cause increased migration compared to SVF, the use of PP adipose tissue to generate CM result in the increase of both cellular proliferation and migration.

Conclusions

Our findings suggest that the PP depot has the potential to modulate extra-prostatic tumor cells' microenvironment through increased MMPs activity and to promote prostate cancer cell survival and migration. Adipocyte-derived factors likely have a relevant proliferative and motile role.

Related collections

Most cited references 45

Record: found
Abstract: found
Article: not found

Endocrine and signalling role of adipose tissue: new perspectives on fat.

P Trayhurn (2005)

White adipose tissue (WAT) is now recognized as a major endocrine and secretory organ, releasing a wide range of protein factors and signals termed adipokines - in addition to fatty acids and other lipid moieties. A paradigm shift came with the discovery of leptin, a pleiotropic hormone which is a critical signal to the hypothalamus in the control of appetite and energy balance. A number of adipokines, including adiponectin, tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-8, IL-10, monocyte chemoattractant protein-1, macrophage migration inhibitory factor, nerve growth factor, vascular endothelial growth factor, plasminogen activator inhibitor-1 and haptoglobin, are linked to inflammation and the inflammatory response. Obesity is characterized by a state of mild inflammation, and the expression and release of inflammation-related adipokines generally rises as adipose tissue expands; a notable exception is adiponectin, with its anti-inflammatory action, the levels of which fall. WAT may be the main site of inflammation in obesity, increased circulating levels of inflammatory markers reflecting spillover from an 'inflamed' tissue, leading to the obesity-associated pathologies of type 2 diabetes and the metabolic syndrome. From the wide range of adipokines now identified, it is evident that WAT is highly integrated into overall physiological regulation, involving extensive crosstalk with other organs and multiple metabolic systems. Whether major changes in adipokine production in obesity, particularly of those factors linked to inflammation, are unique to this condition, or are a feature of all situations in which there are substantial increases in adipose mass (such as pregnancy, and pre-hibernatory and pre-migratory fattening) requires consideration.

0 comments Cited 107 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Stromelysin-3 is a potent negative regulator of adipogenesis participating to cancer cell-adipocyte interaction/crosstalk at the tumor invasive front.

Isabelle Stoll, E R Motrescu, Kumari Andarawewa … (2005)

The initial invasive processes during cancer development remain largely unknown. Stromelysin-3/matrix metalloproteinase 11 (ST3/MMP11) is associated with tumor invasion and poor prognosis. We present novel evidence that adipocytes present at human breast tumor invasive front are induced by cancer cells to express ST3. Using mouse syngeneic model, light and electron microscopy showed that in ST3-deficient mice but not in wild-type mice, forced cancer cell-adipocyte interaction/crosstalk results in adipocyte membrane alteration, allowing cancer cell fat infiltration and death. Thus, adipocytes are involved in initial cancer cell survival into connective tissue, and this effect is ST3 mediated. This suggested that ST3 might play a role in adipocyte metabolism. Accordingly, ST3-deficient mice exhibited fat excess and increased mRNA levels of peroxisome proliferator-activated receptor gamma (PPARgamma) and adipocyte protein 2 (aP2) adipogenic markers, indicating that, in vivo, ST3 negatively regulates fat homeostasis. Moreover, ST3-deficient mouse embryonic fibroblasts exhibited a dramatic enhanced potential to differentiate into adipocytes associated with increased PPARgamma and aP2 expression, and recombinant ST3 treatment reverted their differentiation. Thus, in vitro, ST3 reduces adipocyte differentiation in an autocrine manner. High fibroblasts/adipocytes ratio is a stroma feature, and peritumoral fibroblast origin remains debated. Our results support the concept that invading cancer cells aberrantly restore the negative ST3 function on adipogenesis into proximal adipocytes/preadipocytes, leading to the accumulation/maintenance of a particular peritumoral fibroblast subpopulation. Accordingly, in human breast tumors, we observed that ST3-expressing peritumoral fibroblasts are distinct from alpha-smooth muscle actin-expressing myofibroblasts. This constitutes the first report of implication of a MMP in cancer cell-adipocyte interaction/crosstalk during early steps of connective tissue invasion.

0 comments Cited 69 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Molecular insights into prostate cancer progression: the missing link of tumor microenvironment.

Leland Chung, Adam G Baseman, Vasily Assikis … (2004)

Tumor cell genotype and phenotype have been considered the only determinants supporting cancer growth and metastasis. This review focuses on the published literature that suggests that tumor-microenvironment interaction has a decisive role in controlling local cancer growth, invasion and distant metastasis. As this review shows, genetic alterations in prostate cancer cells alone are not enough to confer metastatic status without a supporting tumor microenvironment. Effective therapeutic targeting requires a deeper understanding of the interplay between tumor and stroma. Approaches co-targeting tumor and stroma already show promise over the conventional targeting of tumor cells alone in preventing prostate cancer progression and eradicating preexisting or newly developed prostate cancers in bone and visceral organs. A literature survey using the MEDLINE database was performed in basic and clinical publications relevant to tumor-host microenvironment interaction. Information pertinent to the biology and therapy of prostate cancer local growth and distant metastases was specifically emphasized. Tumor associated stroma actively fuel the progression of prostate cancer from localized growth to the invasion of surrounding tissues, and the development of distant bone and visceral organ metastasis. In concert with this progression tumor cells recovered from metastatic sites could represent a subpopulation of preexisting tumor cells or could be a newly acquired variant subsequent to tumor-stromal interaction. Experimental data from our laboratory and others suggest that permanent genetic and phenotypic changes occur in prostate cancer cells after 3-dimensional co-culture in vitro or when co-inoculated and grown with inductive stromal cells in vivo. These results support the idea that newly acquired variants are the dominant mechanism of prostate cancer progression. Intercellular communication between prostate cancer cells and organ specific stroma, including prostate and marrow stroma, could involve diffusible soluble and solid matrix molecules as mediators, leading to the development of metastasis. This presents a new opportunity for therapeutic targeting for the treatment of benign and malignant growth of the prostate glands. This review summarizes specific research implicating tumor-microenvironment interaction as the molecular basis of cancer progression, providing a rationale for targeting tumor and the tumor associated microenvironment in the management of androgen independent and bone metastatic prostate cancer progression in patients. Cancer is not a single cell disease. Aberrant cancer cells and their interactive microenvironment are needed for prostate cancer to progress to androgen independence and distant metastasis. It is highly plausible that newly evolved prostate cancer cell clones dominate cancer metastasis after cell-cell and cell-matrix interaction with the host microenvironment, rather than the selection or expansion of a preexisting prostate cancer cell clone(s). Based on this premise potential molecular targets in the microenvironment are especially emphasized. Further elucidation of the molecular mechanisms underlying tumor-stromal interaction may yield improved medical treatments for prostate cancer growth and metastasis.

0 comments Cited 69 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Journal ID (iso-abbrev): J. Exp. Clin. Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date Collection: 2012

Publication date (Electronic): 2 April 2012

Volume: 31

Issue: 1

Page: 32

Affiliations

[1 ]Molecular Oncology Group-CI, Portuguese Institute of Oncology, Porto, Portugal

[2 ]Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal

[3 ]Research Department-Portuguese League Against Cancer (NRNorte), LPCC, Porto, Portugal

[4 ]Biomaterials Division, NEWTherapies Group, INEB, Porto, Portugal

[5 ]Department of Pathology and Oncology, Faculty of Medicine, Porto, Portugal

[6 ]General Pathology Laboratory, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

[7 ]CIMAGO, Centre of Investigation in Environment, Genetics and Oncobiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

[8 ]CNC, Centre of Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal

[9 ]Urology Department, Porto Hospital Centre, Porto, Portugal

[10 ]Urology Department, Porto Military Hospital, Porto, Portugal

[11 ]Urology Department, Portuguese Institute of Oncology, Porto, Portugal

[12 ]Urology Department, S. João Hospital, Porto, Portugal

[13 ]Molecular Oncology Group - CI, Portuguese Institute of Oncology, Porto Centre, Edifício Laboratórios - Piso 4, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal

Article

Publisher ID: 1756-9966-31-32

DOI: 10.1186/1756-9966-31-32

PMC ID: 3379940

PubMed ID: 22469146

SO-VID: fadc3806-7c69-49d8-a422-db34357bbb32

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 23 February 2012

Date accepted : 2 April 2012

Comments

Comment on this article

scite_

Cited by 52

See all cited by

Human periprostatic adipose tissue promotes prostate cancer aggressiveness in vitro

Read this article at

Abstract

Background

Methods

Results

Conclusions

Related collections

Karger: Oncology

Most cited references 45

Endocrine and signalling role of adipose tissue: new perspectives on fat.

Stromelysin-3 is a potent negative regulator of adipogenesis participating to cancer cell-adipocyte interaction/crosstalk at the tumor invasive front.

Molecular insights into prostate cancer progression: the missing link of tumor microenvironment.

Author and article information

Journal

Affiliations

Article

History

Categories

Comments

Comment on this article

Similar content 214

Cited by 52