Human Adipose Tissue Macrophages Display Activation of Cancer-related Pathways

Thérèse Hérvée Mayi,Mehdi Daoudi,Bruno Derudas,Barbara Gross,Gael Bories,Kristiaan Wouters,John Brozek,Robert Caiazzo,Violeta Raverdi,Marie Pigeyre,Paola Allavena,Alberto Mantovani,François Pattou,Bart Staels,Giulia Chinetti-Gbaguidi

doi:10.1074/jbc.m111.315200

Abstract

Obesity is associated with a significantly increased risk for cancer suggesting that adipose tissue dysfunctions might play a crucial role therein. Macrophages play important roles in adipose tissue as well as in cancers. Here, we studied whether human adipose tissue macrophages (ATM) modulate cancer cell function. Therefore, ATM were isolated and compared with monocyte-derived macrophages (MDM) from the same obese patients. ATM, but not MDM, were found to secrete factors inducing inflammation and lipid accumulation in human T47D and HT-29 cancer cells. Gene expression profile comparison of ATM and MDM revealed overexpression of functional clusters, such as cytokine-cytokine receptor interaction (especially CXC-chemokine) signaling as well as cancer-related pathways, in ATM. Comparison with gene expression profiles of human tumor-associated macrophages showed that ATM, but not MDM resemble tumor-associated macrophages. Indirect co-culture experiments demonstrated that factors secreted by preadipocytes, but not mature adipocytes, confer an ATM-like phenotype to MDM. Finally, the concentrations of ATM-secreted factors related to cancer are elevated in serum of obese subjects. In conclusion, ATM may thus modulate the cancer cell phenotype.

Highlights

Obesity increases the risk for cancer development, suggesting that adipose tissue dysfunctions might play a crucial role therein
Indirect co-culture experiments were performed on human T47D breast cancer and HT-29 colon adenocarcinoma cells in the presence of conditioned media (CM) from adipose tissue macrophages (ATM) or monocyte-derived macrophages (MDM) isolated from the same obese subjects
These results indicate that ATM-CM, but not MDM-CM can modulate the phenotype of human cancer cells

Summary

Background

Obesity increases the risk for cancer development, suggesting that adipose tissue dysfunctions might play a crucial role therein. We found that conditioned medium from ATM, but not from autologous monocyte-derived macrophages (MDM) isolated from the same morbidly obese patients, induced phenotypic changes and activation of human breast cancer cells. We show that the ATM phenotype is programmed by the cellular environment as demonstrated by indirect co-culture experiments applying the preadipocyte-conditioned media to MDM from lean subjects, resulting in an ATM-like phenotype These data indicate that the TAM-like human ATM phenotype is directed by surrounding cell types and suggest that factors released by ATM may contribute to cancer initiation and progression in obese patients. These observations suggest that ATM may be potential contributors to cancer development in obese humans

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION