Contribution of obese adipose tissue-derived stem cells to hepato-or breast-carcinoma inflammation, through promotion of Th17 cells and activation of IL-1b by monocytes
Résumé
Background and aims:
As opposed with lean adipose tissues (AT), obese AT are heavily infiltrated with variety of inflammatory cells such as macrophages and Th17 cells. Obesity-mediated chronic low-grade inflammation is known to contribute to tumor progression in various cancers, including hepatic and breast cancers. Because we have previous-ly demonstrated, using co-culture experiments, that obese AT-derived stem cells (obASC) contribute to AT inflammation through promotion of Th17 cells, and activation of IL-1β-secreting monocytes, we postulated herein that such inflammatory environment could contribute to tumor progression in cancer-suffering obese patients.
Materials and methods:
Human ASC were isolated from AT of obese donors. Mononuclear cells (MNC) were collected from healthy blood donors. Co-cultures of obASC and MNC were activated for 48 hours with phytohemagglutinin A ( PHA), a T cell mitogen, or not. Conditionned media (CM) were collected, and added for 24h to cultures of HuH7 (hepatocarinoma cell line) or of two breast carcinoma cell lines, i.e MCF-7, or MDA-MB-231. Levels of inflammatory or angiogenic gene expression were evaluated by qRT-PCR. Expression of CXCR4 (a marker of invasiveness) was measured by flow cytometry in the HuH7 cell line.
Results:
CM from PHA-activated-obASC/MNC co-cultures enhanced IL-1 β ,IL-8andVEGF α mRNA expression in HuH7 cells by 1942.2, 45.7 and 6.1 -fold, respectively, as compared with no treatment. A putative effect of CM on HuH7 invasiveness was supported by a 2- and 3-fold increase in MMP-9, and CXCR4 expression, respectively. In addition, IL-1β, IL-8 and VEGF-α mRNA expression were increased by 34.3, 33.2, and 2.97 fold respectively in MCF-7 cells, and by 85.8, 52.0 , and 1.34 fold respectively, in MDA-MB-231 cells. These results indicated thus a differential sensitivity of cancer cell lines to CM from PHA-activated-ob ASC/MNC co-cultures, with a preponderant increase of IL-1 β mRNA levels in hepatocarcinoma cells versus a similar increase of IL-1β and IL-8 gene expression in breast carcinoma cells.
Conclusion:
Our results suggest that in cancer-suffering obese patients, interaction of obASC with AT-infiltrating immune cells contribute to the establishment of an inflammatory environment, propitious to tumor inflammation and/or tumor migration. Whether this inflammation could occur through propagation of obese AT inflammatory environment towards tumors, or through migration of ASC inside tumors and then inter-action with tumor infiltrating immune cells, remain to be explored.