Human Adipose Tissue-Derived Stromal/Stem Cells Promote Migration and Early Metastasis of Triple Negative Breast Cancer Xenografts

Abstract

BackgroundFat grafting is used to restore breast defects after surgical resection of breast tumors. Supplementing fat grafts with adipose tissue-derived stromal/stem cells (ASCs) is proposed to improve the regenerative/restorative ability of the graft and retention. However, long term safety for ASC grafting in proximity of residual breast cancer cells is unknown. The objective of this study was to determine the impact of human ASCs derived from abdominal lipoaspirates of three donors, on a human breast cancer model that exhibits early metastasis.Methodology/Principal FindingsHuman MDA-MB-231 breast cancer cells represents “triple negative” breast cancer that exhibits early micrometastasis to multiple mouse organs [1]. Human ASCs were derived from abdominal adipose tissue from three healthy female donors. Indirect co-culture of MDA-MB-231 cells with ASCs, as well as direct co-culture demonstrated that ASCs had no effect on MDA-MB-231 growth. Indirect co-culture, and ASC conditioned medium (CM) stimulated migration of MDA-MB-231 cells. ASC/RFP cells from two donors co-injected with MDA-MB-231/GFP cells exhibited a donor effect for stimulation of primary tumor xenografts. Both ASC donors stimulated metastasis. ASC/RFP cells were viable, and integrated with MDA-MB-231/GFP cells in the tumor. Tumors from the co-injection group of one ASC donor exhibited elevated vimentin, matrix metalloproteinase-9 (MMP-9), IL-8, VEGF and microvessel density. The co-injection group exhibited visible metastases to the lung/liver and enlarged spleen not evident in mice injected with MDA-MB-231/GFP alone. Quantitation of the total area of GFP fluorescence and human chromosome 17 DNA in mouse organs, H&E stained paraffin sections and fluorescent microscopy confirmed multi-focal metastases to lung/liver/spleen in the co-injection group without evidence of ASC/RFP cells.ConclusionsHuman ASCs derived from abdominal lipoaspirates of two donors stimulated metastasis of MDA-MB-231 breast tumor xenografts to multiple mouse organs. MDA-MB-231 tumors co-injected with ASCs from one donor exhibited partial EMT, expression of MMP-9, and increased angiogenesis.

Adipose-Derived Stems Cells and Their Role in Human Cancer Development, Growth, Progression, and Metastasis: A Systematic Review

“…All studies included in this review were published in English or had an expanded abstract in English. Investigations that used mixed animal and human cells in vivo were included, for example, those using human ASCs in mice to study tumor behavior (38,39). Special attention was given to peer-reviewed articles that explicitly addressed the relationship between human cancer development, growth, metastasis, and ASCs.…”

Human Adipose-Derived Mesenchymal Stromal Cells May Promote Breast Cancer Progression and Metastatic Spread

“…17,28 Recently, Rowan et al found significantly increased multiorgan spreading of MDA tumors and partial epithelialto-mesenchymal transition after local addition of human adipose-derived mesenchymal stromal cells; however, in contrast to earlier reports, they found no increase of breast cancer cell growth. 16 In our study, we could demonstrate dose-dependent effects, which may have a high impact on the clinical scenario.…”

“…[8][9][10] Because of these functionalities, local and migrating stem cells have been suspected to endorse breast cancer development. 11,12 Suggested by reports, adipose-derived mesenchymal stromal cells, and more in general mesenchymal stem cells, can promote progression and metastasis of breast cancer [13][14][15][16][17] through homing of stem cells to tumors as an evident process. [18][19][20] Cytokines and chemokines might play a role in breast cancer growth, 21,22 metastasis, or recurrence, with growing evidence that growth and progression of breast tumors depend on their microenvironment as well.…”

Effect of adipose-derived stem cell-conditioned medium on the proliferation and migration of B16 melanoma cells

“…However, numerous studies have demonstrated the anti-proliferative or anti-tumorigenic effects of ASCs. For example, preconditioned endothelial progenitor cells have been observed to reduce melanoma metastasis by cell-cell interactions induced by secreted protein, acidic and rich in cysteine, as well as endocytosis (9). Human ESCs have been reported to secrete soluble factors that arrest the growth of human epithelial cancer cell lines (10).…”

“…A similar tumorigenic effect was observed in human prostate (6) and breast (7) cancer cells in mice. Furthermore, co-culture of ASCs enhanced the proliferation of human squamous cell carcinoma cells (8) and the migration of breast cancer cells in a xenograft model (9). However, conversely, numerous studies have reported suppressive effects of ASCs on tumorigenesis.…”