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Abstract
Background: The close proximity of adipose tissue and mammary epithelium predispose involvement of adipose cells in breast cancer development. Adipose-tissue stem cells (ASCs) contribute to tumor stroma and promote growth of cancer cells. In our previous study, we have shown that murine ASCs, which undergo polyploidization during their prolonged in vitro culturing, enhanced the proliferation of 4T1 murine breast cancer cells in IGF1 dependent manner.Aims: In the present study, our aim was to clarify the regulation of ASC-derived IGF1.Methods: 4T1 murine breast carcinoma cells were co-transplanted with visceral fat-derived ASCs (vASC) or with the polyploid ASC.B6 cell line into female BALB/c mice and tumor growth and lung metastasis were monitored. The conditioned media of vASCs and ASC.B6 cells were subjected to LC-MS/MS analysis and the production of IGFBP2 was verified by Western blotting. The regulatory effect was examined by adding recombinant IGFBP2 to the co-culture of ASC.B6 and 4T1. Akt/protein kinase B (PKB) activation was detected by Western blotting.Results: Polyploid ASCs promoted the tumor growth and metastasis more potently than vASCs with normal karyotype. vASCs produced the IGF1 regulator IGFBP2, which inhibited proliferation of 4T1 cells. Downregulation of IGFBP2 by polyploidization of ASCs and enhanced secretion of IGF1 allowed survival signaling in 4T1 cells, leading to Akt phosphorylation.Conclusions: Our results implicate that ASCs in the tumor microenvironment actively regulate the growth of breast cancer cells through the IGF/IGFBP system.
Highlights
Nowadays, stem cell-based therapies are feasible tools for treatment of various diseases
Our results implicate that Adipose-tissue derived stem cells (ASCs) in the tumor microenvironment actively regulate the growth of breast cancer cells through the IGF/IGFBP system
To compare the tumor-promoting activity of ASCs, we co-injected 4T1 murine breast cancer cells with visceral fat-derived ASCs (vASC) at low passage number (p3) or with polyploid ASC.B6 cells into the mammary pad of female BALB/c mice
Summary
Stem cell-based therapies are feasible tools for treatment of various diseases. Fewer studies reach clinical phase II or beyond, and the first marketing authorization of an allogeneic stem cell therapy was approved in 2018 for the treatment of complex perianal fistulas in Crohn’s disease [3]. Many clinics use the so called stromal vascular fraction (SVF), isolated in a single step from the autologous adipose tissue [5]. This method avoids cell expansion in vitro; it escapes careful characterization of the utilized stem cell product. Adipose-tissue stem cells (ASCs) contribute to tumor stroma and promote growth of cancer cells. We have shown that murine ASCs, which undergo polyploidization during their prolonged in vitro culturing, enhanced the proliferation of 4T1 murine breast cancer cells in IGF1 dependent manner
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