Polyploid Adipose Stem Cells Shift the Balance of IGF1/IGFBP2 to Promote the Growth of Breast Cancer

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. Keywords: adipose stem cells, breast cancer, tumor stroma, insulin-like growth factor 1, insulin-like growth factor binding protein 2

A Multilevel Approach to the Causes of Genetic Instability in Stem Cells

“…There are also evidences that points to a stable proportion of aneuploid subclones that could be increased in ASC cultures up to 16 passages (7.1%) and further during senescence (19.%), but without acquire tumorigenic capacity as was tested in nude mice (Roemeling-van Rhijn et al 2013). Emergence of polyploidy may enhance cancer cell proliferation as have been reported in a murine model, where the polyploid ASCs was more efficient promoting breast tumor growth and metastasis than ASCs, derived from visceral adipocytes with a normal karyotype (Fajka-Boja et al 2020). It must be stressed that quiescence of MSCs favors the generation and accumulation of genetic alterations that may result in genetic instability, especially after genotoxic insults.…”

Imidazo[1,2-b]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells

“…The weights of the spleens were as follows in the naïve; 99, 8, 13, 14, and 12 mg, and in the tumor-bearing mice; 781, 812, 968, 1350, and 935 m. The weights of the tumors were as follows; 2523, 3037, 2064, 2877, and 1522 mg; the volume of the tumors were as follows; 1272, 1329, 650, 1573, and 807 mm 3 after 28 days from the injection. The volume of the tumor was measured by a caliper and calculated by the following equation; D × d 2 × 0.5 , where D = major diameter, d = minor diameter as we described previously for the 4T1 breast cancer model [ 79 , 80 ]. After euthanizing the animals, the spleens were removed and homogenized freshly on cell strainer (70 μm pore size, Merck Millipore) using piston of a syringe and sterile PBS.…”

Adipose tissue-derived stem cells in breast reconstruction: a brief review on biology and translation

“…However, no matter ADSCs were isolated from breast cancer adjacent adipose, benign breast tumor adjacent adipose, or normal breast adipose, all cells were able to promote the proliferation of MCF-7 breast cancer cells in vitro, and cancer-associated ADSCs seemed to exhibit more significant effect than ADSCs from normal fat tissue [ 88 ]. Multiple signaling pathways such as HGF/c-Met, miR20b, and IGF1/IGFBP2 are involved in the process of ADSCs promoting tumor cell proliferation [ 89 – 91 ]. ADSCs can also upregulate the epithelial-mesenchymal transition markers of breast cancer cells, such as fibronectin, alpha smooth muscle actin, and vimentin, and promote the ability of tumor metastasis and invasion [ 89 , 92 , 93 ].…”