Human Adipocytes Stimulate Invasion of Breast Cancer MCF-7 Cells by Secreting IGFBP-2

Abstract

Background and AimsA better understanding of the effects of human adipocytes on breast cancer cells may lead to the development of new treatment strategies. We explored the effects of adipocytes on the migration and invasion of breast cancer cells both in vitro and in vivo.MethodsTo study the reciprocal effects of adipocytes and cancer cells, we co-cultured human mature adipocytes and breast cancer cells in a system devoid of heterogeneous cell-cell contact. To analyze the factors that were secreted from adipocytes and that affected the invasive abilities of breast cancer cells, we detected different cytokines in various co-culture media. To study the communication of mature adipocytes and breast cancer cells in vivo, we chose 10 metastatic pathologic samples and 10 non-metastatic pathologic samples to do immunostaining.ResultsThe co-culture media of human MCF-7 breast cancer cells and human mature adipocytes increased motility of MCF-7 cells. In addition, MMP-2 was remarkably up-regulated, whereas E-cadherin was down-regulated in these MCF-7 cells. Based on our co-culture medium chip results, we chose four candidate cytokines and tested their influence on metastasis individually. We found that IGFBP-2 enhanced the invasion ability of MCF-7 cells in vitro more prominently than did the other factors. In vivo, metastatic human breast tumors had higher levels of MMP-2 than did non-metastatic tumor tissue, whereas adipocytes around metastatic breast tumors had higher levels of IGFBP-2 than did adipocytes surrounding non-metastatic breast tumors.ConclusionsIGFBP-2 secreted by mature adipocytes plays a key role in promoting the metastatic ability of MCF-7 breast cancer cells.

Adipocyte lipolysis links obesity to breast cancer growth: adipocyte-derived fatty acids drive breast cancer cell proliferation and migration

“…Breast cancer cells exposed to adipocyte conditioned media, or in co-culture with adipocytes, have previously been shown to have modified proliferation, migration, and invasion [9, 12, 13, 46, 49–52]. Similar effects have been observed in 3-D cultures [53, 54] and xenograft models [13, 55].…”

“…Several studies have shown the role of endocrine and paracrine signaling mechanisms in driving adipocyte-cancer cell crosstalk [9, 12, 13]. We next sought to address the possibility that adipocyte-derived fatty acids could act as a metabolic stimulus on breast cancer cell proliferation and migration in vitro.…”

“…Further, there is close juxtaposition of adipocytes and breast cancer cells during early local invasion [8–10] and adipocytes are proposed to be obligate partners in cancer progression [11]. Adipocytes alter breast cancer cell growth, migration, and invasion in vitro [9, 12, 13]. However, most attention to date has focused on the production of hormones, growth factors, and cytokines by adipose tissue in tumor progression (see review [14]).…”

The potential role of leptin in tumor invasion and metastasis

“…In the breast tumor microenvironment, adipocytes have been reported to produce a number of biologically active compounds including different cytokines, e.g., MMP-11, plasminogen activator inhibitor-1 (PAI-1), collagen VI, IL-1β, IL-6, tumor necrosis factor – α (TNF-α), insulin-like growth factor-I (IGF-I), and leptin; many of which are metastasis-associated proteins [34–36]. In particular, Wolfson et al suggested that leptin has a key effect on breast cancer; and in adipocyte-adjacent breast cancer cells, due to stimulation of various regulatory pathways such as Notch, Wnt and Nanog signaling axis [37].…”

Transitions from mono- to co- to tri-culture uniquely affect gene expression in breast cancer, stromal, and immune compartments

“…targeted therapies such as tamoxifen, traztuzimab), an understanding of the crosstalk between cancer and non-cancer cells has proved to be less forthcoming in part because of limited models that allow dissection of the individual contributions of a complex cellular milieu. Simple co-culture models have been successfully implemented to identify factors mediating interactions between cancer and stromal compartments and point toward phenotypic changes that occur as a result (Wang et al 2015; Furukawa et al 2015; Wan et al 2014; Hollmén et al 2015; Rozenchan et al 2009; Straussman et al 2012). However, more complex in vitro models incorporating aspects of the microenvironment such as dimensionality (Weigelt et al 2014; Thoma et al 2014; Sung et al 2013; Krishnan et al 2011; Bin Kim et al 2004) and structure (Bischel et al 2015; Pisano et al 2015; Zervantonakis et al 2012; Choi et al 2015) have more successfully recreated functional responses of breast cancer seen in vivo .…”