Interleukin-6 (IL-6) is a pleiotropic cytokine that is produced by fibroblasts, macrophages and lymphocytes. IL-6 is important in the regulation of local oestrogen biosynthesis in breast tissues by activating enzymes involved in oestrogen synthesis: aromatase, oestradiol 17p-hydroxysteroid dehydrogenase and estrone sulfatase (Speirs et al. 1993; Duncan et al. 1994; Singh et al. 1995; Newman et al. 2000). In vitro, IL-6 can activate ERa in primary breast cancer cells (Speirs et al. 2000). Prostaglandin E2 (PGE2) can have similar stimulatory effects on oestrogen synthesis and also regulates IL-6 production in fibroblasts (Singh et al. 1999; Zhang et al. 1988).
The significance of IL-6 in breast cancer is not clear (Knüpfer and PreiB 2007) probably due to its multiple variable effects. The in vitro data, its ability to regulate local oestrogen synthesis and its expression in stromal cells of breast cancers suggest that further studies to investigate whether it has a role in endocrine resistance as indicated.
Interactions between cancer cells and the tumour microenvironment are dynamic, involving cross talk. Analysing the effect of stromal cells on cancer cells can be done in several ways: culture with conditioned medium from stromal cells; two dimensional co-culture of stromal cells and cancer cells; three dimensional model of stromal cells and cancer cells within a stroma; in vivo animal models. Co-culture experiments can provide useful data but in order to recapitulate what is happening in a human breast cancer a three dimensional model (Nelson and Bissell 2005) or in vivo model is required. The following describes two recent studies that have used models to assess the microenvironment and endocrine resistance, plus some preliminary data (Hiscox and Walker, unpublished data).
5.4.1 Effect of Fibroblast Conditioned Medium on Cell Migration of Resistance Cells
In order to extend studies of the effect of stromal cells on migration of Fulvestrant resistant MCF-7 cells (Hiscox et al. 2006) wild type MCF-7, tamoxifen resistant MCF-7 and Fulvestrant resistant MCF-7 were cultured with fibroblast conditioned medium from four separate donors. These were all from fibroblasts isolated from reduction mammoplasties from women 18-45 yrs (median 26yrs) after two to four passages. Figure 5.1 shows that all conditioned media result in increased migration of the resistant cells compared to wild type, with effects being greater on tamoxifen resistant cells. Since there is evidence of increased c-Met in Fulvestrant resistant cells then analysis of this in the tamoxifen resistant cells needs to be undertaken. Comparison with conditioned medium from TAFs will be of interest in view of the differences identified in fibroblasts from tumour and normal breast.
5.4.2 Three Dimensional Co-Culture of Breast Tumour Fibroblasts and Tamoxifen Sensitive and Resistant Cells
Shekvar et al. (2007) co-cultured fibroblasts from ER and Progesterone receptor (PgR) negative and ER and PgR positive cancers with premalignant (EIII8) and cancer (MCF-7) tamoxifen sensitive cells and EIII8 tamoxifen resistant cells within matrigel as ECM. They found that EIII8 sensitive cells became resistant when cultured with fibroblasts from ER and PgR negative cancers but that this was not mediated by EGFR or IGFR1. All cells exhibited an altered epithelial morphology on
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