Mammary Stroma & Conjugated Linoleic Acid

#B177 The Mammary Stroma as a Target for the Chemopreventive Activity of Conjugated Linoleic Acid.

Margot Ip, Patricia A. Masso-Welch, Clement Ip, Danilo Zangani,

Roswell Park Cancer Inst., Buffalo, NY.

Conjugated linoleic acid (CLA) has been shown to have marked chemopreventive activity in rat mammary carcinogenesis models.

In part, CLA exerts this effect by acting directly on the mammary epithelium to inhibit DNA synthesis and stimulate apoptosis.

The objective of our current studies has been to determine if CLA might also act indirectly, by modifying the mammary stroma.

To examine this, we investigated the effect of CLA on a multipotent stromal-vascular cell (MSC) population which is present in the rat mammary gland, and which is able to acquire a fibroblastic, adipocyte or endothelial phenotype, depending on culture conditions (Zangani et al, Differentiation 64: 91, 1999).

In these in vitro experiments, t10,c12-CLA was found to be a potent adipogenic factor, stimulating MSC to the adipogenic differentiation pathway even in the absence of exogenous hormonal supplementation; c9,t11-CLA was less effective.

This effect of CLA was accompanied by a rapid loss in the DNA-binding activity of the PPARã/RXRá heterodimeric transcription factor complex, suggesting that PPARã may play a key role in initiating the recruitment of MSC into the adipogenic pathway.

DNA-binding activity of other transcription factors examined was not decreased, demonstrating the specificity of this response.

Significantly, concurrent with MSC differentiation along the adipogenic lineage, there was a decreased ability of MSC to form microcapillary networks in vitro on an EHS tumor-derived reconstituted basement membrane (RBM).

This suggested that CLA might inhibit angiogenesis in vivo.

To test this, mice were fed diets with or without CLA for 6 weeks, and then injected subcutaneously with an angiogenic gel substrate composed of RBM supplemented with bFGF and heparan sulfate.

One week later, the RBM pellets were harvested and examined histologically.

These studies demonstrated that functional angiogenesis (formation of red blood cell-containing vessels) was decreased by ~80%. CLA also significantly decreased serum and mammary gland concentrations of vascular endothelial growth factor (VEGF), and the mammary gland VEGF receptor, flk-1.

In summary, the ability of CLA to modulate mammary stromal cell differentiation and decrease angiogenesis may contribute to its efficacy in inhibiting mammary carcinogenesis.

Supported by AICR 02A112-REN, DAMD17-00-1-0286 and NIH CA61763.

Frontiers in Cancer Prevention Research, 2003 AACR

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