Abstract 565: Effects of zoledronic acid on the interaction between mesenchymal stem cells and breast cancer cells

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Zoledronic acid (ZA) is the mainstay of treatment of bone metastases associated with a wide variety of tumors, including breast cancer. It has been recently shown that ZA increases the progression free-survival of estrogen receptor (ER)-positive breast cancer patients by reducing both loco-regional and distant metastases, suggesting that this compound might act directly on breast cancer cells. However, ZA very rapidly concentrates in the bone following intravenous administration, and therefore this drug is unlikely to have a direct effect on cell populations outside the bone. Recent reports have shown that bone-marrow-derived mesenchymal stem cell (MSCs) are recruited to the stroma of developing tumors where they increase the metastatic potential of breast cancer cells by secreting cytokines, chemokines and growth factors that sustain breast cancer migration, invasion and metastasis. In particular, the chemokine CCL5 (RANTES) plays an important role in this phenomenon. Therefore, we investigated the effects of ZA on the ability of primary MSCs to secrete cytokines and growth factors that might be involved in breast cancer progression. We found that treatment with ZA produced marginal effects on the growth of human primary MSCs with an approximately 25% growth inhibition at 20 μM. In contrast, treatment with similar concentrations of ZA almost completely suppressed the ability of MSCs to secrete RANTES (>90% reduction). The effect of ZA on RANTES was quite specific, since marginal inhibition of the secretion of different angiogenic growth factors, such as VEGF, IL-8 and bFGF was observed. Treatment of MSCs with ZA also produced a 50% reduction in the levels of secretion of IL-6 that has been previously shown to act as a potent paracrine growth factor for human breast cancer cells. Both RANTES and IL-6 transcripts were significantly reduced in MSCs following exposure to ZA, suggesting a transcriptional regulation of these cytokines by ZA. Conditioned medium from ZA-treated MSCs showed a reduced ability to promote the migration of ER-positive MCF-7 breast cancer cells through a fibronectin-coated membrane as compared with conditioned medium from untreated cells. In addition, antibodies anti-RANTES and anti-IL-6, alone or in combination, produced an approximately 50% reduction of the migration of MCF-7 induced by conditioned medium from untreated MSCs. In co-culture assays, treatment with ZA reduced the ability of MSCs to sustain the growth of breast cancer cells. Finally, the migration of MSCs was reduced by approximately 45% following treatment with ZA. Taken together, these data suggest that ZA might exert its antitumor activity in the bone marrow microenvironment by inhibiting the migration of MSCs and by blocking the ability of MSCs to secrete factors involved in breast cancer progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 565.