Cell adhesion to extracellular matrix requires

Cell adhesion to extracellular matrix requires the interaction of different molecules like selectins, cadherins and integrins [21]. Especially αvβ3 integrin has been proposed to mediate the adhesion of malignant cells in different entities such as multiple myeloma and breast cancer [22,23]. Upon exposure to mevalonate pathway inhibitors we observed an impaired adhesion of breast cancer cells that was exclusive to αvβ3 ligands. Consequently, decreased αvβ3 expression was confirmed with two different methods. In HUVEC decreased cell surface levels of αvβ3 and αvβ5 following treatment with zoledronic buy enba have been previously reported [24] and these effects have been linked to an inhibition of prenylation dependent pathways [12]. This study did not investigate the impact of mevalonate pathway inhibition on the adhesion of estrogen receptor negative breast cancer cells, which is a study limitation. Furthermore, the limiting factor of translating preclinical anti-tumor effects of zoledronic acid are the high concentrations required to achieve these results. Concentrations between 10 to 100µM are commonly required in vitro to achieve consistent effects and although these concentrations may theoretically accumulate in the bone, they are certainly not reached in serum where bisphosphonate concentrations decline rapidly (within hours) following infusion. In this study zoledronic acid concentrations of 10µM were required to yield a robust cellular response. Interestingly, considerably lower concentrations of atorvastatin were needed to achieve comparable results. Although statins are not established agents in the treatment of cancer, there is increasing evidence that statins may have tumor modulating activity in vitro[25] and in vivo[26,27]. Furthermore, some observational studies have shown a reduction in cancer-related mortality by statins [28]. Atorvastatin potently suppressed the adhesion of breast cancer cells in this study supporting the potential anti-cancer effects of statins. The higher potency of statins compared to bisphosphonates may have clinical implications as the high concentrations of zoledronic acid required to achieve similar results may limits its translational potential.
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Introduction The proteoglycan syndecan-1 (also known as CD138) interacts with a variety of proteins via its heparin sulfate side chains or the core protein itself and therefore regulates key cellular functions such as apoptosis, proliferation, and epithelial-mesenchymal transition [1–7]. Because of its various interactions, several studies have investigated the role of syndecan-1 in tumor progression. While in multiple myeloma, high serum levels of soluble syndecan-1 correlate with a poor prognosis, the association of syndecan-1 expression and clinical outcome was ambiguous in breast cancer [8–11]. One study found a correlation between stromal and epithelial syndecan-1 expression and poor prognosis, whereas another study observed a poor clinical outcome in breast cancer cases without syndecan-1 expression [9,10]. Although the exact reasons for these different findings remain unclear, it has been suggested that they may related to the presence of two functionally different syndecan-1 isoforms [5]. While membranous syndecan-1 facilitates the proliferation of breast cancer cells, the soluble form triggers invasion [5]. Despite extensive efforts to unravel the role of syndecan-1 in breast cancer, little is known about how it is regulated. Of note, zoledronic acid, a widely used drug against osteoporosis and skeletal metastases, was found to inhibit syndecan-1 expression in breast cancer cell lines [12]. In multiple myeloma, the interaction between syndecan-1 and osteoprotegerin (OPG), the physiological antagonist of the osteoclast promoting factor receptor activator of NF-κB (RANKL), has been investigated in more detail [13]. The observed syndecan-1-mediated internalization and degradation of OPG may explain low OPG serum levels in patients with multiple myeloma [13]. Furthermore, two other studies demonstrated that tumor-derived syndecan-1 affects bone physiology [14,15].