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Acquisition of an invasive phenotype of cancer cells in primary tumors is an absolute requirement for bone metastasis. The majority of bone metastases is derived from epithelial cancers, particularly those of the breast and prostate. Accumulating evidence suggest that transformed epithelial cells can activate embryonic programs of epithelial plasticity and switch from a sessile, epithelial phenotype to a motile, mesenchymal phenotype also referred to as epithelial-to-mesenchymal transition (EMT). Induction of EMT can, therefore, lead to invasion of surrounding stroma, intravasation, dissemination and colonization of distant sites. In bone/bone marrow disseminated tumor cells can partially regain their original epithelial characteristics via a mesenchymal-to-epithelial transition (MET) as glandular structures in bone metastasis are frequently observed. To date, the importance of epithelial plasticity in cancer cells disseminated to the bone/bone marrow microenvironment has remained largely elusive. Interestingly, a number of growth factors that play a prominent role in EMT induction in the primary tumor have been identified as important stimulators of skeletal metastasis formation. Recent studies have demonstrated that EMT may render cancer cells with properties of stem cells, which in turn can lead to escape from immune surveillance, increased resistance to apoptosis, diminished senescence and, last-but-not least, therapy resistance. This review will discuss current concepts regarding the role of epithelial plasticity in the multistep processes of bone metastasis, the issue of minimal residual disease, cancer stem cells and the importance of EMT in the development of novel targeted drug therapy., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Breast cancer frequently metastasizes to bone, where tumor cells induce osteoclasts to locally destroy bone. During bone resorption, growth factors are locally released that may support bone metastatic growth. Differently from most other tissues, drugs that can limit local turnover, such as bisphosphonates and osteoprotegerin (OPG), are available for bone. We examined the hypothesis that inhibition of bone resorption by two different mechanisms may also affect the growth of cancer cells in bone. For this, we tested the effects of high doses of OPG and zoledronic acid (ZOL) on progression of MDA-231-B/Luc+ breast cancer cells in the bone microenvironment using whole body bioluminescent reporter imaging (BLI). Both treatments significantly inhibited the development of radiographically detectable osteolytic lesions. Histologic examination corroborated the radiographic findings, showing that both treatments preserved the integrity of bone trabeculae and prevented bone destruction (significantly higher trabecular bone volumes vs. vehicle). However, whereas practically no TRAcP-positive osteoclasts were observed in tibiae preparations of animals treated with Fc-OPG, TRAcP-positive osteoclasts were still present in the animals treated with ZOL. Intra-bone tumor burden was reduced with ZOL and Fc-OPG treatment. Although there appeared to be a trend for less overall total tumor burden upon treatment with both compounds, this was not significant as assessed by BLI and histomorphometric analysis due to the extramedullary growth of cancer cells which was not affected by these treatments. Collectively, anti-resorptive agents with different mechanisms of action - ZOL and OPG - significantly reduced cancer-induced osteolysis and intra-osseous tumor burden, but failed to restrain local tumor growth. However, interference with the bone micro-environmental growth support could still be of therapeutic relevance when given to patients early in the course of bone metastatic disease.