Prostate cancer is the second leading cause of cancer-related death in men. A typical feature of this disease is its ability to metastasize to bone. It is mainly osteosclerotic, and is caused by a relative excess of osteoblast activity, leading to an abnormal bone formation. Bone metastases are the result of a complex series of steps that are not yet fully understood and depend on dynamic crosstalk between metastatic cancer cells, cellular components of the bone marrow microenvironment, and bone matrix (osteoblasts and osteoclasts). Prostate cancer cells from primary tissue undergo an epithelial-mesenchymal transition to disseminate and acquire a bone-like phenotype to metastasize in bone tissue. This review discusses the biological processes and the molecules involved in the progression of bone metastases. Here we focus on the routes of osteoblast differentiation and activation, the crosstalk between bone cells and tumor cells, and the molecules involved in these processes that are expressed by both osteoblasts and tumor cells. Furthermore, this review deals with the recently elucidated role of osteoclasts in prostate cancer bone metastases. Certainly, to better understand the underlying mechanisms of bone metastasis and so improve targeted bone therapies, further studies are warranted to shed light on the probable role of the premetastatic niche and the involvement of cancer stem cells. Cancer 2010;116:1406-18. V C 2010 American Cancer Society.KEYWORDS: osteoblasts, osteoclasts, prostate cancer, bone, metastasization.Solid tumors, such as breast and prostate cancer, have an affinity to metastasize to bone, causing osteolysis and abnormal bone formation. Bone metastasis starts with the tropism of cancer cells to the bone through specific migratory and invasive processes. Once in the bone marrow, metastatic cells are able to survive and grow. Here, they actively interact with bone marrow stem cells and hematopoietic progenitors in the so-called metastatic niche, where they acquire a bonelike phenotype. This leads to the formation of bone lesions (lytic or osteoblastic), obtained through reciprocal paracrine amplification and cell-to-cell communication with bone cells. The complex molecular pathogenesis mechanisms of bone metastasis offer several potential targets for prevention and therapy.Prostate cancer is the second leading cause of cancer-related death in men, and a typical feature of this disease is its ability to metastasize to bone. Indeed, it has been estimated that >80% of men who die from prostate cancer develop bone metastases.1,2 Although most bone metastases from prostate cancer have been classified as osteoblastic, based on the radiographic appearance of lesions, it is clear that bone resorption and bone formation are dysregulated. 3-5The Metastatic Process: From Primary Tumor to Growth in Bone Tissue The first step in metastasization is the acquisition of motility and invasiveness; capabilities that are not compatible with normal tissue. Cancer cells must therefore shed many of their epithelial ch...

Our preliminary results confirm the usefulness of a multidisciplinary center for the management of patients with bone metastases, especially in terms of decreasing psychophysical suffering.

No abstract

BackgroundZoledronic acid is used to treat bone metastases and has been shown to reduce skeletal-related events and exert antitumor activity. The present in vitro study investigates the mechanism of action of Zoledronic Acid on breast cancer cell lines with different hormonal and HER2 patterns. Furthermore, we investigated the efficacy of repeated versus non-repeated treatments.MethodsThe study was performed on 4 breast cancer cell lines (BRC-230, SkBr3, MCF-7 and MDA-MB-231). Non-repeated treatment (single exposure of 168 hrs’ duration) with zoledronic acid was compared with repeated treatment (separate exposures, each of 48 hrs’ duration, for a total of 168 hrs) at different dosages. A dose–response profile was generated using sulforhodamine B assay. Apoptosis was evaluated by TUNEL assay and biomolecular characteristics were analyzed by western blot.ResultsZoledronic acid produced a dose-dependent inhibition of proliferation in all cell lines. Anti-proliferative activity was enhanced with the repeated treatment, proving to be statistically significant in the triple-negative lines. In these lines repeated treatment showed a cytocidal effect, with apoptotic cell death caused by caspase 3, 8 and 9 activation and decreased RAS and pMAPK expression. Apoptosis was not observed in estrogen receptor-positive line: p21 overexpression suggested a slowing down of cell cycle. A decrease in RAS and pMAPK expression was seen in HER2-overexpressing line after treatment.ConclusionsThe study suggests that zoledronic acid has an antitumor activity in breast cancer cell lines. Its mechanism of action involves the decrease of RAS and RHO, as in osteoclasts. Repeated treatment enhances antitumor activity compared to non-repeated treatment. Repeated treatment has a killing effect on triple-negative lines due to apoptosis activation. Further research is warranted especially in the treatment of triple-negative breast cancer.