Current Pharmaceutical Design - Volume 16, Issue 11, 2010

Breast cancer is prone to metastasize to bone: around 70-80% of patients with advanced disease exhibit bone metastases. Once metastatic cells are in the bone marrow, they do not, on their own, destroy bone. Instead, they alter the functions of bone-resorbing (osteoclasts) and bone-forming (osteoblasts) cells [1]. For example, breast cancer cells secrete many factors that stimulate the activity of osteoclasts [interleukins IL-6, IL-8 and IL-11, parathyroid hormone related peptide (PTHrP)] and inhibit that of osteoblasts [Noggin, dickkopf-1 (DKK- 1)], leading to the formation of osteolytic lesions [1]. Conversely, cancer cells may release endothelin-1, which stimulates bone formation and inhibits bone resorption, leading to the formation of osteoblastic lesions [1]. Overall, these skeletal lesions (whether they are lytic or blastic) can be fatal or may rapidly impede the quality of life of patients by causing pathological fractures, hypercalcemia, nerve compression and loss of mobility. Most of these patients will also experience substantial, life-altering cancer-induced bone pain. Yet, current treatments are only palliative and do not provide life-prolonging benefit to patients with advanced cancers. There is therefore a need to better understand molecular mechanisms associated with cancer-induced bone diseases in order to improve existing therapies and/or develop new targeted therapies. The realization that normal cells in the bone microenvironment support the development of skeletal lesions has led to the use of bisphosphonates, as inhibitors of osteoclast-mediated bone resorption, in the treatment of patients with bone metastases. Indirect and direct anti-tumor effects of bisphosphonates have been also reported in a number of preclinical studies [2]. In this issue of Current Pharmaceutical Design, Holen and Coleman [3] summarize the main studies that have investigated the anti-tumor effects of bisphosphonates, alone or in combination with other anti-cancer agents, in animal models of breast cancer bone metastasis. The authors also give an overview of the use of bisphosphonates in the treatment of breast cancer, including adjuvant bisphosphonate treatment which may have benefits on disease recurrence when combined with standard endocrine therapy. Finally, the authors show that there are some potential limitations to the use of bisphosphonates, suggesting that additional drugs targeting osteoclasts are needed. The RANK/RANKL signaling pathway is the primary mediator of osteoclast-mediated bone resorption [4]. RANKL, when bound to RANK on the surface of osteoclasts precursors, promotes osteoclastogenesis. There is also a growing body of evidence that bone resorption, governed by RANK/RANKL, plays a critical role in the expansion of tumor cells in bone [4]. The RANK/RANKL signaling pathway is therefore an attractive therapeutic target. In the present issue, Buckle et al. [5] discuss the evidence for the RANK/RANKL system in normal osteoclast biology, its abnormal regulation in the cancer setting and the possible involvement of bone marrow-derived RANKL as a chemoattractant for RANK-expressing tumour cells. In addition, the authors review the effect of blocking the RANK/RANKL pathway in both experimental models and in the clinic [5]. Beside the possible involvement of RANKL as a potentiator of primary tumor cell migration to secondary sites within the skeleton, there is now evidence that chemokines and their receptors are playing a key role in organ-specific cancer metastasis [6]. For example, several chemokine receptors (CXCR3, CXCR4, CCR4, CCR5, and CCR7) expressed by tumor cells are associated with metastases in breast cancer [6-8], among which CXCR4 seems to be a major metastasis-regulator receptor [6]. Here, Hirbe et al. [9] review the current data regarding the role of CXCR4 and its ligand, SDF-1/CXCL-12, in the development of bone metastases. The authors also discuss the potential advantages and risks at targeting this chemokine axis for the prevention of tumor cell spread to bone. Interestingly, it has been very recently shown that CXCL-12 is not only implicated in the homing of breast cancer cells in the bone marrow but also in their survival [10]. CXCL-12, by binding to CXCR4, activates the nonreceptor tyrosine kinase Src which, in turn, stimulates the AKT cell survival pathway in breast cancer cells [10]. Given that several agents that target Src have become available for clinical testing [11], one could envision using Src inhibitors (and/or CXCR4 antagonists ?) as a means to block tumor growth at an early stage in the course of the metastatic disease. Once cancer cells have reached and invaded the bone marrow, they start to grow and form small clumps of cancer cells called micrometastases. Invasion of the bone marrow cavity by cancer cells requires the coordinated action of integrins and proteases. Their functions in cancer and (bone) metastasis formation have been very recently reviewed [12,13] and, therefore, will not be discussed here. Invading cancer cells that form micrometastases need also to adapt to the bone microenvironment (a process called osteomimetism), in order to survive and acquire the ability to grow into a clinically detectable bone metastasis [1]. For example, breast cancer cells that metastasize to bone specifically express transcription factors (Runx2, MSX2), extracellular matrix proteins (osteonectin, osteocalcin, …), proteases (cathepsin K), and other bone-related factors [connexin 43, cadherin-11, bone morphogenetic proteins (BMPs)] that, under physiological conditions, regulate osteoblast differentiation and osteoclast activity [1]. In this issue, Buijs et al. [14] review the biological functions of BMPs, which can be produced by cancer cells, and they discuss their role during the progression of bone metastases. The authors also discuss the possibility that BMP7 could serve as therapeutic molecule, interfering with transforming growth factor-β (TGF-β) signaling. In skeletal tissue, TGF-β is indeed a major bone-derived factor responsible for driving a feed-forward vicious cycle of breast cancer growth in bone. It regulates the expression of many factors (integrin αvβ3, CXCR4, IL-6, IL-8, IL-11, metalloproteinase MMP-1, endothelin-1, etc…) that are involved in bone metastasis formation. Here, Juarez and Guise [15] summarize the current knowledge of TGF-β in bone metastases, the use of TGF-β inhibitors and its potential for clinical use and consequences.

Accelerated bone loss is a common clinical feature of advanced breast cancer, and anti-resorptive bisphosphonates are the current standard therapy used to reduce the number and frequency of skeletal-related complications experienced by patients. Bisphosphonates are potent inhibitors of bone resorption, acting by inducing osteoclast apoptosis and thereby preventing the development of cancer-induced bone lesions. In clinical use bisphosphonates are mainly considered to be bone-specific agents, but anti-tumour effects have been reported in a number of in vitro and in vivo studies. By combining bisphosphonates with chemotherapy agents, growth and progression of breast cancer bone metastases can be virtually eliminated in model systems. Recent clinical trials have indicated that there may be additional benefits from bisphosphonate treatment, including positive effects on recurrence and survival when added to standard endocrine therapy. Whereas the ability of bisphosphonates to reduce cancer-induced bone disease is well established, their potential direct anti-tumour effect remain controversial. Ongoing clinical trials will establish whether bisphosphonates can inhibit the development of bone metastases in high-risk breast cancer patients. This review summarizes the main studies that have investigated the effects of bisphosphonates, alone and in combination with other anti-cancer agents, using in vivo model systems of breast cancer bone metastases. We also give an overview of the use of bisphosphonates in the treatment of breast cancer, including examples of key clinical trials. The potential side effects and future clinical applications of bisphosphonates will be outlined.

Cancers which damage the human skeleton include multiple myeloma, where the primary tumour colonises bone directly, or breast and prostate cancer, where malignant cells travel from the primary tumour to form clonal outgrowths within the bone. Owing to the interaction of tumour cells with those normally found in the bone microenvironment, such as osteoclasts and osteoblasts, these cancers affect the closely linked processes of bone formation and resorption. As a result, these twin processes contribute to the clinical manifestations of cancer metastasis, including bone pain and pathological fractures. A critical component of physiologically normal bone remodelling, the RANK/RANKL/OPG pathway, has been implicated in the formation of osteolytic, and possibly osteoblastic, lesions, which characterise the bone disease associated with these malignancies. In these cancers that affect the skeleton in this way the abnormally regulated RANK/RANKL system appears to be the final effector pathway. As a result, there has been much research focused upon targeting these molecules using OPG constructs, peptidomimetics, soluble receptor constructs and antibodies to RANKL, in preclinical studies. The success of these studies has paved the way for a clinical programme, the success of which is likely to lead to a new therapeutic approach to treating cancers that develop in the skeleton.

Chemokines and chemokine receptors play diverse roles in homeostasis. The chemokine stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 have critical functions in the immune, circulatory, and central nervous systems and have also been implicated in tumor biology and metastasis. Here we review the current data regarding the role of the CXCR4/SDF-1 chemokine axis in the development of bone metastases, derived from tumor models of breast or prostate cancers. There is substantial evidence that CXCR4 and SDF-1 directly influence the survival and proliferation of tumor cells. In regards to bone metastases, the CXCR4/SDF-1 axis also appears to facilitate tumor cell recruitment to the bone marrow microenvironment via a homing mechanism. This makes disruption of the chemokine axis an attractive therapeutic target for the prevention of tumor cell spread to bone. However, within the bone microenvironment, SDF-1 and CXCR4 appear to have conflicting roles. While genetic disruption of CXCR4 enhances osteoclast activity and therefore stimulates tumor cell growth in the bone - likely via release of bone-derived growth factors - SDF-1 has been shown to have either a stimulatory effect or no effect on osteoclasts. In short, the effects of the CXCR4/SDF-1 axis on tumor cell growth within the bone are not yet fully defined. Further, there are theoretical risks that blockade of this chemokine axis could impair immune function or mobilize tumor cells leading to other sites of metastasis. As such, caution should be taken when designing therapeutic strategies targeting this chemokine axis.

Breast and prostate cancer are osteotropic cancers, i.e., carcinomas that have a special predilection to form bone metastases. At postmortem examination, ∼70% of patients dying of these cancers have evidence of metastatic bone disease. Bone Morphogenetic Proteins (BMPs) were first identified by their ability to induce ectopic bone formation in vivo. Since prostate cancer cells express several BMPs, BMPs have been implicated in the osteoblastic phenotype of bone metastases. In addition to their osteogenic function, BMPs turned out to be multifunctional proteins regulating cell growth, differentiation, migration, and apoptosis in various target cells, including breast and prostate cancer cells. Especially in the last decade, studies have focused on the role of several BMPs in osteotropic cancers. In this review, the role of BMPs, particularly that of BMP7, in breast and prostate cancer will be discussed.

Breast and prostate cancer frequently metastasizes to the skeleton and causes bone destruction. In skeletal tissue, transforming growth factor-β (TGF-β) is a major bone-derived factor responsible for driving a feed-forward vicious cycle of breast cancer growth in bone. TGF-β is released from bone in active form by osteoclastic resorption and increases the tumor secretion of factors, which stimulate osteolytic destruction of the bone adjacent to the tumor. Moreover it activates epithelial-mesenchymal transition and tumor cell invasion, increases angiogenesis and induces immunosuppression. Blocking the TGF-β signaling pathway to interrupt this vicious cycle between tumor and bone offers a target for therapeutic intervention to decrease skeletal metastasis. Here we summarize the current knowledge of TGF-β in bone metastases, the use of TGF-β inhibitors and its potential for clinical use and consequences.

Alcohol dependence is a major disease burden of adults in modern society worldwide. There is no cure for alcohol dependence. In this study, we have examined the molecular targets of ethanol-induced toxicity in humans based on a systematic review of literature data and then discussed current and potential therapeutic targets for alcohol abuse and dependence. Using human samples with ethanol exposure, microarray analyses of gene expression have shown that numerous genes are up- and/or down-regulated by alcohol exposure. The ethanol-responsive genes mainly encode functional proteins such as proteins involved in nucleic acid binding, transcription factors, selected regulatory molecules, and receptors. These genes are also correlated with important biological pathways, such as angiogenesis, integrin signaling pathway, inflammation, wnt signaling pathway, platelet-derived growth factor signaling pathway, p53 pathway, epidermal growth factor receptor signaling pathway and apoptosis signaling pathway. Currently, only three medications were approved by the U.S. Food and Drug Administration (FDA) for the treatment of alcohol abuse and alcohol dependence, including the aldehyde dehydrogenase inhibitor disulfiram, the μ-opioid receptor antagonist naltrexone, and the N-methyl-D-aspartate (NMDA) receptor inhibitor acamprosate (oral and injectable extended-release formulations). In addition, a number of agents are being investigated as novel treatments for alcohol abuse and dependence. These include selective 5-HT reuptake inhibitors (e.g. fluoxetine), 5-HT1 receptor agonists (e.g. buspirone), 5-HT2 receptor antagonists (e.g. ritanserin), 5-HT3 receptor antagonists (e.g. ondansetron), dopamine receptor antagonists (e.g. aripiprazole and quetiapine), dopamine receptor agonists (e.g. bromocriptine), GABAB receptor agonists (e.g. baclofen), and cannabinoid-1 (CB1) receptor antagonists. Some of these agents have shown promising efficacy in initial clinical studies. However, further randomized studies with larger samples are warranted to establish their efficacy and safety profiles in the treatment of alcohol dependence.