Mechanisms of cancer metastasis to the bone

Some of the most common human cancers, including breast cancer, prostate cancer, and lung cancer, metastasize with avidity to bone. What is the basis for their preferential growth within the bone microenvironment? Bidirectional interactions between tumor cells and cells that make up bone result in a selective advantage for tumor growth and can lead to bone destruction or new bone matrix deposition. This review discusses our current understanding of the molecular components and mechanisms that are responsible for those interactions.     

Dynamic process of prostate cancer metastasis to bone

Prostate cancer metastasis to the bone occurs at high frequency in patients with advanced disease, causing significant morbidity and mortality. Over a century ago, the "seed and soil" theory was proposed to explain organ-specific patterns of metastases. Today, this theory continues to be relevant as we continue to discover factors involved in the attraction and subsequent growth of prostate cancer cells to the bone. These include the accumulation of genetic changes within cancer cells, the preferential binding of cancer cells to bone marrow endothelial cells, and the release of cancer cell chemoattractants from bone elements. A key mediator throughout this metastatic process is the integrin family of proteins. Alterations in integrin expression and function promote dissociation of cancer cells from the primary tumor mass and migration into the blood stream. Once in circulation, integrins facilitate cancer cell survival through interactions between other cancer cells, platelets, and endothelial cells of the target bone. Furthermore, dynamic changes in integrins and in integrin-associated signal transduction aid in the extravasation of cancer cells into the bone and in expansion to a clinically relevant metastasis. Thus, we will review the critical roles of integrins in the process of prostate cancer bone metastasis, from the escape of cancer cells from the primary tumor, to their survival in the harsh "third microenvironment" of the circulation, and ultimately to their attachment and growth at distant bone sites.     

Skeletal metastases: decreasing tumor burden by targeting the bone microenvironment

Several common cancers often metastasize to the skeleton in advanced disease. Bone metastases are incurable and cause protracted, severe symptoms. Growth of tumor in bone is driven by a vicious cycle: tumor-secreted factors stimulate bone cells, which in turn release growth factors and cytokines. The bone-derived factors fuel the vicious cycle by acting back on the tumor cells. The vicious cycle offers novel targets for the treatment of advanced cancers. Treatments can inhibit bone cells (osteoclasts and osteoblasts) that are stimulated by tumor-secreted factors. Drugs can also inhibit tumor responses to factors enriched in the bone microenvironment, such as transforming growth factor-beta. Animal models show that these approaches, especially combination treatments, can reduce tumor burden. The results suggest a novel paradigm in which tumor growth can be effectively inhibited by drugs that target cells in the bone microenvironment and not the tumor cells themselves.     

A paradigm for the treatment of prostate cancer bone metastases based on an understanding of tumor cell-microenvironment interactions

The pliability of cancer cells to mutate into several different phenotypes in an attempt to find one that will survive and colonize at the metastatic site is a tremendous "hurdle" to overcome in designing novel cancer therapeutics. New targets of therapy are essential if we are to effectively overcome the evasiveness of cancer. The interaction between the tumor cell and the surrounding microenvironment creates a vicious cycle that perpetuates disease survival and progression. The future of cancer therapy resides in the ability to focus on the recruited and exploited relationships of the cancer cell with the host environment. These therapies target cancer cell growth early and interrupt the vicious cycle that is created by the tumor cells interacting with bone components by inhibiting osteoclasts, osteoblasts, stromal cells, and endothelial cells. They alter the bone microenvironment, creating a hostile "soil" that prevents the "seed" from developing into bone metastases and represent a potential new platform for the development of prostate cancer therapeutics.     

Tumor microenvironment: the role of the tumor stroma in cancer

The tumor microenvironment, composed of non-cancer cells and their stroma, has become recognized as a major factor influencing the growth of cancer. The microenvironment has been implicated in the regulation of cell growth, determining metastatic potential and possibly determining location of metastatic disease, and impacting the outcome of therapy. While the stromal cells are not malignant per se, their role in supporting cancer growth is so vital to the survival of the tumor that they have become an attractive target for chemotherapeutic agents. In this review, we will discuss the various cellular and molecular components of the stromal environment, their effects on cancer cell dynamics, and the rationale and implications of targeting this environment for control of cancer. Additionally, we will emphasize the role of the bone marrow-derived cell in providing cells for the stroma.     

肿瘤细胞和骨微环境在骨转移中的作用

随着肿瘤治疗水平的提高,肿瘤患者的生存期显著延长,转移性骨肿瘤的发生率呈增长趋势.骨转移引起的剧烈的临床症状和其较长的潜伏期,以及缺乏有效的治疗方法,极大降低了患者的生活质量.本文主要综述了骨转移相关的细胞特征及骨微环境在骨转移中的作用,并分析了影响骨转移形成的相关分子因素,为骨转移的定向分子治疗提供进一步的理论依据.     

Modulation of prostate cancer growth in bone microenvironments

Bone remains one of the major sites, and most lethal host organs, for prostate cancer metastasis. Prostate cell spread and establishment in bone depends on multiple reciprocal modifications of bone stromal and epithelial cancer cell behaviors. This review focuses on recent advances in the characterization of cell-cell and cell-matrix interplay, effects on cell growth, adhesion and invasion, and several therapeutic possibilities for co-targeting prostate cancer cells and bone stroma. We address the topic from three main perspectives: (1) the normal and aging bone stromal environment, (2) the "reactive" bone stromal environment, and (3) the cancerous prostate epithelial cells themselves. First, normal, and especially aging, bones provide uniquely rich and "fertile soil" for roaming cancer cells. The interactions between prostate cancer cells and insoluble extracellular matrices, soluble growth factors, and/or sex steroid hormones trigger bone remodeling, through increased osteoclastogenesis and furthur matrix metalloproteinase activity. Second, after cancer cell arrival and establishment in the bone, host stromal cells respond, becoming "reactive" in a process again involving extracellular matrix remodeling, together with growth factor and steroid receptor signaling this process ultimately enhances cancer cell migration, stromal transdifferentiation, and invasion of the cancer tissues by stromal, inflammatory, and immune-responsive cells. Third, prostate cancer cells also respond to supportive bone microenvironments, where soluble and matrix-associated molecules affect cancer cell growth and gene expression, especially altering cancer cell surface receptor and integrin-mediated cell signaling. We discuss both integrin cell-matrix and gap junctional cell-cell communication between cancer cells and their microenvironments during prostate cancer progression.     

The role of microRNAs in prostate cancer migration,invasion, and metastasis

Prostate cancer (PCa) is considered the most prevalent malignancy and the second major cause of cancer-related death in males from Western countries. PCa exhibits variable clinical pictures, ranging from dormant to highly metastatic cancer. PCa suffers from poor prognosis and diagnosis markers, and novel biomarkers are required to define disease stages and to design appropriate therapeutic approach by considering the possible genomic and epigenomic differences. MicroRNAs (miRNAs) comprise a class of small noncoding RNAs, which have remarkable functions in cell formation, differentiation, and cancer development and contribute in these processes through controlling the expressions of protein-coding genes by repressing translation or breaking down the messenger RNA in a sequence-specific method. miRNAs in cancer are able to reflect informative data about the current status of disease and this might benefit PCa prognosis and diagnosis since that is concerned to PCa patients and we intend to highlight it in this paper.     

Role of Wnts in prostate cancer bone metastases

Prostate cancer (CaP) is unique among all cancers in that when it metastasizes to bone, it typically forms osteoblastic lesions (characterized by increased bone production). CaP cells produce many factors, including Wnts that are implicated in tumor-induced osteoblastic activity. In this prospectus, we describe our research on Wnt and the CaP bone phenotype. Wnts are cysteine-rich glycoproteins that mediate bone development in the embryo and promote bone production in the adult. Wnts have been shown to have autocrine tumor effects, such as enhancing proliferation and protecting against apoptosis. In addition, we have recently identified that CaP-produced Wnts act in a paracrine fashion to induce osteoblastic activity in CaP bone metastases. In addition to Wnts, CaP cells express the soluble Wnt inhibitor dickkopf-1 (DKK-1). It appears that DKK-1 production occurs early in the development of skeletal metastases, which results in masking of osteogenic Wnts, thus favoring osteolysis at the metastatic site. As metastases progress, DKK-1 expression decreases allowing for unmasking of Wnt's osteoblastic activity and ultimately resulting in osteosclerosis at the metastatic site. We believe that DKK-1 is one of the switches that transitions the CaP bone metastasis activity from osteolytic to osteoblastic. Wnt/DKK-1 activity fits a model of CaP-induced bone remodeling occurring in a continuum composed of an osteolytic phase, mediated by receptor activator of NFkB ligand (RANKL), parathyroid hormone-related protein (PTHRP) and DKK-1; a transitional phase, where environmental alterations promote expression of osteoblastic factors (Wnts) and decreases osteolytic factors (i.e., DKK-1); and an osteoblastic phase, in which tumor growth-associated hypoxia results in production of vascular endothelial growth factor and endothelin-1, which have osteoblastic activity. This model suggests that targeting both osteolytic activity and osteoblastic activity will provide efficacy for therapy of CaP bone metastases.     

The role of Snail in prostate cancer

Prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of death from cancer in men. Epithelial-mesenchymal transition (EMT) is a process by which cancer cells invade and migrate, and is characterized by loss of cell-cell adhesion molecules such as E-cadherin and increased expression of mesenchymal proteins such as vimentin; EMT is also associated with resistance to therapy. Snail, a master regulator of EMT, has been extensively studied and reported in cancers such as breast and colon; however, its role in prostate cancer is not as widely reported. The purpose of this review is to put together recent facts that summarize Snail signaling in human prostate cancer. Snail is overexpressed in prostate cancer and its expression and activity is controlled via phosphorylation and growth factor signaling. Snail is involved in its canonical role of inducing EMT in prostate cancer cells; however, it plays a role in non-canonical pathways that do not involve EMT such regulation of bone turnover and neuroendocrine differentiation. Thus, studies indicate that Snail signaling contributes to prostate cancer progression and metastasis and therapeutic targeting of Snail in prostate cancer holds promise in ?future.     

The role of Snail in prostate cancer

Prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of death from cancer in men. Epithelial-mesenchymal transition (EMT) is a process by which cancer cells invade and migrate, and is characterized by loss of cell-cell adhesion molecules such as E-cadherin and increased expression of mesenchymal proteins such as vimentin; EMT is also associated with resistance to therapy. Snail, a master regulator of EMT, has been extensively studied and reported in cancers such as breast and colon; however, its role in prostate cancer is not as widely reported. The purpose of this review is to put together recent facts that summarize Snail signaling in human prostate cancer. Snail is overexpressed in prostate cancer and its expression and activity is controlled via phosphorylation and growth factor signaling. Snail is involved in its canonical role of inducing EMT in prostate cancer cells; however, it plays a role in non-canonical pathways that do not involve EMT such regulation of bone turnover and neuroendocrine differentiation. Thus, studies indicate that Snail signaling contributes to prostate cancer progression and metastasis and therapeutic targeting of Snail in prostate cancer holds promise in �future.     

Phenotypic variations of TRAIL sensitivity in cloned populations of prostate cancer cells

Factors that regulate the induction of apoptosis of tumour cells are potential candidates for therapeutic intervention for the majority of cancers. Studying modifiers of apoptotic responses, such as members of the tumour necrosis factor receptor superfamily, may give clues as to how induction of apoptosis in tumours could be maximized to enhance the benefit of treatment regimes. Tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL) is a promising anti‐tumour molecule since its activity is specific for tumour cell populations. TRAIL binds to death receptors, inducing apoptosis in susceptible cells. The mechanisms which determine whether tumour cells are susceptible to TRAIL are unclear, and several mechanisms have been proposed, including expression of osteoprotegerin (OPG), decoy receptors, and factors that affect intracellular signalling of pro‐apoptotic molecules, such as c‐FLIP. Here we show that experiments to modulate the activity of one of these factors, OPG, by over‐expression and also by stable knockdown of OPG expression, alters the TRAIL sensitivity of PC3 prostate cancer cells. However we show that some observed effects, which appear to support the hypothesis that OPG prevents TRAIL‐induced apoptosis of tumour cells, may be due to variation of the TRAIL response of sub‐clones of tumour cells, even within a cloned population. These results highlight potential limitations of experiments designed to test contribution of factors affecting intrinsic apoptosis susceptibility using cloned tumour cell populations. J. Cell. Biochem. 104: 1452–1464, 2008. © 2008 Wiley‐Liss, Inc.     

BMP2 signalling activation enhances bone metastases of non‐small cell lung cancer

Distant metastases occur when non‐small cell lung cancer (NSCLC) is at late stages. Bone metastasis is one of the most frequent metastases of NSCLC and leads to poor prognosis. It has been reported that high expression of BMP2 in NSCLC correlates with poor survival, but whether BMP2 contributes to NSCLC bone metastasis remains largely unknown. The activation of BMP signalling is found in metastatic bone tumours of mice Lewis lung carcinoma and predicts poor survival in human NSCLC. BMP2 signalling activation can enhance bone metastasis of Lewis lung carcinoma. Moreover, BMP2 secreted by stroma fibroblasts can promote the migration and invasion of NSCLC cells. Besides, in combination with pre‐osteoblast and LLCs, BMP2 could enhance the differentiation of macrophages into osteoclasts to play roles in the osteolytic mechanism of NSCLC bone metastasis. Interestingly, NSCLC cells can also enrich BMP2 to pre‐osteoblasts to function in the osteoblastic mechanism. Our results firstly demonstrate the detailed mechanisms about what roles BMP2 signalling play in enhancing NSCLC bone metastases. These findings provide a new potential therapy choice for preventing bone metastases of NSCLC via the inhibition of BMP2 signalling.     

Angiogenesis and prostate cancer tumor growth

The initiation of new blood vessels through angiogenesis is critical to tumor growth. Tumor cells release soluble angiogenic factors that induce neovascularization, without which nutrients and oxygen would not be available to allow tumors to grow more than 2-3 mm in diameter. This "angiogenic switch" or angiogenic phenotype requires an imbalance between proangiogenic and antiangiogenic factors since the formation of new blood vessels is highly regulated. This review discusses angiogenesis mediators, and the potential for manipulation of angiogenic factors as a practical cancer therapy, particularly in prostate cancer.     

The role of the disintegrin metalloproteinase ADAM15 in prostate cancer progression

The metalloproteinase ADAM15 is a multi‐domain disintegrin protease that is upregulated in a variety of human cancers. ADAM15 mRNA and protein levels are increased in prostate cancer and its expression is significantly increased during metastatic progression. It is likely that ADAM15 supports disease progression differentially through the action of its various functional domains. ADAM15 may downregulate adhesion of tumor cells to the extracellular matrix, reduce cell–cell adhesion, and promote metastasis through the activity of its disintegrin and metalloproteinase domains. Additionally, ADAM15 can influence cell signaling by shedding membrane‐bound growth factors and other proteins that interact with receptor tyrosine kinases, leading to receptor activation. There is also evidence supporting a role for ADAM15 in angiogenesis and angioinvasion of tumor cells, which are critical for unrestrained tumor growth and metastatic spread. Given its diverse functions, ADAM15 may represent a pivotal regulatory component of tumor progression, an important target for therapeutic intervention, or emerge as a biomarker of disease progression. J. Cell. Biochem. 106: 967–974, 2009. © 2009 Wiley‐Liss, Inc.     

The tumor microenvironment: An irreplaceable element of tumor budding and epithelial-mesenchymal transition-mediated cancer metastasis

Tumor budding occurs at the invasive front of cancer; the tumor cells involved have metastatic and stemness features, indicating a poor prognosis. Tumor budding is partly responsible for cancer metastasis, and its initiation is based on the epithelial-mesenchymal transition (EMT) process. The EMT process involves the conversion of epithelial cells into migratory and invasive cells, and is a profound event in tumorigenesis. The EMT, associated with the formation of cancer stem cells (CSCs) and resistance to therapy, results from a combination of gene mutation, epigenetic regulation, and microenvironmental control. Tumor budding can be taken to represent the EMT in vivo. The EMT process is under the influence of the tumor microenvironment as well as tumor cells themselves. Here, we demonstrate that the tumor microenvironment dominates EMT development and impacts cancer metastasis, as well as promotes CSC formation and mediates drug resistance. In this review, we mainly discuss components of the microenvironment, such as the extracellular matrix (ECM), inflammatory cytokines, metabolic products, and hypoxia, that are involved in and impact on the acquisition of tumor-cell motility and dissemination, the EMT, metastatic tumor-cell formation, tumor budding and CSCs, and cancer metastasis, including subsequent chemo-resistance. From our point of view, the tumor microenvironment now constitutes a promising target for cancer therapy.