Osteosarcoma is the most frequent malignant primary bone tumor characterized by a high potency to form lung metastases which is the main cause of death. Unfortunately, the conventional chemotherapy is not fully effective on osteosarcoma metastases. The progression of a primary tumor to metastasis requires multiple processes, which are neovascularization, proliferation, invasion, survival in the bloodstream, apoptosis resistance, arrest at a distant organ, and outgrowth in secondary sites. Consequently, recent studies have revealed new insights into the molecular mechanisms of metastasis development. The understanding of the mechanism of molecular alterations can provide the identification of novel therapeutic targets and/or prognostic markers for osteosarcoma treatment to improve the clinical outcome.
1. Introduction
Osteosarcoma (OS) most often occurs, during childhood and adolescence, in the metaphysis of long bones, including large growth plates with high proliferation activity and bone turnover [1]. Historically, patients with primary OS have been treated with resection surgery alone, resulting in poor prognosis. Clinical outcome of localized OS has improved with neoadjuvant chemotherapies, based on methotrexate, cisplatin, doxorubicin, and ifosfamide treatments. The 5-year survival has indeed increased to around 60%. However, the 5-year survival of patients with OS metastasis still remains about 30% [2–7]. OS metastases appear most frequently in the lung [8] and are the main cause of death for patients with OS, because micrometastases are undetectable at initial diagnosis [9, 10]. Taken together, OS patients with metastases present further worse clinical results than those without metastases. Thus, more effective treatments and/or a more personalized therapy (i.e., treatments according to specific genes or protein profile expressions) are needed for patients with OS associated with pulmonary metastases.
The establishment of cancer metastasis involves several complex steps: intravasation, survival in the circulation, arrest at a distant organ, extravasation, and growth in secondary sites (Figure 1). Molecular alterations of these steps have been practically analyzed. The understanding of metastasis mechanism might allow us to find new molecular targets for improvement of the patients’ survival. This paper describes the molecular factors associated with OS development and summarizes the main molecular alterations involved in this bone disease, especially in metastatic OS, which strongly contribute to the development of novel therapeutic approaches.
The main steps of the tumor metastatic process. Tumor cells proliferate at the primary site and neovascularization is induced by tumor environment such as hypoxia. In turn, they migrate and invade into the bloodstream. These tumor cells in the circulation need to survive against anoikis to arrest in a distant organ. Metastatic colonization at the secondary site involves the interactions between tumor cells and the microenvironment.
2. Neovascularization is a Key Parameter in Osteosarcoma Growth
Nutriments and oxygen required for the metabolism of normal and tumor cells are delivered by blood vessels. Neoformation of blood vessels allows growth, invasion, and metastatic spread of cancer cells in malignant pathologies. [11, 12]. The process of neovascularization is generally regulated by a balance between angiogenic inducers and inhibitors. The shift in favor of angiogenic inducers, known as the “angiogenic switch,” promotes the formation of a new blood supply enhancing tumor growth and metastasis. Neovascularization is induced by the tumor environment such as hypoxia, acidosis, or inflammation in an oncologic context. In these conditions, both tumor cells and host endothelial cells can increase the expression of proangiogenic: vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), and transforming growth factor (TGF-β) [13–17]. Tumor cells also secrete proteolytic enzymes such as matrix metalloproteinases (MMPs), which degrade basement membrane and extracellular matrix (ECM) promoting cell dissemination [18, 19]. MMP-9 is indeed highly related to the angiogenic switch because it can activate proangiogenic factors [20, 21]. Several studies have demonstrated that VEGF or TGF-β expression is associated with an increase of tumor vascularity, invasion, and poor prognosis in OS [22–24]. It has been shown that high serum-VEGF levels in OS correlate with tumor progression, metastasis, and poor prognosis [25, 26]. However, the relationship between an increase of tumor vascularity and a poor prognosis is controversial in OS [27–29].
The well-known angiogenic inhibitors are angiostatin and endostatin. Angiostatin is a cleavage product of plasminogen [30], whereas endostatin is the carboxyl-terminal fragment of collagen XVIII [31]. They inhibit endothelial cell proliferation and migration [32]. The resulting antiangiogenic activity has been demonstrated in various tumor models in vivo [33–38]. Based on these (pre)clinical results, clinical trials are currently running to evaluate the effect of human recombinant endostatin. Although showed a well tolerability and safety in patients with malignant solid tumors, it induces a minor antitumor effect not related to the vascular changes [39–41]. Inhibition of neovascularization should suppress tumor growth despite tumor cell heterogeneity because blood supply is necessary for all tumors to survive. Furthermore, the available data from animal models and phase I and II clinical trials of angiostatin and endostatin have shown that these agents are well-tolerated at therapeutic doses: 15–600 mg/m2/day added to those patients, although the use of antiangiogenic therapy has raised the debate about interference with normal physiological processes such as wound healing and tissue repair [31, 39–43].
3. Migration and Invasion: Two Potential Therapeutic Targets
Tumor migration and invasion through the ECM are critical in metastatic dissemination [15, 16]. Degradation of the ECM, which leads to migration, invasion, and metastasis, releases MMPs (MMP-2 and MMP-9, in particular) and m-calpain in OS [44–46]. In addition, the Wnt/β-catenin, Src-kinase and Notch signaling pathways are also involved in migration and invasion [47–55].
MMPs are a family of zinc endopeptidases consisting of at least 20 different members and regulate different cellular metabolic processes [56, 57]. They induce a variety of biological effects including growth, morphogenesis, apoptosis, tissue destruction, and cancer formation [58, 59]. Recently, bisphosphonates have been shown to downregulate MMPs expression and reduce the invasive potency of OS cells [60–64]. Disulfiram is also able to control the invasion and metastasis in human OS cells through the MMP-2 and MMP-9 inhibition [65]. Both of m-calpain expression and MMP-2 secretion are inhibited by a siRNA targeting m-calpain in SAOS-2 cells [46]. m-calpain is also essential in the invasion and human OS metastasis [46]. These agents related to proteases represent new therapeutic targets and approaches to decrease the OS migration and invasion.
Wnt signaling pathway coordinates osteoblast proliferation and differentiation [66]. Disruptions in various components of the Wnt pathway result in disordered bone development and homeostasis [67]. The β-catenin-dependent Wnt signaling pathway is regulated by secreted Wnt antagonists divided into two groups. Wnt inhibitory factor 1 (WIF-1) and the secreted frizzled-related protein family directly bind to Wnt ligands while the Dickkopf families and sclerostin are blocking Wnt receptors trough the endocytosis of low-density lipoprotein receptor-related protein 5/6 coreceptors [68–71]. This Wnt binding leads to the activation of disheveled, which in turn, releases β-catenin from the axin-adenomatous polyposis coli-glycogen synthase kinase-3β complex, causing stabilization and accumulation of β-catenin in the cytoplasm. After its translocation to the nucleus, β-catenin binds to the T-cell factor/lymphocyte enhancer factor family of transcription factors and promotes downstream target oncogenes such as c-myc, cyclin D, survivin, and MMPs. These mechanisms are involved in proliferation, invasion, and metastasis in various human cancers [72–75]. OS frequently expresses high levels of cytoplasmic and/or nuclear β-catenin [76], which is also associated with metastasis [77, 78]. These findings suggest that aberrant Wnt activation is crucial in multiple cancers, including OS [79–81]. A preclinical study has demonstrated that the inhibition of Wnt/β-catenin pathway induced lower levels of nuclear β-catenin, resulting in downregulation of the β-catenin-targeted genes such as MMP-9, cyclin-D, c-myc, and survivin [82]. Several reports have demonstrated that WIF-1 silencing due to hypermethylation results in Wnt signaling activation in a variety of cancer. WIF-1 can inhibit the cell growth of those cancer cells [79, 80, 83–86]. The downregulation of WIF-1 expression plays a role in OS progression. Reexpression of WIF-1 also suppressed Wnt signaling pathway, resulting in the tumor growth and lung metastasis in vivo in OS mouse models [50]. These results indicate that WIF-1 can be a therapeutic agent against OS metastasis. However, the function of Wnt antagonists including WIF-1 is still unclear and further investigations are needed.
Notch signaling regulates development of many tissues and cell types through diverse effects on cell fate decision, stem cell renewal, differentiation, survival, and proliferation [87]. Notch signaling is one of several evolutionarily conserved signaling pathways in the development of multicellular organisms. Its temporal-spatial expression effects can specify diverse cellular events, including proliferation, differentiation, apoptosis, and stem cell maintenance. In mammals, there are four Notch receptors: Notch1-4, and eleven ligands [88]. The first targets of Notch are two basic helix-loop-helix transcriptional repressor families: the Hairy/enhancer-of-split (Hes) and the Hes with YRWP motif families [89]. Notch has been considered as a promoter of invasion in OS. The Notch receptor 1, 2, and Hes1 genes induced by Notch increase in highly metastatic OS. The Hes1 gene was inversely associated with the survival rate in human OS [52–55]. The OS cell invasion was reduced by an inhibition of the Notch signaling pathway whereas the cell proliferation was not blocked in a preclinical setting. The Notch-inhibited cells were less able to induce lung metastases in an orthotopic mouse than the negative controls. However, the mechanism in the inhibition of the Notch pathway and the downregulation of invasion resulted from Hes1 remains not clear [53, 55].
Src is a nonreceptor tyrosine kinase and encoded by the c-Src as a protooncogene. Src kinase activity is regulated by several receptor tyrosine kinases (RTKs) such as epidermal growth factor (EGF) RTK, PDGF-RTK, and integrin receptors [90–92]. Src family kinases are critical in the metastatic dissemination, such as cell proliferation, adhesion, invasion, survival, and angiogenesis. Either overexpression or activation of c-Src has been shown to occur in cancer development [49]. Src, involved in tumor metastasis widely, could be a novel therapeutic target in OS metastasis. Dasatinib, known as a Src kinase inhibitor, suppresses Bcr-Abl tyrosine kinase. The effect and safety of dasatinib have been established as therapeutic agent for imatinib-resistant chronic myelogenous leukemia in early-phase clinical trials. Also, several studies have shown that the dasatinib acts against Bcr-Abl-positive leukemic cell lines as well as other malignancies. The c-Src-mediated signaling pathways, related to tumor proliferation, adhesion, or migration, have been shown in various malignancies such as prostate cancer, lung cancer, and sarcoma [93–95]. In preclinical studies, dasatinib suppressed tumor migration and invasion with inhibition of the Src kinase activity and its downstream signaling in OS cell lines in vitro [48, 96]. On the other hand, dasatinib had no effect on pulmonary metastases in vivo [48]. At present, the other specific Src kinase inhibitor, called saracatinib, is under investigation in phase II clinical trial of OS lung metastases (clinicaltrials.gov/ct2/show/NCT00752206).
4. Apoptosis Resistance and OS Progression
Apoptosis is involved in cell survival in cancer metastasis through the all stages via two pathways. The first one is regulated by a death-receptor-bound to Fas or tumor-necrosis factor (TNF) family member, death-inducing signaling complex, and caspase-8. The second one is associated with p53, Bcl2 family member, cytochrome-c, and caspase-9. When caspase-8 or -9 is activated, caspases of the downstream can be cleaved inducing cell death. Fas and its ligand (FasL) belong to the TNF death receptor superfamily and regulate tumorigenesis in a variety of primary malignancies and metastases [97–99]. Fas/FasL complex, constitutively expressed in lung tissue, enhances the Fas-apoptosis pathway and leads to cell death [100, 101]. Fas receptor has been well known as a death receptor mediated apoptosis in a variety of tumor cells. Recent studies have revealed that Fas is also proapoptotic related to tumor proliferation, differentiation, and migration [102–104]. Thus, apoptosis resistance is crucial for establishment of tumor metastasis; it is implicated in treatment resistance with cancer metastasis [105]. Fas expression is often decreased in OS lung metastasis, whereas it is highly expressed in the primary tumors [100, 101, 106]. Furthermore, Fas-negative expressions correlate with tumor development and poor prognosis [100, 101, 107–109]. Inhibition of Fas signaling and/or the loss of FasL can develop the proliferation of Fas-positive OS cells in the lungs and can promote the growth of lung metastases in OS models in vivo [107].
Interleukin- (IL-) 12 increased the expressions of Fas receptor in OS lung metastasis through stimulation of the Fas promoter activity. In turn, the metastatic cells acquired the susceptibility to FasL in relation to Fas-induced apoptosis in the lung microenvironment [110]. In vivo, combination therapy of IL-12 with ifosfamide induces FasL expression, increasing the therapeutic efficacy via the Fas/FasL pathway [111]. Muramyl tripeptide phosphatidyl ethanolamine (MTP-PE) induces IL-12 production in OS patients through activation of macrophages [1, 112]. MTP-PE also up-regulates Fas expression when exogenous IL-12 is administered to the patients [106]. The combination of MTP-PE with ifosfamide induces IL-12 and FasL, respectively, consequently the clinical outcome of the treated patients can be improved through the activation of tumor apoptosis [106]. These results suggest that Fas death receptor pathway may enhance the efficacy of chemotherapy in OS.
IL-18, which is an interferon-γ-inducing factor [113], affects an antitumor effect via the activation of natural killer (NK) cells or cytotoxic T cells [113, 114], inhibition of angiogenesis [115] and induction of FasL on Fas-positive tumor cells [116]. IL-18 has been shown to inhibit metastasis in OS cells through the activation of T-cells and NK-cells and the induction of the FasL expression [117]. In addition, the combination of ifosfamide with IL-18 suppresses the development of OS lung metastasis [118]. Taken together, Fas death receptor pathway is essential in the establishment of OS lung metastasis, and it may be a novel therapeutic target. However, the molecular mechanism of the loss of Fas-mediated apoptosis in OS metastases is unknown.
5. Survival in the Blood Circulation: Anoikis Resistance
Cancer metastases require the anoikis-resisted cells to survive in the circulation. Anoikis, Greek for “homelessness,” regulates cell homeostasis in tissues. Normal epithelial cells become apoptotic when exposed to anchorage-independent environments [119, 120]. In turn, once tumor cells have entered into the bloodstream to disseminate distantly, the cell-cell adhesions or ECM attachments are lost, which results in the specific apoptosis called anoikis [121]. Therefore, metastatic cells need to acquire the resistance to anoikis to survive during dissemination and colonization of secondary distant sites in the circulation.
Acquisition of anoikis resistance has been described in nonepithelial malignancies such as OS [122]. Many studies demonstrated the survival mechanism of cancer cells in the evasion of anoikis with various means such as Src/PI3K/Akt pathway, focal adhesion kinase, or Bcl-2 [123, 124]. Several studies have shown that β4 integrin expression is involved in cancer progression [125–127]. The β4 integrin expression is also implicated in the survival of OS cells in the circulation, because knockdown of β4 integrin suppressed the cell-proliferation under anchorage-independent sites in OS cells [128]. In addition, the knockdown of β4 integrin in a mouse model inhibited lung metastases, and β4 integrin-ezrin interaction appears to be essential for β4 integrin expression. However, the relation between ezrin and β4 integrin is still unknown [128]. Cell-cell adhesions can activate integrin signaling in anchorage-independent conditions and integrin expression patterns may contribute to the resistance to anoikis [129].
Switch from αVβ5 to αVβ6 integrin may suppress anoikis in squamous cell carcinoma cells through the activation of PI3K/Akt signaling pathway [130]. The PI3K/Akt pathway, which depends on Src kinase activation, is important for human OS cells to avoid anoikis [47]. Src has another role related to anoikis resistance with caveolin-1 in OS cells. Caveolin-1 is the major protein component of caveolae [131], which regulates several intracellular signaling pathways [132]. Caveolin-1 is highly expressed in osteoblasts [133] and its overexpression in OS cells inhibited anchorage-independent growth, invasion, and migration by blocking c-Src and c-Met tyrosine kinases in vitro [134]. In addition, Caveolin-1 overexpression suppressed the OS metastasis in vivo [134].
6. Arrest and Extravasation: Final Step of Cell Migration
The mechanism of migration arrest of metastatic cells is controversial. Metastatic tumor cells are generally thought to be trapped in the microcirculation because their size is larger than that of normal cells [135]. When the tumor cells in the bloodstream are trapped, microembolisms are structured, and the interaction with the local microenvironment begins consequently. Interestingly, cancer cells have the tendency to prefer a specific target organ in metastasis processes: Over 80% of all metastases in OS occur in the lungs [136]. This result suggests that circulating tumor cells can select their optimal sites to survive and grow via interactions with distinct molecules expressed on the endothelial cells in the distant organs [16]. In the circulation, cell colonization in the distant organs is mediated through the secretion of chemokines and proteinases, involved in extravasations [15, 16]. Recently, chemokines are regarded as important factors to control a site specificity of cancer metastasis including OS-lung relation [137–140]. C-X-C-motif chemokine receptor 4 (CXCR4) and its ligand C-X-C-motif chemokine ligand 12 (CXCL12) have been shown to regulate an organ-specific metastasis by the formation of chemotactic gradients in several cancer [141–143]. Binding of CXCR4 to CXCL12 allows adhesion and extravasation of OS cells in pulmonary metastasis [138, 139, 144, 145]. These results suggest that abundant expressions of CXCL12 in the lung may be involved in the high frequency of pulmonary metastases in OS. Highly CXCR4 expressions in OS-patient samples adversely correlated to event-free, overall, and metastasis-free survival [138]. These data suggest that CXCR4 could be useful as a prognostic factor in OS metastasis.
CXCR3, another chemokine receptor, has been identified in a variety of malignancies including OS [138, 146–148]. Its ligands, CXCL9, 10, and 11, are expressed in lungs. The inhibition of CXCR3 chemokine pathway down regulates the growth of OS lung metastasis. Recent study has demonstrated that CXCR3 inhibitor decreased the proliferation, survival and invasion of the tumor cells in an animal model of OS lung metastasis. In other words, the interaction between CXCR3 and its ligands can directly enhance the invasion, survival, and proliferation of tumor cells in the metastatic organ. This result suggests that targeting CXCR3 can specifically inhibit OS lung metastasis [144].
7. Adhesion Step in the Metastatic Process
Establishment at a distant organ requires that the metastatic cell connects to its new environment and re-establishes cell-cell adhesions. Ezrin is a membrane-cytoskeleton linker protein that acts as membrane organizers and linkers between plasma membrane and cytoskeleton controlling cell-microenvironment and cell-cell interactions [149]. In addition, ezrin associates with several signaling transductions, such as Rho and PI3K/Akt pathways [150, 151]. Recently, high level expression of ezrin protein is correlated to metastasis in several cancers [152–154] as well as OS [155, 156]. High expression of ezrin is associated with pulmonary metastasis in animal models [155, 157], and with poor outcome in pediatric OS patients [155]. Phosphorylated ezrin was shown to express at just early phase in lung metastasis [155] whereas it was dynamically expressed at both the early and late time point [156].
Sorafenib is a multipotent drug, and several molecular targets of sorafenib such as Raf kinases are implicated in OS development [158, 159]. Recent preclinical study has reported that sorafenib suppressed the development of lung metastases via downregulation of ezrin-activated mitogen-activated protein kinase (MAPK)/Akt signaling [160]. In addition, sorafenib could induce apoptosis through a decrease of expression of the antiapoptotic Bcl-2 family [160]. These data suggest sorafenib may be a novel potential therapeutic option in patients with OS metastasis.
8. Main Signaling Pathways Involved in Proliferation of Metastatic OS
OS pathogenesis is clearly related with bone growth during adolescence, suggesting a potential relationship with higher expression of hormone levels [161, 162]. Thus, several studies have suggested that molecular alterations in the growth hormone (GH)/insulin-like growth factor I (IGF-I) signaling pathways could lead to OS development in vitro and in vivo [163, 164]. OS cells show both IGF-I and IGF-I receptor expression and highly response to IGF-I in vitro [164]. Serum IGF-I levels in mice with hypophysectomy are significantly downregulated, which is decreasing tumor growth and development of metastasis [165].
A phase I trial in patients with metastatic and/or recurrent OS was performed with somatostatin analog (OncoLar) to reduce serum IGF-I [166]. In this trial, OncoLar treatment in 21 OS patients resulted in a 46% decrease in serum IGF-I levels without toxicity. In a preclinical study conducted on dogs with naturally occurring OS, OncoLar [167] reduced serum IGF-I levels were by approximately 43% without toxicity. However, no difference in primary tumor necrosis, apoptosis, or survival was observed in dogs treated with a combination of OncoLar and chemotherapy in comparison with just chemotherapy. These observations indicate that the extent or duration of serum IGF-I suppression induced by OncoLar was not enough to improve a clinical outcome. IGF-I receptor (IGF-IR) axis is also implicated in OS development; inhibition of IGF-IR could inhibit tumor growth, activate apoptosis and up-regulate the chemosensitivity and radiosensitivity in OS cells [168, 169].
Recently, human monoclonal antibodies targeting the IGF-IR were tested in both preclinical and clinical studies. Inhibition of IGF-IR with some monoclonal antibodies enhances the antitumor effects in several OS xenograft models [170, 171]. More recently, a clinical study has demonstrated that high IGF-IR expression is a poor prognostic factor for OS patients leading to OS development and metastasis [172]. Thus, IGF-IR targeting therapy can be a novel strategy for the treatment of OS associated with metastasis.
9. Dormancy
Unfortunately, tumor metastasis occasionally occurs for patients with malignancies a long time after the success of primary therapy [173, 174]. This latency period is generally the result of tumor dormancy, which is frequently asymptomatic and clinically undetectable for months or years until relapse. Once tumor cells are settled in a secondary site, they can grow, die by apoptosis, or remain dormant. Two ways of tumor dormancy have been described, (i) tumor mass dormancy (dormant micrometastases) and (ii) cellular dormancy [174–176]. In dormant micrometastases, tumor cells generally divide but the growth is limited. Cellular dormancy (dormant single tumor cell) can occur when tumor cells enter in a quiescence state and do not divide any more. Tumor cells in dormancy are usually resistant to conventional drug because current treatments target cells in division. However, the mechanisms allowing dormant tumor cells to survive to conventional chemotherapies and then resume the tumor outgrowth remain unknown.
Dormant micrometastases are thought to be present under a balance between cell proliferation and apoptosis [176, 177]. Dormant state of micrometastases is involved in lack of nutrition and oxygen from vasculature in relation to angiogenic switch and/or the adaptive immune system [178–182]. Endothelial cells in the microenvironment can enhance dormant tumor cells via cell-to-cell interactions and induction of angiogenesis [180]. The ECM also plays an important role in activation of dormant cells. When tumor cells fail to adhere to the ECM, they may enter in dormancy. It has been postulated that micrometastases fail to properly connect to the ECM and survive in the dormant state because they are deprived of growth factors and angiogenic signaling. Adhesion to the ECM could induce tumor cells to switch a dormancy state to a proliferation state via integrin signaling [181]. On the other hand, both tumor cells and host stromal cells modulate the microenvironment such as ECM and vascular walls. Those mechanisms may regulate the maintenance in dormancy or the activation metastatic growth for a single tumor cell or micrometastases respectively (Figure 2) [17, 181].
Tumor metastasis dormancy is associated with the risk of recurrence of OS and late development of lung metastases. Tumor dormancy is thought to consist of tumor mass dormancy (dormant micrometastases) and cellular dormancy. In tumor mass dormancy (dormant micrometastases), tumor cells generally divide but not in cellular dormancy. The tumor growth is strictly limited by the lack of blood supply or immune system. Dormant state of micrometastases is involved in angiogenic switch and/or the adaptive immune system. Dormancy therapy could contribute to improve the treatment of patients with cancer.
In vivo molecular mechanisms of a variety of cancers including OS in dormant state have been assessed with genome transcriptional analysis [181]. This study suggests that antiangiogenic proteins such as angiomotin, which has been shown to suppress tumor growth and keep dormancy of tumor metastases [179], are upregulated during dormancy. Thus, the tumor proliferation and invasion are inhibited under preangiogenic state. Tumor cells in proliferation state also increased the key cancer pathways such as EGF receptor-1, IGF-IR, and PI3K. The mechanism of regulating tumor dormancy is unknown in OS. However, if it is possible to induce and/or keep in a dormant state or to induce cell death in residual dormant cells by targeting their survival and drug resistance mechanisms, the treatment for the patients with OS may be further improved.
10. Conclusion
OS associated with metastases still have poor clinical outcome, and conventional therapies are not fully effective. In addition, clinical output of novel available chemotherapeutic approaches is still unclear. Recent studies have disclosed new insights into the molecular mechanisms of metastasis as above mentioned. However, much more unknown questions remain; determinant factors of selective colonization in different organs, the mechanisms of tumor dormancy, and the mechanisms of metastasis suppressors, and so forth. Thus, future research critically needs to be directed towards identifying the molecular alterations in OS microenvironments.
Acknowledgment
Dr. K. Ando received a postdoctoral fellowship from the Région des Pays de La Loire (France).
MeyersP. A.GorlickR.Osteosarcoma19974449739892-s2.0-003075437010.1016/S0031-3955(05)70540-XRosenG.CaparrosB.HuvosA. G.Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy1982496122112302-s2.0-0020059356BacciG.LonghiA.CesariM.VersariM.BertoniF.Influence of local recurrence on survival in patients with extremity osteosarcoma treated with neoadjuvant chemotherapy: the experience of a single institution with 44 patients200610612270127062-s2.0-3374519418210.1002/cncr.21937BrulandO. S.PihlA.On the current management of osteosarcoma. A critical evaluation and a proposal for a modified treatment strategy19973311172517312-s2.0-003140661910.1016/S0959-8049(97)00252-9LonghiA.ErraniC.De PaolisM.MercuriM.BacciG.Primary bone osteosarcoma in the pediatric age: state of the art20063264234362-s2.0-3374815654510.1016/j.ctrv.2006.05.005HeymannD.RédiniF.Bone sarcomas: pathogenesis and new therapeutic approaches201189402414HeymannD.2010Academic PressBacciG.FerrariS.LonghiA.PerinS.ForniC.FabbriN.SalducaN.VersariM.SmithK. V. J.Pattern of relapse in patients with osteosarcoma of the extremities treated with neoadjuvant chemotherapy200137132382-s2.0-003514456010.1016/S0959-8049(00)00361-0DunnD.DehnerL. P.Metastatic osteosarcoma to lung: a clinicopathologic study of surgical biopsies and resections1977406305430642-s2.0-0017708682EnnekingW. F.SpanierS. S.GoodmanM. A.A system for the surgical staging of musculoskeletal sarcoma19801531061202-s2.0-0019202519FolkmanJ.The role of angiogenesis in tumor growth19923265712-s2.0-0026846928ThompsonW. D.ShiachK. J.FraserR. A.Tumours acquire their vasculature by vessel incorporation, not vessel ingrowth198715143233322-s2.0-0023243816SengerD. R.GalliS. J.DvorakA. M.PerruzziC. A.Susan HarveyV.DvorakH. F.Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid198321945879839852-s2.0-0021111648LeungD. W.CachianesG.KuangW. J.GoeddelD. V.FerraraN.Vascular endothelial growth factor is a secreted angiogenic mitogen19892464935130613092-s2.0-0024818355EcclesS. A.WelchD. R.Metastasis: recent discoveries and novel treatment strategies20073699574174217572-s2.0-3424859455310.1016/S0140-6736(07)60781-8SteegP. S.Tumor metastasis: mechanistic insights and clinical challenges20061288959042-s2.0-3374685195610.1038/nm1469KaplanR. N.PsailaB.LydenD.Bone marrow cells in the “pre-metastatic niche”: within bone and beyond20062545215292-s2.0-3384604475010.1007/s10555-006-9036-9DanøK.AndreasenP. A.Grøndahl-HansenJ.KristensenP.NielsenL. S.SkriverL.Plasminogen activators, tissue degradation, and cancer1985441392662-s2.0-002178094910.1016/S0065-230X(08)60028-7GeorgesS.Ruiz VelascoC.TrichetV.FortunY.HeymannD.PadrinesM.Proteases and bone remodelling200920129412-s2.0-6094908978210.1016/j.cytogfr.2008.11.005BergersG.BrekkenR.McMahonG.VuT. H.ItohT.TamakiK.TanzawaK.ThorpeP.ItoharaS.WerbZ.HanahanD.Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis20002107377442-s2.0-000039174610.1038/35036374IozzoR. V.ZoellerJ. J.NyströmA.Basement membrane proteoglycans: modulators par excellence of cancer growth and angiogenesis20092755035132-s2.0-6674909883210.1007/s10059-009-0069-0LeeY. H.TokunagaT.OshikaY.SutoR.YanagisawaK.TomisawaM.FukudaH.NakanoH.AbeS.TateishiA.KijimaH.YamazakiH.TamaokiN.UeyamaY.NakamuraM.Cell-retained isoforms of vascular endothelial growth factor (VEGF) are correlated with poor prognosis in osteosarcoma1999357108910932-s2.0-003316689410.1016/S0959-8049(99)00073-8KayaM.WadaT.AkatsukaT.KawaguchiS.NagoyaS.ShindohM.HigashinoF.MezawaF.OkadaF.IshiiS.Vascular endothelial growth factor expression in untreated osteosarcoma is predictive of pulmonary metastasis and poor prognosis2000625725772-s2.0-18844467502FranchiA.ArganiniL.BaroniG.CalzolariA.CapannaR.CampanacciD.CaldoraP.MasiL.BrandiM. L.ZampiG.Expression of transforming growth factor β isoforms in osteosarcoma variants: association of TGFβ1 with high-grade osteosarcomas199818532842892-s2.0-003187333510.1002/(SICI)1096-9896(199807)185:3<284::AID-PATH94>3.0.CO;2-ZScotlandiK.PicciP.KovarH.Targeted therapies in bone sarcomas2009978438532-s2.0-7284913018310.2174/156800909789760410AbdeenA.ChouA. J.HealeyJ. H.KhannaC.OsborneT. S.HewittS. M.KimM.WangD.MoodyK.GorlickR.Correlation between clinical outcome and growth factor pathway expression in osteogenic sarcoma200911522524352502-s2.0-7044937212110.1002/cncr.24562MantadakisE.KimG.ReischJ.McHardK.MaaleG.LeaveyP. J.TimmonsC.Lack of prognostic significance of intratumoral angiogenesis in nonmetastatic osteosarcoma20012352862892-s2.0-003492362010.1097/00043426-200106000-00010MikulicD.dank.mikulic@zg.tel.hrIlićI.ĆepulićM.OrlićD.GiljevićJ. S.FattoriniI.SeiwerthS.Tumor angiogenesis and outcome in osteosarcoma200421761161910.1080/08880010490501015KreuterM.BiekerR.BielaekS. S.AurasT.BuergerH.GoshegerG.JurgensH.BerdelW. E.MestersR. M.Prognostic relevance of increased angiogenesis in osteosarcoma20041024853185372-s2.0-1114424549910.1158/1078-0432.CCR-04-0969O'ReillyM. S.HolmgrenL.ShingY.ChenC.RosenthalR. A.MosesM.LaneW. S.CaoY.SageE. H.FolkmanJ.Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma19947923153282-s2.0-002797009210.1016/0092-8674(94)90200-3O'ReillyM. S.BoehmT.ShingY.FukaiN.VasiosG.LaneW. S.FlynnE.BirkheadJ. R.OlsenB. R.FolkmanJ.Endostatin: an endogenous inhibitor of angiogenesis and tumor growth19978822772852-s2.0-003145461710.1016/S0092-8674(00)81848-6DhanabalM.VolkR.RamchandranR.SimonsM.SukhatmeV. P.Cloning, expression, and in vitro activity of human endostatin199925823453522-s2.0-003354212910.1006/bbrc.1999.0595BlezingerP.WangJ.GondoM.QuezadaA.MehrensD.FrenchM.SinghalA.SullivanS.RollandA.RalstonR.MinW.Systemic inhibition of tumor growth and tumor metastases by intramuscular administration of the endostatin gene19991743433482-s2.0-003289217910.1038/7895YoonS. S.EtoH.LinC. M.NakamuraH.PawlikT. M.SongS. U.TanabeK. K.Mouse endostatin inhibits the formation of lung and liver metastases19995924625162562-s2.0-0033572414YokoyamaY.DhanabalM.GriffioenA. W.SukhatmeV. P.RamakrishnanS.Synergy between angiostatin and endostatin: inhibition of ovarian cancer growth2000608219021962-s2.0-0034655135KiskerO.BeckerC. M.ProxD.FannonM.D'AmatoR.FlynnE.FoglerW. E.SimB. K. L.AllredE. N.Pirie-ShepherdS. R.FolkmanJ.Continuous administration of endostatin by intraperitoneally implanted osmotic pump improves the efficacy and potency of therapy in a mouse xenograft tumor model20016120766976742-s2.0-0035887379ShiW.TeschendorfC.MuzyczkaN.SiemannD. W.Adeno-associated virus-mediated gene transfer of endostatin inhibits angiogenesis and tumor growth in vivo2002965135212-s2.0-003627567510.1038/sj.cgt.7700463FeldmanA. L.AlexanderH. R.HewittS. M.LorangD.ThiruvathukalC. E.TurnerE. M.LibuttiS. K.Effect of retroviral endostatin gene transfer on subcutaneous and intraperitoneal growth of murine tumors20019313101410202-s2.0-0035806489MundhenkeC.ThomasJ. P.WildingG.LeeF. T.KelzcF.ChappellR.NeiderR.SebreeL. A.FriedlA.Tissue examination to monitor antiangiogenic therapy: a phase I clinical trial with endostatin2001711336633742-s2.0-0035187305EderJ. P.Jr.SupkoJ. G.ClarkJ. W.PuchalskiT. A.Garcia-CarboneroR.RyanD. P.ShulmanL. N.ProperJ.KirvanM.RattnerB.ConnorsS.KeoganM. T.JanicekM. J.FoglerW. E.SchnipperL.KinchlaN.SidorC.PhillipsE.FolkmanJ.KufeD. W.Phase I clinical trial of recombinant human endostatin administered as a short intravenous infusion repeated daily20022018377237842-s2.0-003710650810.1200/JCO.2002.02.082HerbstR. S.HessK. R.TranH. T.TsengJ. E.MullaniN. A.CharnsangavejC.MaddenT.DavisD. W.McConkeyD. J.O'ReillyM. S.EllisL. M.PludaJ.HongW. K.AbbruzzeseJ. L.Phase I study of recombinant human endostatin in patients with advanced solid tumors20022018379238032-s2.0-003710626110.1200/JCO.2002.11.061ThomasJ. P.ArzoomanianR. Z.AlbertiD.MarnochaR.LeeF.FriedlA.TutschK.DresenA.GeigerP.PludaJ.FoglerW.SchillerJ. H.WildingG.Phase I pharmacokinetic and pharmacodynamic study of recombinant human endostatin in patients with advanced solid tumors20032122232312-s2.0-003744012310.1200/JCO.2003.12.120DeschaseauxF.SensébéL.HeymannD.Mechanisms of bone repair and regeneration20091594174292-s2.0-7024914728510.1016/j.molmed.2009.07.002BjornlandK.FlatmarkK.PettersenS.AaasenA. O.FodstadØ.MælandsmoG. M.Matrix metalloproteinases participate in osteosarcoma invasion200512721511562-s2.0-2314445531210.1016/j.jss.2004.12.016KansaraM.ThomasD. M.Molecular pathogenesis of osteosarcoma20072611182-s2.0-3384688263010.1089/dna.2006.0505FanD. G.DaiJ. Y.TangJ.WuM. M.SunS. G.JiangJ. L.FanQ. Y.Silencing of calpain expression reduces the metastatic potential of human osteosarcoma cells20093312126312672-s2.0-7154916927610.1016/j.cellbi.2009.08.014Díaz-MonteroC. M.WygantJ. N.McIntyreB. W.PI3-K/Akt-mediated anoikis resistance of human osteosarcoma cells requires Src activation20064210149115002-s2.0-3374518256410.1016/j.ejca.2006.03.007HingoraniP.ZhangW.GorlickR.KolbE. A.Inhibition of Src phosphorylation alters metastatic potential of osteosarcoma in vitro but not in vivo20091510341634222-s2.0-6614919240910.1158/1078-0432.CCR-08-1657KimL. C.SongL.HauraE. B.Src kinases as therapeutic targets for cancer20096105875952-s2.0-7034975851010.1038/nrclinonc.2009.129RubinE. M.GuoY.TuK.XieJ.ZiX.HoangB. H.Wnt inhibitory factor 1 decreases tumorigenesis and metastasis in osteosarcoma2010937317412-s2.0-7794966798410.1158/1535-7163.MCT-09-0147GuoY.ZiX.KoontzZ.KimA.XieJ.GorlickR.HolcombeR. F.HoangB. H.Blocking Wnt/LRP5 signaling by a soluble receptor modulates the epithelial to mesenchymal transition and suppresses met and metalloproteinases in osteosarcoma Saos-2 cells20072579649712-s2.0-3444727947610.1002/jor.20356EnginF.BertinT.MaO.JiangM. M.WangL.SuttonR. E.DonehowerL. A.LeeB.Notch signaling contributes to the pathogenesis of human osteosarcomas2009188146414702-s2.0-6454914929210.1093/hmg/ddp057HughesD. P. M.How the NOTCH pathway contributes to the ability of osteosarcoma cells to metastasize20091524794962-s2.0-7795367475410.1007/978-1-4419-0284-9_28TanakaM.SetoguchiT.HirotsuM.GaoH.SasakiH.MatsunoshitaY.KomiyaS.Inhibition of Notch pathway prevents osteosarcoma growth by cell cycle regulation200910012195719652-s2.0-6734918292310.1038/sj.bjc.6605060ZhangP.YangY.Zweidler-McKayP. A.HughesD. P. M.Critical role of notch signaling in osteosarcoma invasion and metastasis20081410296229692-s2.0-4964910379310.1158/1078-0432.CCR-07-1992SoiniY.SattaJ.MäättäM.Autio-HarmainenH.Expression of MMP2, MMP9, MT1-MMP, TIMP1, and TIMP2 mRNA in valvular lesions of the heart20011942225231KatoY.YamashitaT.IshikawaM.Relationship between expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 and invasion ability of cervical cancer cells2002935655692-s2.0-0036581406LeeP. P. H.HwangJ. J.MurphyG.IpM. M.Functional significance of MMP-9 in tumor necrosis factor-induced proliferation and branching morphogenesis of mammary epithelial cells200014110376437732-s2.0-0033752746SoreideK.JanssenE. A.KömerH.BaakJ. P. A.Trypsin in colorectal cancer: molecular biological mechanisms of proliferation, invasion, and metastasis200620921471562-s2.0-3374445767810.1002/path.1999ChengY. Y.HuangL.LeeK. M.LiK.KumtaS. M.Alendronate regulates cell invasion and MMP-2 secretion in human osteosarcoma cell lines20044254104152-s2.0-194245471410.1002/pbc.20019HeikkilaP.TeronenO.HirnM. Y.SorsaT.TervahartialaT.SaloT.KonttinenY. T.HalttunenT.MoilanenM.HanemaaijerR.LaitinenM.Inhibition of matrix metalloproteinase-14 in osteosarcoma cells by clodronate2003111145522-s2.0-003831001110.1016/S0022-4804(03)00000-0XinZ. F.KimY. K.JungS. T.Risedronate inhibits human osteosarcoma cell invasion2009281, article 1052-s2.0-6924913627310.1186/1756-9966-28-105HeymannD.OryB.GouinF.GreenJ. R.RédiniF.Bisphosphonates: new therapeutic agents for the treatment of bone tumors20041073373432-s2.0-304279696410.1016/j.molmed.2004.05.007MoriceauG.OryB.GobinB.VerrecchiaF.GouinF.BlanchardF.RediniF.HeymannD.Therapeutic approach of primary bone tumours by bisphosphonates20101627298129872-s2.0-7864984153210.2174/138161210793563554ChoH. J.LeeT. S.ParkJ. B.ParkK. K.ChoeJ. Y.SinD. I.ParkY. Y.MoonY. S.LeeK. G.YeoJ. H.HanS. M.ChoY. S.ChoiM. R.ParkN. G.LeeY. S.ChangY. C.Disulfiram suppresses invasive ability of osteosarcoma cells via the inhibition of MMP-2 and MMP-9 expression2007406106910762-s2.0-36949040617MacsaiC. E.FosterB. K.XianC. J.Roles of Wnt signalling in bone growth, remodelling, skeletal disorders and fracture repair200821535785872-s2.0-4294911732310.1002/jcp.21342GlassD. A.BialekP.AhnJ. D.StarbuckM.PatelM. S.CleversH.TaketoM. M.LongF.McMahonA. P.LangR. A.KarsentyG.Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation2005857517642-s2.0-2024437361310.1016/j.devcel.2005.02.017KawanoY.KyptaR.Secreted antagonists of the Wnt signalling pathway200311613262726342-s2.0-003878331610.1242/jcs.00623BaronR.RawadiG.Minireview: targeting the Wnt/β-catenin pathway to regulate bone formation in the adult skeleton20071486263526432-s2.0-3425082397310.1210/en.2007-0270CanalisE.GiustinaA.BilezikianJ. P.Mechanisms of anabolic therapies for osteoporosis200735798509162-s2.0-3454830640810.1056/NEJMra067395HsiehJ. C.KodjabachianL.RebbertM. L.RattnerA.SmallwoodP. M.SamosC. H.NusseR.DawidI. B.NathansJ.A new secreted protein that binds to Wnt proteins and inhibits their activites199939867264314362-s2.0-003311849210.1038/18899TetsuO.McCormickF.β-catenin regulates expression of cyclin D1 in colon carcinoma cells199939867264224262-s2.0-003311980110.1038/18884HeT. C.SparksA. B.RagoC.HermekingH.ZawelL.Da CostaL. T.MorinP. J.VogelsteinB.KinzlerK. W.Identification of c-MYC as a target of the APC pathway19982815382150915122-s2.0-003248343910.1126/science.281.5382.1509CrawfordH. C.FingletonB. M.Rudolph-OwenL. A.Heppner GossK. J.RubinfeldB.PolakisP.MatrisianL. M.The metalloproteinase matrilysin is a target of β-catenin transactivation in intestinal tumors19991818288328912-s2.0-003352912610.1038/sj.onc.1202627KimP. J.PlesciaJ.CleversH.FearonE. R.AltieriD. C.Survivin and molecular pathogenesis of colorectal cancer200336293792052092-s2.0-003849821310.1016/S0140-6736(03)13910-4HaydonR. C.DeyrupA.IshikawaA.HeckR.JiangW.ZhouL.FengT.KingD.ChengH.BreyerB.PeabodyT.SimonM. A.MontagA. G.HeT. C.Cytoplasmic and/or nuclear accumulation of the β-catenin protein is a frequent event in human osteosarcoma200210243383422-s2.0-003688830910.1002/ijc.10719IwayaK.OgawaH.KurodaM.IzumiM.IshidaT.MukaiK.Cytoplasmic and/or nuclear staining of beta-catenin is associated with lung metastasis20032065255292-s2.0-014202999310.1023/A:1025821229013IwaoK.MiyoshiY.NawaG.YoshikawaH.OchiT.NakamuraY.Frequent β-catenin abnormalities in bone and soft-tissue tumors19999022052092-s2.0-0033052527HoangB. H.KuboT.HealeyJ. H.SowersR.MazzaB.YangR.HuvosA. G.MeyersP. A.GorlickR.Expression of LDL receptor-related protein 5 (LRP5) as a novel marker for disease progression in high-grade osteosarcoma200410911061112-s2.0-074228787810.1002/ijc.11677HoangB. H.KuboT.HealeyJ. H.YangR.NathanS. S.KolbE. A.MazzaB.MeyersP. A.GorlickR.Dickkopf 3 inhibits invasion and motility of Saos-2 osteosarcoma cells by modulating the Wnt-β-catenin pathway2004648273427392-s2.0-924424066410.1158/0008-5472.CAN-03-1952PolakisP.Wnt signaling and cancer20001415183718512-s2.0-0033895709LeowP. C.TianQ.OngZ. Y.YangZ.EeP. L. R.Antitumor activity of natural compounds, curcumin and PKF118-310, as Wnt/β-catenin antagonists against human osteosarcoma cells20102867667822-s2.0-7795437598710.1007/s10637-009-9311-zMazieresJ.HeB.YouL.XuZ.LeeA. Y.MikamiI.ReguartN.RosellR.McCormickF.JablonsD. M.Wnt inhibitory factor-1 is silenced by promoter hypermethylation in human lung cancer20046414471747202-s2.0-314267945310.1158/0008-5472.CAN-04-1389LinY. C.YouL.XuZ.HeB.MikamiI.ThungE.ChouJ.KuchenbeckerK.KimJ.RazD.YangC. T.ChenJ. K.JablonsD. M.Wnt signaling activation and WIF-1 silencing in nasopharyngeal cancer cell lines200634126356402-s2.0-3144445576610.1016/j.bbrc.2005.12.220AiL.TaoQ.ZhongS.FieldsC. R.KimW. J.LeeM. W.CuiY.BrownK. D.RobertsonK. D.Inactivation of Wnt inhibitory factor-1 (WIF1) expression by epigenetic silencing is a common event in breast cancer2006277134113482-s2.0-3374563486410.1093/carcin/bgi379YamashitaS.TsujinoY.MoriguchiK.TatematsuM.UshijimaT.Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2′-deoxycytidine treatment and oligonucleotide microarray200697164712-s2.0-3294448103710.1111/j.1349-7006.2006.00136.xArtavanis-TsakonasS.RandM. D.LakeR. J.Notch signaling: cell fate control and signal integration in development199928454157707762-s2.0-003361752210.1126/science.284.5415.770KopanR.IlaganM. X.The canonical notch signaling pathway: unfolding the activation mechanism200913722162332-s2.0-6424917220310.1016/j.cell.2009.03.045IsoT.KedesL.HamamoriY.HES and HERP families: multiple effectors of the Notch signaling pathway200319432372552-s2.0-003736392210.1002/jcp.10208MaaM. C.LeuT. H.MccarleyD. J.SchatzmanR. C.ParsonsS. J.Potentiation of epidermal growth factor receptor-mediated oncogenesis by c-Src: implications for the etiology of multiple human cancers19959215698169852-s2.0-002912126710.1073/pnas.92.15.6981MoriS.RonnstrandL.YokoteK.EngstromA.CourtneidgeS. A.Claesson-WelshL.HeldinC. H.Identification of two juxtamembrane autophosphorylation sites in the PGDF β-receptor; Involvement in the interaction with Src family tyrosine kinases1993126225722642-s2.0-0027251468PlayfordM. P.SchallerM. D.The interplay between Src and integrins in normal and tumor biology20042348792879462-s2.0-794423325110.1038/sj.onc.1208080TalpazM.ShahN. P.KantarjianH.DonatoN.NicollJ.PaquetteR.CortesJ.O'BrienS.NicaiseC.BleickardtE.Blackwood-ChirchirM. A.IyerV.ChenT. T.HuangF.DecillisA. P.SawyersC. L.Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias200635424253125412-s2.0-3374510255510.1056/NEJMoa055229JohnsonF. M.SaigalB.TalpazM.DonatoN. J.Dasatinib (BMS-354825) tyrosine kinase inhibitor suppresses invasion and induces cell cycle arrest and apoptosis of head and neck squamous cell carcinoma and non-small cell lung cancer cells20051119, part 1692469322-s2.0-2644446815210.1158/1078-0432.CCR-05-0757SchittenhelmM. M.ShiragaS.SchroederA.CorbinA. S.GriffithD.LeeF. Y.BokemeyerC.DeiningerM. W. N.DrukerB. J.HeinrichM. C.Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies20066614734812-s2.0-3154445927210.1158/0008-5472.CAN-05-2050ShorA. C.KeschmanE. A.LeeF. Y.Muro-CachoC.LetsonG. D.TrentJ. C.PledgerW. J.JoveR.Dasatinib inhibits migration and invasion in diverse human sarcoma cell lines and induces apoptosis in bone sarcoma cells dependent on Src kinase for survival2007676280028082-s2.0-3404726569110.1158/0008-5472.CAN-06-3469Owen-SchaubL. B.Van GolenK. L.HillL. L.PriceJ. E.Fas and Fas ligand interactions suppress melanoma lung metastasis19981889171717232-s2.0-003247660910.1084/jem.188.9.1717SayersT. J.BrooksA. D.LeeJ. K.FentonR. G.KomschliesK. L.WiggintonJ. M.Winkler-PickettR.WiltroutR. H.Molecular mechanisms of immune-mediated lysis of murine renal cancer: differential contributions of perforin-dependent versus fas-mediated pathways in lysis by NK and T cells19981618395739652-s2.0-0032532283LeeJ. K.SayersT. J.BrooksA. D.BackT. C.YoungH. A.KomschliesK. L.WiggintonJ. M.WiltroutR. H.IFN-γ-dependent delay of in vivo tumor progression by Fas overexpression on murine renal cancer cells200016412312392-s2.0-0033985454GordonN.ArndtC. A.HawkinsD. S.DohertyD. K.InwardsC. Y.MunsellM. F.StewartJ.KoshkinaN. V.KleinermanE. S.ekleiner@mdanderson.orgFas expression in lung metastasis from osteosarcoma patients2005271161161510.1097/01.mph.0000188112.42576.dfWorthL. L.LafleurE. A.JiaS. F.KleinermanE. S.Fas expression inversely correlates with metastatic potential in osteosarcoma cells2002948238272-s2.0-0036636786PeterM. E.BuddR. C.DesbaratsJ.HedrickS. M.HueberA. O.NewellM. K.OwenL. B.PopeR. M.TschoppJ.WajantH.WallachD.WiltroutR. H.ZörnigM.LynchD. H.The CD95 receptor: apoptosis revisited200712934474502-s2.0-3424753668210.1016/j.cell.2007.04.031ChenL.ParkS. M.TumanovA. V.HauA.SawadaK.FeigC.TurnerJ. R.FuY. X.RomeroI. L.LengyelE.PeterM. E.CD95 promotes tumour growth201046572974924962-s2.0-7795297386010.1038/nature09075StrasserA.JostP. J.NagataS.The many roles of FAS receptor signaling in the immune system20093021801922-s2.0-6014908539610.1016/j.immuni.2009.01.001IgneyF. H.KrammerP. H.Death and anti-death: tumour resistance to apoptosis2002242772882-s2.0-0036547417GorlickR.AndersonP.AndrulisI.ArndtC.BeardsleyG. P.BernsteinM.BridgeJ.CheungN. K.DomeJ. S.EbbD.GardnerT.GebhardtM.GrierH.HansenM.HealeyJ.HelmanL.HockJ.HoughtonJ.HoughtonP.HuvosA.KhannaC.KieranM.KleinermanE.LadanyiM.LauC.MalkinD.MarinaN.MeltzerP.MeyersP.SchofieldD.SchwartzC.SmithM. A.ToretskyJ.TsokosM.WexlerL.WiggintonJ.WithrowS.SchoenfeldtM.AndersonB.Biology of ghildhood osteogenic sarcoma and potential targets for therapeutic development: meeting summary2003915544254532-s2.0-0344198135KoshkinaN. V.KhannaC.MendozaA.GuanH.DeLauterL.KleinermanE. S.Fas-negative osteosarcoma tumor cells are selected during metastasis to the lungs: the role of the fas pathwayin the metastatic process of osteosarcoma20075109919992-s2.0-3594895198910.1158/1541-7786.MCR-07-0007LafleurE. A.JiaS. F.WorthL. L.ZhouZ.Owen-SchaubL. B.KleinermanE. S.Interleukin (IL)-12 and IL-12 gene transfer up-regulate Fas expression in human osteosarcoma and breast cancer cells20016110406640712-s2.0-0035872424LafleurE. A.KoshkinaN. V.StewartJ.JiaS. F.WorthL. L.DuanX.KleinermanE. S.Increased Fas expression reduces the metastatic potential of human osteosarcoma cells20041023811481192-s2.0-974423516710.1158/1078-0432.CCR-04-0353ZhouZ.LafleurE. A.KoshkinaN. V.WorthL. L.LesterM. S.KleinermanE. S.Interleukin-12 up-regulates Fas expression in human osteosarcoma and Ewing's sarcoma cells by enhancing its promoter activity20053126856912-s2.0-2994444236010.1158/1541-7786.MCR-05-0092DuanX.JiaS. F.KoshkinaN.KleinermanE. S.Intranasal interleukin-12 gene therapy enhanced the activity of ifosfamide against osteosarcoma lung metastases20061066138213882-s2.0-3364483808010.1002/cncr.21744MoriK.AndoK.HeymannD.Liposomal muramyl tripeptide phosphatidyl ethanolamine: a safe and effective agent against osteosarcoma pulmonary metastases2008821511592-s2.0-4074914346010.1586/14737140.8.2.151Lebel-BinayS.BergerA.ZinzindohouéF.CugneneP. H.ThiounnN.FridmanW. H.PagèsF.Interleukin-18: biological properties and clinical implications200011115252-s2.0-0012122533GolabJ.Interleukin 18—Interferon γ inducing factor—a novel player in tumour immunotherapy?20001243323382-s2.0-003392424810.1006/cyto.1999.0563CaoR.FarneboJ.KurimotoM.CaoY.Interleukin-18 acts as an angiogenesis and tumor suppressor19991315219522022-s2.0-0032786495OhtsukiT.MicallefM. J.KohnoK.TanimotoT.IkedaM.KurimotoM.Interleukin 18 enhances Fas ligand expression and induces apoptosis in Fas-expressing human myelomonocytic KG-1 cells1997175325332582-s2.0-0030728769NakamuraY.YamadaN.ynaoko@hyo-med.ac.jpOhyamaH.NakashoK.NishizawaY.OkamotoT.FutaniH.YoshiyaS.OkamuraH.TeradaN.Effect of interleukin-18 on metastasis of mouse osteosarcoma cells20065591151115810.1007/s00262-005-0097-3YamadaN.HataM.OhyamaH.YamanegiK.KogoeN.NakashoK.FutaniH.OkamuraH.TeradaN.Immunotherapy with interleukin-18 in combination with preoperative chemotherapy with ifosfamide effectively inhibits postoperative progression of pulmonary metastases in a mouse osteosarcoma model20093041761842-s2.0-6974910273610.1159/000236410BoudreauN.SympsonC. J.WerbZ.BissellM. J.Suppression of ICE and apoptosis in mammary epithelial cells by extracellular matrix199526751998918932-s2.0-0028927484GrossmannJ.WaltherK.ArtingerM.KiesslingS.SchölmerichJ.Apoptotic signaling during initiation of detachment-induced apoptosis ("anoikis") of primary human intestinal epithelial cells20011231471552-s2.0-0034913123FrischS. M.ScreatonR. A.Anoikis mechanisms20011355555622-s2.0-003548003210.1016/S0955-0674(00)00251-9Diaz-MonteroC. M.McIntyreB. W.Acquisition of anoikis resistance in human osteosarcoma cells20033916239524022-s2.0-014148322210.1016/S0959-8049(03)00575-6LiottaL. A.KohnE.Anoikis: cancer and the homeless cell200443070039739742-s2.0-434468743410.1038/430973aMehlenP.PuisieuxA.Metastasis: a question of life or death2006664494582-s2.0-3374568452710.1038/nrc1886TrusolinoL.BertottiA.ComoglioP. M.A signaling adapter function for α6β4 integrin in the control of HGF-dependent invasive growth200110756436542-s2.0-003597714710.1016/S0092-8674(01)00567-0NikolopoulosS. N.BlaikieP.YoshiokaT.GuoW.GiancottiF. G.Integrin β4 signaling promotes tumor angiogenesis2004654714832-s2.0-794422401210.1016/j.ccr.2004.09.029GuoW.PylayevaY.PepeA.YoshiokaT.MullerW. J.InghiramiG.GiancottiF. G.β4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis200612634895022-s2.0-3374676445710.1016/j.cell.2006.05.047WanX.KimS. Y.GuentherL. M.MendozaA.BriggsJ.YeungC.CurrierD.ZhangH.MacKallC.LiW. J.TuanR. S.DeyrupA. T.KhannaC.HelmanL.Beta4 integrin promotes osteosarcoma metastasis and interacts with ezrin20092838340134112-s2.0-7034944096610.1038/onc.2009.206ChiarugiP.GiannoniE.Anoikis: a necessary death program for anchorage-dependent cells20087611135213642-s2.0-5594912846510.1016/j.bcp.2008.07.023JanesS. M.WattF. M.fiona.watt@cancer.org.ukSwitch from αvβ5 to αvβ6 integrin expression protects squamous cell carcinomas from anoikis2004166341943110.1083/jcb.200312074StanR. V.Radu.V.Stan@Dartmouth.eduStructure of caveolae20051746333434810.1016/j.bbamcr.2005.08.008RothbergK. G.HeuserJ. E.DonzellW. C.YingY. S.GlenneyJ. R.AndersonR. G. W.Caveolin, a protein component of caveolae membrane coats19926846736822-s2.0-0026559095SolomonK. R.DanciuT. E.AdolphsonL. D.HechtL. E.HauschkaP. V.Caveolin-enriched membrane signaling complexes in human and murine osteoblasts20001512238023902-s2.0-0033695837CantianiL.ManaraM. C.ZucchiniC.De SanctisP.ZuntiniM.ValvassoriL.SerraM.OliveroM.Di RenzoM. F.ColomboM. P.PicciP.ScotlandiK.Caveolin-1 reduces osteosarcoma metastases by inhibiting c-Src activity and met signaling20076716767576852-s2.0-3454802914310.1158/0008-5472.CAN-06-4697Al-MehdiA. B.TozawaK.FisherA. B.ShientagL.LeeA.MuschelR. J.Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis2000611001022-s2.0-003397205910.1038/71429JeffreeG. M.PriceC. H.SissonsH. A.The metastatic patterns of osteosarcoma1975321871072-s2.0-0016747453LinF.ZhengS.-E.ShenZ.TangL.-N.ChenP.SunY.-J.ZhaoH.YaoY.larry_lin57@hotmail.comRelationships between levels of CXCR4 and VEGF and blood-borne metastasis and survival in patients with osteosarcoma201128264965310.1007/s12032-010-9493-4LaverdiereC.HoangB. H.YangR.SowersR.QinJ.MeyersP. A.HuvosA. G.HealeyJ. H.GorlickR.Messenger RNA expression levels of CXCR4 correlate with metastatic behavior and outcome in patients with osteosarcoma2005117256125672-s2.0-1764442069110.1158/1078-0432.CCR-04-1089HuangC. Y.LeeC. Y.ChenM. Y.YangW. H.ChenY. H.ChangC. H.HsuH. C.FongY. C.TangC. H.Stromal cell-derived factor-1/CXCR4 enhanced motility of human osteosarcoma cells involves MEK1/2, ERK and NF-κB-dependent pathways200922112042122-s2.0-6924924704810.1002/jcp.21846MurphyP. M.Chemokines and the molecular basis of cancer metastasis2001345118338352-s2.0-003585601010.1056/NEJM200109133451113MüllerA.HomeyB.SotoH.GeN.CatronD.BuchananM. E.McClanahanT.MurphyE.YuanW.WagnerS. N.BarreraJ. L.MoharA.VerásteguiE.ZlotnikA.Involvement of chemokine receptors in breast cancer metastasis2001410682450562-s2.0-003528243210.1038/35065016MurakamiT.MakiW.CardonesA. R.FangH.Tun KyiA.NestleF. O.HwangS. T.Expression of CXC chemokine receptor-4 enhances the pulmonary metastatic potential of murine B16 melanoma cells20026224732873342-s2.0-0037115647ScottonC. J.WilsonJ. L.ScottK.StampG.WilbanksG. D.FrickerS.BridgerG.BalkwillF. R.Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer20026220593059382-s2.0-0037108923PradelliE.Karimdjee-SoilihiB.MichielsJ. F.RicciJ. E.MilletM. A.VandenbosF.SullivanT. J.CollinsT. L.JohnsonM. G.MedinaJ. C.KleinermanE. S.Schmid-AllianaA.Schmid-AntomarchiH.Antagonism of chemokine receptor CXCR3 inhibits osteosarcoma metastasis to lungs200912511258625942-s2.0-7035070775910.1002/ijc.24665de NigrisF.RossielloR.SchianoC.ArraC.Williams-IgnarroS.BarbieriA.LanzaA.BalestrieriA.GiulianoM. T.IgnarroL. J.NapoliC.Deletion of Yin Yang 1 protein in osteosarcoma cells on cell invasion and CXCR4/angiogenesis and metastasis2008686179718082-s2.0-4094912025010.1158/0008-5472.CAN-07-5582RobledoM. M.BartoloméR. A.LongoN.Rodriguez-FradeJ. M.MelladoM.LongoI.Van MuijenG. N. P.Sánchez-MateosP.TeixidóJ.Expression of functional chemokine receptors CXCR3 and CXCR4 on human melanoma cells20012764845098451052-s2.0-003597689910.1074/jbc.M106912200JonesD.BenjaminR. J.ShahsafaeiA.DorfmanD. M.The chemokine receptor CXCR3 is expressed in a subset of B-cell lymphomas and is a marker of B-cell chronic lymphocytic leukemia20009526276322-s2.0-0034651010Goldberg-BittmanL.NeumarkE.Sagi-AssifO.AzenshteinE.MeshelT.WitzI. P.Ben-BaruchA.The expression of the chemokine receptor CXCR3 and its ligand, CXCL10, in human breast adenocarcinoma cell lines2004921-21711782-s2.0-184266306810.1016/j.imlet.2003.10.020MangeatP.RoyC.MartinM.ERM proteins in cell adhesion and membrane dynamics1999951871922-s2.0-003294007110.1016/S0962-8924(99)01544-5HiraoM.SatoN.KondoT.YonemuraS.MondenM.SasakiT.TakaiY.TsukitaS.TsukitaS.Regulation mechanism of ERM (ezrin/radixin/moesin) protein/plasma membrane association: possible involvement of phosphatidylinositol turnover and rho-dependent signaling pathway1996135137512-s2.0-002979548810.1083/jcb.135.1.37GautreauA.PoulletP.LouvardD.ArpinM.Ezrin, a plasma membrane-microfilament linker, signals cell survival through the phosphatidylinositol 3-kinase/Akt pathway19999613730073052-s2.0-003359495010.1073/pnas.96.13.7300HunterK. W.Ezrin, a key component in tumor metastasis20041052012042-s2.0-234247796410.1016/j.molmed.2004.03.001IlmonenS.VaheriA.Asko-SeljavaaraS.CarpenO.Ezrin in primary cutaneous melanoma20051845035102-s2.0-1644437023010.1038/modpathol.3800300WengW. H.ÅhlénJ.ÅströmK.LuiW. O.LarssonC.Prognostic impact of immunohistochemical expression of ezrin in highly malignant soft tissue sarcomas20051117619862042-s2.0-2434446430010.1158/1078-0432.CCR-05-0548KhannaC.WanX.BoseS.CassadayR.OlomuO.MendozaA.YeungC.GorlickR.HewittS. M.HelmanL. J.The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis20041021821862-s2.0-1114435729810.1038/nm982RenL.HongS. H.CassavaughJ.OsborneT.ChouA. J.GorlickR.HewittS. M.KhannaC.The actin-cytoskeleton linker protein ezrin is regulated during osteosarcoma metastasis by PKC20092867928022-s2.0-6014910998110.1038/onc.2008.437KhannaC.KhanJ.NguyenP.PrehnJ.CaylorJ.YeungC.TrepelJ.MeltzerP.HelmanL.Metastasis-associated differences in gene expression in a murine model of osteosarcoma2001619375037592-s2.0-0035328785IkedaS.SumiiH.AkiyamaK.WatanabeS.ItoS.InoueH.TakechiH.TanabeG.OdaT.Amplification of both c-myc and c-raf-1 oncogenes in a human osteosarcoma1989801692-s2.0-0024786623WilhelmS. M.CarterC.TangL.WilkieD.McNabolaA.RongH.ChenC.ZhangX.VincentP.McHughM.CaoY.ShujathJ.GawlakS.EveleighD.RowleyB.LiuL.AdnaneL.LynchM.AuclairD.TaylorI.GedrichR.VoznesenskyA.RiedlB.PostL. E.BollagG.TrailP. A.BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis20046419709971092-s2.0-494424911710.1158/0008-5472.CAN-04-1443PignochinoY.GrignaniG.CavalloniG.MottaM.TapparoM.BrunoS.BottosA.GammaitoniL.MigliardiG.CamussiG.AlberghiniM.TorchioB.FerrariS.BussolinoF.FagioliF.PicciP.AgliettaM.Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrin pathways20098, article 1182-s2.0-7454921054010.1186/1476-4598-8-118HesseV.JahreisG.SchambachH.VogelH.VilserC.SeewaldH. J.BornerA.DeichlA.Insulin-like growth factor I correlations to changes of the hormonal status in puberty and age199410242892982-s2.0-0028168816KawaiN.KanzakiS.smkanzak@cc.okayama-u.ac.jpTakano-WatouS.TadaC.YamanakaY.MiyataT.OkaM.SeinoY.Serum free insulin-like growth factor I (IGF-I), total IGF-I, and IGF- binding protein-3 concentrations in normal children and children with growth hormone deficiency1999841828910.1210/jc.84.1.82HerzliebN.GallaherB. W.BertholdA.HilleR.KiessW.Insulin-like growth factor-I inhibits the progression of human U-2 OS osteosarcoma cells towards programmed cell death through interaction with the IGF-I receptor200046171772-s2.0-0003482410KappelC. C.Velez-YanguasM. C.HirschfeldS.HelmanL. J.Human osteosarcoma cell lines are dependent on insulin-like growth factor I for in vitro growth19945410280328072-s2.0-0028332784PollakM.SemA. W.RichardM.TetenesE.BellR.Inhibition of metastatic behavior of murine osteosarcoma by hypophysectomy199284129669712-s2.0-0026721016ManskyP. J.LiewehrD. J.SteinbergS. M.ChrousosG. P.AvilaN. A.LongL.BernsteinD.MackallC. L.HawkinsD. S.HelmanL. J.Treatment of metastatic osteosarcoma with the somatostatin analog oncoLar: significant reduction of insulin-like growth factor-1 serum levels200224644044610.1097/00043426-200208000-00007KhannaC.PrehnJ.HaydenD.CassadayR. D.CaylorJ.JacobS.BoseS. M.HongS. H.HewittS. M.HelmanL. J.A randomized controlled trial of octreotide pamoate long-acting release and carboplatin versus carboplatin alone in dogs with naturally occurring osteosarcoma: evaluation of insulin-like growth factor suppression and chemotherapy200287240624122-s2.0-0035992429WangY. H.WangZ. X.QiuY.XiongJ.ChenY. X.MiaoD. S.DeW.Lentivirus-mediated RNAi knockdown of insulin-like growth factor-1 receptor inhibits growth, reduces invasion, and enhances radiosensitivity in human osteosarcoma cells20093271-22572662-s2.0-6734916545810.1007/s11010-009-0064-yWangY. H.XiongJ.WangS. F.YuY.WangB.ChenY. X.ShiH. F.QiuY.Lentivirus-mediated shRNA targeting insulin-like growth factor-1 receptor (IGF-1R) enhances chemosensitivity of osteosarcoma cells in vitro and in vivo20103411-22252332-s2.0-7795501385410.1007/s11010-010-0453-2KolbE. A.GorlickR.HoughtonP. J.MortonC. L.LockR.CarolH.Patrick ReynoldsC.MarisJ. M.KeirS. T.BillupsC. A.SmithM. A.Initial testing (stage 1) of a monoclonal antibody (SCH 717454) against the IGF-1 receptor by the pediatric preclinical testing program2008506119011972-s2.0-4234908330710.1002/pbc.21450KolbE. A.KamaraD.ZhangW.LinJ.HingoraniP.BakerL.HoughtonP.GorlickR.R1507, a fully human monoclonal antibody targeting IGF-1R, is effective alone and in combination with rapamycin in inhibiting growth of osteosarcoma xenografts201055167752-s2.0-7795325642610.1002/pbc.22479WangY. H.HanX. D.QiuY.Increased expression of insulin-like growth factor-1 receptor is correlated with tumor metastasis and prognosis in patients with osteosarcoma20121053235243PantelK.BrakenhoffR. H.Dissecting the metastatic cascade2004464484562-s2.0-2942538264Aguirre-GhisoJ. A.Models, mechanisms and clinical evidence for cancer dormancy20077118348462-s2.0-3554893683310.1038/nrc2256NaumovG. N.TownsonJ. L.MacDonaldI. C.WilsonS. M.BramwellV. H. C.GroomA. C.ChambersA. F.Ineffectiveness of doxorubicin treatment on solitary dormant mammary carcinoma cells or late-developing metastases20038231992062-s2.0-034750492810.1023/B:BREA.0000004377.12288.3cHolmgrenL.O'ReillyM. S.FolkmanJ.Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression1995121491532-s2.0-0028951043WikmanH.VessellaR.PantelK.Cancer micrometastasis and tumour dormancy20081167-87547702-s2.0-5204911609410.1111/j.1600-0463.2008.01033.xNaumovG. N.BenderE.ZurakowskiD.KangS. Y.SampsonD.FlynnE.WatnickR. S.StraumeO.AkslenL. A.FolkmanJ.AlmogN.A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype20069853163252-s2.0-3364476305010.1093/jnci/djj068CaoY.O'ReillyM. S.MarshallB.FlynnE.JiR. W.FolkmanJ.Expression of angiostatin cDNA in a murine fibrosarcoma suppresses primary tumor growth and produces long-term dormancy of metastases19981015105510632-s2.0-0032031748FavaroE.AmadoriA.IndraccoloS.Cellular interactions in the vascular niche: implications in the regulation of tumor dormancy20081167-86486592-s2.0-5204909182610.1111/j.1600-0463.2008.01025.xBarkanD.GreenJ. E.ChambersA. F.Extracellular matrix: a gatekeeper in the transition from dormancy to metastatic growth2010467118111882-s2.0-7795059440010.1016/j.ejca.2010.02.027KoebelC. M.VermiW.SwannJ. B.ZerafaN.RodigS. J.OldL. J.SmythM. J.SchreiberR. D.Adaptive immunity maintains occult cancer in an equilibrium state200745071719039072-s2.0-3684901016710.1038/nature06309