Role of the MET/HGF receptor in proliferation and invasive behavior of osteosarcoma

Coltella, Nadia; Manara, Maria Cristina; Cerisano, Vanessa; Trusolino, Livio; Renzo, Maria Flavia Di; Scotlandi, Katia; Ferracini, Riccardo

doi:10.1096/fj.02-0576fje

Cited by 74 publications

(77 citation statements)

References 48 publications

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“…(57) It is likely that several metastatic processes are linked to c-MET signaling, including cell motility, invasion, proliferation, and survival. (58) Since c-MET is a growth factor receptor with an intracellular tyrosine kinase activity, the development of small-molecule inhibitors of c-MET has been possible. The inhibition of c-MET has been effective in suppressing metastatic phenotype in osteosarcoma cells and preclinical models.…”

Section: Etiology Of Osteosarcomamentioning

confidence: 99%

Osteosarcoma

Görlick

Khanna

2010

Journal of Bone and Mineral Research

154

126

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It has been difficult to identify the molecular features central to the pathogenesis of osteosarcoma owing to a lack of understanding of the cell or origin, the absence of identifiable precursor lesions, and its marked genetic complexity at the time of presentation. Interestingly, several human genetic disorders and familial cancer syndromes, such as Li-Fraumeni syndrome, are linked to an increased risk of osteosarcoma. Association of these same genetic alterations and osteosarcoma risk have been confirmed in murine models. Osteosarcoma is associated with a variety of genetic abnormalities that are among the most commonly observed in human cancer; it remains unclear, however, what events initiate and are necessary to form osteosarcoma. The availability of new resources for studying osteosarcoma and newer research methodologies offer an opportunity and promise to answer these currently unanswered questions. Even in the absence of a more fundamental understanding of osteosarcoma, association studies and preclinical drug testing may yield clinically relevant information. ß

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Section: Etiology Of Osteosarcomamentioning

confidence: 99%

Osteosarcoma

Görlick

Khanna

2010

Journal of Bone and Mineral Research

154

126

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“…7 MET activity was associated with proliferation, metastasis and chemotherapy resistance in osteosarcomas, and K252a, a specific MET-inhibitor, was able to revert HGF dependent growth of osteosarcoma cells in vitro, emphasizing its oncogenic role. [8][9][10] The role of MET in ES is however largely unknown.…”

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confidence: 99%

Expression and clinical relevance of MET and ALK in Ewing sarcomas

Fleuren

Roeffen

Leenders

et al. 2013

Intl Journal of Cancer

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Because novel therapeutic options are limited in Ewing sarcomas (ES), we investigated the expression, genetic aberrations and clinical relevance of MET and anaplastic lymphoma kinase (ALK) in ES and determined the relevance of targeting these receptors. MET and ALK protein expression was determined immunohistochemically in 31 (50 samples) and 36 (59 samples) ES patients, respectively. Samples included primary tumors, postchemotherapy resections, metastases and relapses. MET and ALK RTK domains were sequenced in respectively 33 and 32 tumors. Five ES cell lines were treated in vitro with the MET/ALKinhibitor crizotinib, the ALK-inhibitor NVP-TAE684 or the MET-inhibitor cabozantinib and analyzed by MTT assays. Modest to high MET and ALK expression was detected in the majority of ES (86 and 69%, respectively). ALK expression was significantly lower in postchemotherapy resections compared to paired untreated primary tumors (p 5 0.031, z 5 22.310, n 5 11). In primary tumors (n 5 20), membranous MET expression significantly correlated with a poor overall survival (OS) (60 vs. 197 months, p 5 0.014). There was a trend toward a poor event-free survival (67 vs. 111 months, p 5 0.078) and OS (88 vs. 128 months, p 5 0.074) in patients with highest ALK levels (n 5 29). ALK or MET RTK domain aberrations were demonstrated in 5/32 (16%) and 3/33 (9%) tumors, respectively. Crizotinib (IC 50 1.22-3.59 lmol/L), NVP-TAE684 (IC 50 0.15-0.79 lmol/L) and cabozantinib (IC 50 2.69-8.27 lmol/L) affected ES cell viability in vitro. Altogether, our data suggest that MET and ALK are potential novel therapeutic targets in ES and targeting these receptors may be of great interest to rationally design future studies in ES.Ewing sarcoma (ES) is the second most common primary malignant bone tumor occurring in children and adolescents. Although multimodal treatment has improved the prognosis of patients with localized ES during the last decades, the final outcome has not improved for patients with metastatic disease and side effects of treatment could be severe. 1,2 This urges the need for novel therapeutic strategies, including targeted therapies directed against molecules involved in the pathogenesis and progression of ES, 3 Although at present some receptor tyrosine kinases (RTKs) have been implicated in ES, predominantly the insulin-like growth factor-1 receptor (IGF-1R), and to a lesser extent also platelet-derived growth factor receptor (PDGFR) and c-KIT, the role of several other receptors remains to be investigated. 4 In this study, we addressed the role of MET and anaplastic lymphoma kinase (ALK) in ES.MET is a RTK known to be deregulated in many cancers. At present, the hepatocyte growth factor (HGF) is the only known ligand for MET. Upon receptor binding, MET undergoes rapid tyrosine phosphorylation and several intracellular signaling cascades are activated, including the phosphatidylinositol 3 (PI3)/Akt kinase and extracellular signal regulated kinase (Erk) pathways. Several studies have shown that HGF/ MET signaling is involved in c...

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“…Overall, in vitro results with PF-2341066 were consistent with published reports using other Met inhibitors (eg, SU11274 and PHA-665752) to inhibit the malignant behavior of cultured OS cells. (3,21,22) Until recently, the OS field lacked a clinically relevant xenograft model capable of recapitulating the features of human OS, including mixed osteoblastic/lytic lesions in the metaphyseal region of the humerus, femur, or tibia and pulmonary metastasis. (1,2) MNNG cells are one of several recently characterized OS cell lines that mimic human OS when orthotopically xenografted into nude mice.…”

Section: Discussionmentioning

confidence: 99%

“…(20) Despite the important role of Met in the development and maintenance of OS, pharmacologic Met inhibition has been addressed only in in vitro studies. (21,22) These studies demonstrated that Met inhibitors antagonize liganddependent and -independent OS proliferation, survival, and motility. (21,22) Given the importance of Met signaling in human OS, we hypothesized that the novel, orally bioavailable Met inhibitor PF-2341066 (15,23) would have efficacy in an orthotopic xenograft model of OS.…”

Section: Introductionmentioning

confidence: 98%

“…(21,22) These studies demonstrated that Met inhibitors antagonize liganddependent and -independent OS proliferation, survival, and motility. (21,22) Given the importance of Met signaling in human OS, we hypothesized that the novel, orally bioavailable Met inhibitor PF-2341066 (15,23) would have efficacy in an orthotopic xenograft model of OS. In this study, we evaluated the effects of PF-2341066 on the behavior of OS cells versus immortalized osteoblasts in vitro as well as on OS xenograft growth and associated osteolysis and extracortical bone matrix formation in vivo.…”

Section: Introductionmentioning

confidence: 98%

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The orally bioavailable met inhibitor PF-2341066 inhibits osteosarcoma growth and osteolysis/matrix production in a xenograft model

Sampson

Martin

Morris

et al. 2011

Journal of Bone and Mineral Research

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Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. Ninety percent of patients who present with metastatic and 30% to 40% of patients with nonmetastatic disease experience relapse, creating an urgent need for novel therapeutic strategies. The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are important for mitosis, motility, and cell survival. Upregulation of Met/HGF signaling via receptor overexpression, amplification, or mutation drives the proliferation, invasiveness, and metastasis of a variety of cancer cells, including OS, prompting the development of Met/HGF inhibitors. OS cells depend on Met overexpression because introduction of dominant-negative Met inhibits in vivo tumorigenicity. Despite the importance of Met/HGF signaling in the development and maintenance of OS, the potential efficacy of pharmacologic Met inhibition in OS has been addressed only in in vitro studies. PF-2341066 is an orally bioavailable, selective ATP-competitive Met inhibitor that showed promising results recently in a phase I clinical trial in non-small cell lung cancer (NSCLC) patients. We tested the ability of PF-2341066 to inhibit malignant properties of osteosarcoma cells in vitro and orthotopic xenograft growth in vivo. In vitro, PF-2341066 inhibited osteosarcoma behavior associated with primary tumor growth (eg, proliferation and survival) as well as metastasis (eg, invasion and clonogenicity). In nude mice treated with PF-2341066 via oral gavage, the growth and associated osteolysis and extracortical bone matrix formation of osteosarcoma xenografts were inhibited by PF-2341066. PF-2341066 may represent an effective new systemic therapy for localized and potentially disseminated osteosarcoma. ß

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Role of the MET/HGF receptor in proliferation and invasive behavior of osteosarcoma

Cited by 74 publications

References 48 publications

Osteosarcoma

Osteosarcoma

Expression and clinical relevance of MET and ALK in Ewing sarcomas

The orally bioavailable met inhibitor PF-2341066 inhibits osteosarcoma growth and osteolysis/matrix production in a xenograft model

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