Retroviruses and oncogenes associated with osteosarcomas

Michiels, Luc; Merregaert, J.

doi:10.1007/978-1-4615-3518-8_2

Cited by 7 publications

(4 citation statements)

References 42 publications

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“…Seven of 41 osteosarcomas had strong amplifications on chromosome 15 with the c-myc oncogene at the amplicon epicenter (Figure 1A). This was consistent with observations that human osteosarcomas also exhibit amplification and overexpression of c-myc (9, 21, 22). The chromosome 9 (band A1) amplicon was observed in 5 of 41 osteosarcomas and contains a cluster of 10 matrix metalloproteinase genes (Figure 1B,C,D).…”

Section: Resultssupporting

confidence: 92%

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MMP13, Birc2 (cIAP1), and Birc3 (cIAP2), Amplified on Chromosome 9, Collaborate with p53 Deficiency in Mouse Osteosarcoma Progression

Ma¹,

Cai²,

Zender

et al. 2009

Cancer Research

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Osteosarcoma is the primary malignant cancer of bone and particularly affects adolescents and young adults, causing debilitation, and sometimes death. As a model for human osteosarcoma we have been studying p53+/− mice, which develop osteosarcoma at high frequency. To discover genes that cooperate with p53 deficiency in osteosarcoma formation we have integrated array comparative genomic hybridization, microarray expression analyses in mouse and human osteosarcomas, and functional assays. In this study we found seven frequent regions of copy number gain and loss in the mouse p53+/− osteosarcomas, but have focused on a recurrent amplification event on mouse chromosome 9A1. This amplicon is syntenic with a similar chromosome 11q22 amplicon identified in a number of human tumor types. Three genes on this amplicon, the matrix metalloproteinase gene MMP13, and the anti-apoptotic genes Birc2 (cIAP1), and Birc3 (cIAP2) show elevated expression in mouse and human osteosarcomas. We developed a functional assay using clonal osteosarcoma cell lines transduced with lentiviral shRNA vectors to show that downregulation of MMP13, Birc2, or Birc3 resulted in reduced tumor growth when transplanted into immunodeficient recipient mice. These experiments revealed that high MMP13 expression enhances osteosarcoma cell survival and that Birc2 and Birc3 also enhance cell survival, but only in osteosarcoma cells with the chromosome 9A1 amplicon. We conclude that the anti-apoptotic genes Birc2 and Birc3 are potential oncogenic drivers in the chromosome 9A1 amplicon.Requests for reprints: Lawrence A.

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Section: Resultssupporting

confidence: 92%

“…As with humans, sporadic osteosarcomas in inbred laboratory strains of mice are generally rare (9). However, in the p53 knockout mouse model generated by our laboratory, 38% of p53+/− mice developed osteosarcomas (10).…”

Section: Introductionmentioning

confidence: 99%

MMP13, Birc2 (cIAP1), and Birc3 (cIAP2), Amplified on Chromosome 9, Collaborate with p53 Deficiency in Mouse Osteosarcoma Progression

Ma¹,

Cai²,

Zender

et al. 2009

Cancer Research

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“…Together, these observations suggest that Nf2 loss can contribute to the formation of a broad spectrum of tumor types in the mouse. Although osteosarcomas are rare in wild-type mice, they are commonly induced by radiation, viruses, or viral oncoproteins (for review, see Michiels and Merregaert 1993). Thus, polyomavirus (Py), the Py early region, simian virus SV40, the SV40 large T-antigen, the FinkelBiskis-Jinkins (FBJ) and Finkel-Biskis-Reilly (FBR) retroviruses, the FBJ-encoded oncoprotein v-fos or its cellular homolog c-fos can all induce the formation of osteosarcomas in mice upon infection or when expressed transgenically (Py and SV40 can also induce the formation of fibrosarcomas).…”

Section: Discussionmentioning

confidence: 99%

Mice heterozygous for a mutation at the Nf2 tumor suppressor locus develop a range of highly metastatic tumors

McClatchey¹,

Saotome²,

Mercer³

et al. 1998

Genes & Development

355

231

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A role for the membrane/cytoskeleton interface in the development and progression of cancer is established, yet poorly understood. The neurofibromatosis type II (NF2) tumor suppressor gene encodes a member of the ezrin/radixin/moesin (ERM) family of membrane/cytoskeleton linker proteins thought to be important for cell adhesion and motility. We report that in contrast to the narrow spectrum of benign tumors in human NF2 patients, Nf2 heterozygous mice develop a variety of malignant tumors. Using the fact that Nf2 is linked to the p53 tumor suppressor locus in the mouse we have also investigated the effects of genetic linkage of cancer-predisposing mutations on tumorigenesis and examined the genetic pathway to tumor formation involving Nf2 loss. Importantly, we observed a very high rate of metastasis associated with Nf2 deficiency, with or without loss of p53 function, and we provide experimental evidence supporting a role for Nf2 loss in metastatic potential. Together, our results suggest an important role for the NF2 tumor suppressor, and perhaps the ERM family in tumor formation and metastasis.[Key Words: Merlin; NF2; tumor suppressor; cytoskeleton; osteosarcoma; metastasis]Received January 20, 1998; revised version accepted February 25, 1998. Neurofibromatosis type II (NF2) is a dominantly inherited disorder featuring the predisposition to develop multiple benign tumors of the central nervous system. The hallmark feature of NF2 is the development of bilateral schwannomas of the eighth cranial (auditory) nerves; NF2 patients are also predisposed to the development of spinal schwannomas, meningiomas, and ependymomas at rates much higher than that of the normal population (Huson 1994). The NF2 tumor suppressor gene was identified by positional cloning and loss of heterozygosity (LOH) studies and found to encode a member of the band 4.1 family of cytoskeletal-associated proteins thought to be involved in the organization of the actin cytoskeleton (Rouleau et al. 1993;Trofatter et al. 1993). The NF2 gene product shares closest similarity to ezrin, radixin, and moesin (the ERM proteins), which comprise a subset of this family, and thus was given the name merlin (moesin-, ezrin-, and radixin-like protein) (Trofatter et al. 1993). The amino-terminal halves of these proteins share the greatest similarity (the band 4.1 domain), with ∼85% amino acid identity among the ERMs (for review, see Tsukita et al. 1997;Vaheri et al. 1997).The ERM proteins localize to cortical actin structures, particularly specialized or dynamic regions, such as membrane ruffles, microvilli, or the cleavage furrow and can bind directly to actin through a highly conserved motif at their extreme carboxyl terminus (for review, see Tsukita et al. 1997;Vaheri et al. 1997). The ERM proteins may be rendered inactive by an intramolecular association; certain stimuli such as phosphorylation or phosphatidyl-4,5-bis-phosphate (PIP2) binding may serve to ''open up'' the protein conformation, allowing homoor heterodimerization, which has been shown to occu...

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“…The study animals were transfected with rhabdomyosarcoma R 1 H [8][9][10][11] cells supplied by Deutsches Krebsforschungszentrum (DKFZ, Heidelberg, Germany). 50 mL of R 1 H tumor cell suspension with a number of 2 3 10 7 cells were injected into the right gastrocnemius muscle.…”

Section: Tumor Modelmentioning

confidence: 99%

Mitoxantrone-Iron Oxide Biodistribution in Blood, Tumor, Spleen, and Liver—Magnetic Nanoparticles in Cancer Treatment

Krukemeyer

Krenn²,

Jakobs³

et al. 2012

Journal of Surgical Research

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Retroviruses and oncogenes associated with osteosarcomas

Cited by 7 publications

References 42 publications

MMP13, Birc2 (cIAP1), and Birc3 (cIAP2), Amplified on Chromosome 9, Collaborate with p53 Deficiency in Mouse Osteosarcoma Progression

MMP13, Birc2 (cIAP1), and Birc3 (cIAP2), Amplified on Chromosome 9, Collaborate with p53 Deficiency in Mouse Osteosarcoma Progression

Mice heterozygous for a mutation at the Nf2 tumor suppressor locus develop a range of highly metastatic tumors

Mitoxantrone-Iron Oxide Biodistribution in Blood, Tumor, Spleen, and Liver—Magnetic Nanoparticles in Cancer Treatment

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