Growth Factor Responses and Protooncogene Expression of Murine Mesothelial Cell Lines Derived from Asbestos-Induced Mesotheliomas

Goodglick, Lee; Vaslet, Charles A.; Messier, Norma J.; Kane, Agnes B.

doi:10.1177/019262339702500605

Cited by 31 publications

(34 citation statements)

References 32 publications

(23 reference statements)

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“…Because of the long latency and unpredictable development of disease following inoculation with asbestos, many investigators have used models of mesothelioma in which cultured malignant cell lines are injected s.c. into syngeneic mice (36,42). Although this cell transplantation model generates tumors that are clearly mesotheliomas, the disease is anatomically dislocated.…”

Section: Discussionmentioning

confidence: 99%

A Novel SV40 TAg Transgenic Model of Asbestos-Induced Mesothelioma: Malignant Transformation Is Dose Dependent

et al. 2006

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Although it has been clear for >40 years that mesothelioma can be caused by asbestos, not all patients with this disease have a history of asbestos exposure. Other factors, including non-asbestos fibers and ionizing radiation, are known to cause malignant transformation of mesothelial cells. In addition, it is likely that genetics will play some role in susceptibility. Recently, it has been suggested that SV40 viral oncogenes could contribute to the carcinogenicity of asbestos. To better understand the role of SV40, we used the mesothelin promoter to construct MexTAg mice that express SV40 large T antigen (TAg) in the mesothelial compartment. We generated four MexTAg lines that carry high, intermediate, and low copy numbers of the transgene. All of these mice show a relatively low level of spontaneous tumor development. High-copy, 299h mice rapidly developed mesotheliomas when exposed to asbestos, and these tumors were faster growing and more invasive than those developing in wild-type and single-copy (266s) mice. In addition, we found a direct relationship between transgene copy number and survival after exposure to asbestos. A single copy of TAg was sufficient to immortalize mesothelial cells in vitro, but these cells did not show evidence of malignant transformation. In contrast, cell lines developed from mesothelial cells of animals carrying multiple copies of TAg were growth factor independent and could be cloned at limiting dilution in soft agar. These data provide the first in vivo demonstration of co-carcinogenicity between SV40 and asbestos. (Cancer Res 2006; 66(22): 10786-94)

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Section: Discussionmentioning

confidence: 99%

A Novel SV40 TAg Transgenic Model of Asbestos-Induced Mesothelioma: Malignant Transformation Is Dose Dependent

et al. 2006

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“…Bedding, cages, and euthanized mice were incinerated to dispose of potentially contaminated material. Complete necropsies were done on all mice, and histopathologic diagnosis of malignant mesotheliomas was as previously described (13).…”

Section: Methodsmentioning

confidence: 99%

A Mouse Model Recapitulating Molecular Features of Human Mesothelioma

Altomare¹,

Vaslet

Skele³

et al. 2005

Cancer Research

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146

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Malignant mesothelioma has been linked to asbestos exposure and generally has a poor prognosis because it is often diagnosed in advanced stages and is refractory to conventional therapy. Human malignant mesotheliomas accumulate multiple somatic genetic alterations, including inactivation of the NF2 and CDKN2A/ARF tumor suppressor genes. To better understand the significance of NF2 inactivation in malignant mesothelioma and identify tumor suppressor gene alterations that cooperate with NF2 loss of function in malignant mesothelioma pathogenesis, we treated Nf 2 (+/À) knockout mice with asbestos to induce malignant mesotheliomas. Asbestos-exposed Nf 2 (+/À) mice exhibited markedly accelerated malignant mesothelioma tumor formation compared with asbestos-treated wild-type (WT) littermates. Loss of the WT Nf 2 allele, leading to biallelic inactivation, was observed in all nine asbestos-induced malignant mesotheliomas from Nf 2 (+/À) mice and in 50% of malignant mesotheliomas from asbestos-exposed WT mice. For a detailed comparison with the murine model, DNA analyses were also done on a series of human malignant mesothelioma samples. Remarkably, similar to human malignant mesotheliomas, tumors from Nf 2 (+/À) mice showed frequent homologous deletions of the Cdkn2a/ Arf locus and adjacent Cdkn2b tumor suppressor gene, as well as reciprocal inactivation of Tp53 in a subset of tumors that retained the Arf locus. As in the human disease counterpart, malignant mesotheliomas from the Nf2 (+/À) mice also showed frequent activation of Akt kinase, which plays a central role in tumorigenesis and therapeutic resistance. Thus, this murine model of environmental carcinogenesis faithfully recapitulates many of the molecular features of human malignant mesothelioma and has significant implications for the further characterization of malignant mesothelioma pathogenesis and preclinical testing of novel therapeutic modalities. (Cancer Res 2005; 65(18): 8090-5)

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“…The malignant mesothelioma cell line used in this study, 40L, was derived from lung micrometastases developed in a C57Bl/6 mouse following subcutaneous (s.c.) injection of the primary, asbestos-induced mesothelioma cell line, 40, reported in Goodglick et al (31). I.p.…”

Section: Intraperitonealtransplantation Of Mesothelioma Cellsmentioning

confidence: 96%

Targeting tumor-associated macrophages in an orthotopic murine model of diffuse malignant mesothelioma

Miselis

Rooijen

et al. 2008

Molecular Cancer Therapeutics

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100

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Tumors are a mixture of neoplastic and host stromal cells, which establish a microenvironment that contributes to tumor progression. In this study, the contribution of tumorassociated macrophages (TAMs) to tumor growth and metastasis was examined using an orthotopic, immunocompetent murine model of diffuse malignant peritoneal mesothelioma. The expression profile of cytokines and chemokines in solid tumors was consistent with a

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Growth Factor Responses and Protooncogene Expression of Murine Mesothelial Cell Lines Derived from Asbestos-Induced Mesotheliomas

Cited by 31 publications

References 32 publications

A Novel SV40 TAg Transgenic Model of Asbestos-Induced Mesothelioma: Malignant Transformation Is Dose Dependent

A Novel SV40 TAg Transgenic Model of Asbestos-Induced Mesothelioma: Malignant Transformation Is Dose Dependent

A Mouse Model Recapitulating Molecular Features of Human Mesothelioma

Targeting tumor-associated macrophages in an orthotopic murine model of diffuse malignant mesothelioma

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