Anti-angiogenic and tumor-suppressive roles of candidate tumor-suppressor gene, Fibulin-2, in nasopharyngeal carcinoma

Law, Evan Wai Lok; Cheung, Arthur Kwok Leung; Kashuba, Vladimir I.; Pavlova, Tatiana V.; Zabarovsky, Eugene R.; Lung, Hong Lok; Cheng, Yue; Chua, Dtt; Kwong, Dora Lai-Wan; Tsao, Sai Wah; Sasaki, Takako; Stanbridge, Eric J.; Lung, Maria Li

doi:10.1038/onc.2011.272

Cited by 88 publications

(92 citation statements)

References 31 publications

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“…However, only very few ECM proteins exert a tumor suppressor function: for instance, trombospondin-1 (TSP-1), trombospondin-2 (TSP-2), and fibulin-2 mainly counteract tumor growth and impact angiogenesis (39,40); LTBP-2 impairs migration and invasion ability of neoplastic cells (41). Here, we showed that EMILIN1, an ECM glycoprotein diffusely expressed in between TGF-b and a4/a9 integrin signal pathways.…”

Section: Discussionmentioning

confidence: 92%

An EMILIN1-Negative Microenvironment Promotes Tumor Cell Proliferation and Lymph Node Invasion

Danussi

Petrucco

Wassermann

et al. 2012

Cancer Prevention Research

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The evidence that EMILIN1 (Elastic Microfibril Interface Located proteIN) deficiency in Emilin1 À/À mice caused dermal and epidermal hyperproliferation and an abnormal lymphatic phenotype prompted us to hypothesize the involvement of this extracellular matrix component in tumor development and in lymphatic metastasis. Using the 12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) two-stage model of skin carcinogenesis, we found that Emilin1 À/À mice presented an accelerated formation, a higher incidence, and the development of a larger number of tumors compared with their wild-type littermates. EMILIN1-negative tumors showed more Ki67-positive proliferating cells and higher levels of pErk1/2. In these tumors, PTEN expression was lower. Emilin1 À/À mice displayed enhanced lymphangiogenesis both in the tumor and in the sentinel lymph nodes. Accordingly, tumor growth and lymph node metastasis of transplanted syngenic tumors were also increased in Emilin1 À/À mice. In vitro transmigration assays through lymphatic endothelial cells showed that EMILIN1 deficiency greatly facilitated tumor cell trafficking. Overall, these data established that EMILIN1 exerts a protective role in tumor growth, in tumor lymphatic vessel formation, as well as in metastatic spread to lymph nodes and reinforced the importance of its presence in the microenvironment to determine the tumor phenotype. Cancer Prev Res; 5(9); 1131-43. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 92%

An EMILIN1-Negative Microenvironment Promotes Tumor Cell Proliferation and Lymph Node Invasion

Danussi

Petrucco

Wassermann

et al. 2012

Cancer Prevention Research

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“…Skipping of exon 9 of FBLN2 is also worthy of note (Supplemental Fig. 5), since this gene was recently introduced as a tumor suppressor candidate in nasopharyngeal carcinoma (Law et al 2012). …”

Section: Alternative Splicingmentioning

confidence: 99%

The transcriptional landscape and mutational profile of lung adenocarcinoma

et al. 2012

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All cancers harbor molecular alterations in their genomes. The transcriptional consequences of these somatic mutations have not yet been comprehensively explored in lung cancer. Here we present the first large scale RNA sequencing study of lung adenocarcinoma, demonstrating its power to identify somatic point mutations as well as transcriptional variants such as gene fusions, alternative splicing events, and expression outliers. Our results reveal the genetic basis of 200 lung adenocarcinomas in Koreans including deep characterization of 87 surgical specimens by transcriptome sequencing. We identified driver somatic mutations in cancer genes including EGFR, KRAS, NRAS, BRAF, PIK3CA, MET, and CTNNB1. Candidates for novel driver mutations were also identified in genes newly implicated in lung adenocarcinoma such as LMTK2, ARID1A, NOTCH2, and SMARCA4. We found 45 fusion genes, eight of which were chimeric tyrosine kinases involving ALK, RET, ROS1, FGFR2, AXL, and PDGFRA. Among 17 recurrent alternative splicing events, we identified exon 14 skipping in the protooncogene MET as highly likely to be a cancer driver. The number of somatic mutations and expression outliers varied markedly between individual cancers and was strongly correlated with smoking history of patients. We identified genomic blocks within which gene expression levels were consistently increased or decreased that could be explained by copy number alterations in samples. We also found an association between lymph node metastasis and somatic mutations in TP53. These findings broaden our understanding of lung adenocarcinoma and may also lead to new diagnostic and therapeutic approaches.

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“…All cell lines were treated with varying concentrations of Ro5203280 from 25, 50, 100, 200, 500, and 1,000 nmol/L or with DMSO, which is the in vitro vehicle control. The percentage of cell proliferation inhibition was calculated using the formula: % inhibition ¼ 100 À (cell index of the treated well/cell index of untreated well) Â 100% (24). All experiments were carried out in duplicate at least twice.…”

Section: Real-time Cell Proliferation Assaymentioning

confidence: 99%

“…The protein cell lysates from the cell lines and from mouse tumors were extracted as previously described (24,29). In brief, 1 Â 10 6 cells were seeded on a T25 flask before treatment.…”

Section: Western Blot Analysismentioning

confidence: 99%

Polo-like Kinase Inhibitor Ro5203280 Has Potent Antitumor Activity in Nasopharyngeal Carcinoma

Cheung

Lung

et al. 2013

Molecular Cancer Therapeutics

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Nasopharyngeal carcinoma is a cancer with its highest prevalence among the southern Chinese and is rare elsewhere in the world. The main treatment modalities include chemotherapy and radiotherapy. However, tumor chemoresistance often limits the efficacy of nasopharyngeal carcinoma treatment and reduces survival rates. Thus, identifying new selective chemotherapeutic drugs for nasopharyngeal carcinoma treatment is needed. In this current study, the antitumor efficacy of a polo-like kinase inhibitor, Ro5203280, was investigated. Ro5203280 induces tumor suppression both in vitro and in vivo. An inhibitory effect was observed with the highly proliferating cancer cell lines tested, but not with the nontumorigenic cell line. Real-time cell proliferation and fluorescence-activated cell sorting (FACS) analysis, together with immunohistochemical (IHC), immunofluorescence, and Annexin V staining assays, were used to evaluate the impact of drug treatment on cell cycle and apoptosis. Ro5203280 induces G 2 -M cell-cycle arrest and apoptosis. Western blotting shows it inhibits PLK1 phosphorylation and downregulates the downstream signaling molecule, Cdc25c, and upregulates two important mitosis regulators, Wee1 and Securin, as well as the DNA damagerelated factor Chk2 in vitro and in vivo. In vivo tumorigenicity assays with Ro5203280 intravenous injection showed its potent ability to inhibit tumor growth in mice, with no observable signs of toxicity. These findings suggest the potential usefulness of Ro5203280 as a chemotherapeutic targeting drug for nasopharyngeal carcinoma treatment. Mol Cancer Ther; 12(8); 1393-401. Ó2013 AACR.

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Anti-angiogenic and tumor-suppressive roles of candidate tumor-suppressor gene, Fibulin-2, in nasopharyngeal carcinoma

Cited by 88 publications

References 31 publications

An EMILIN1-Negative Microenvironment Promotes Tumor Cell Proliferation and Lymph Node Invasion

An EMILIN1-Negative Microenvironment Promotes Tumor Cell Proliferation and Lymph Node Invasion

The transcriptional landscape and mutational profile of lung adenocarcinoma

Polo-like Kinase Inhibitor Ro5203280 Has Potent Antitumor Activity in Nasopharyngeal Carcinoma

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