Prognostic Significance of Vascular Endothelial Growth Factor, Tumor Necrosis, and Mitotic Activity Index in Malignant Pleural Mesothelioma

Demırağ, Funda; Ünsal, Ebru; Yılmaz, Aydın; Çağlar, Atalay

doi:10.1378/chest.128.5.3382

Cited by 87 publications

(69 citation statements)

References 21 publications

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“…Necrosis has been recently demonstrated to promote tumor growth through inflammation and angiogenesis, and to be correlated with malignancy and poor prognosis of tumor growth. [18][19][20][21] Thus, the consequences of apoptosis and necrosis are quite different for a whole organism in terms of the effect on inflammatory responses and tumor prognosis.…”

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confidence: 99%

Ursodeoxycholic acid switches oxaliplatin‐induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53‐caspase 8 pathway in HepG2 hepatocellular carcinoma

Lim

Choi

Kang

2010

Intl Journal of Cancer

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Hepatocellular carcinoma (HCC) is resistant to chemotherapy. Recently, however, several oxaliplatin-based combinatorial treatments have shown a promising anti-tumor activity in patients with HCC. Presently, we demonstrate that oxaliplatin triggers necrosis more than apoptosis in HepG2, SK-Hep1, SNU-423 and Hep3B HCC cells, while mainly inducing apoptosis in HCT116 and HT29 colon cancer cells. Interestingly, ursodeoxycholic acid (UDCA), a less hydrophobic bile acid that can suppress carcinogenesis, shifted oxaliplatin-induced necrosis to apoptosis in HepG2 cells. The same effect was produced by hydrophilic bile acids (tauroursodeoxycholic acid and taurohyodeoxycholic acid), but not by highly hydrophobic bile acids (deoxycholic acid and chenodeoxycholic acid). UDCA also triggered the necrosis-to-apoptosis switch when cotreated with other platinum-based chemotherapeutic drugs including cisplatin and carboplatin, suggesting that the cell death mode switching effect of UDCA is a general phenomenon when combined with platinum drugs. Oxaliplatin produced high level of reactive oxygen species (ROS) in HepG2 cells and UDCA significantly reduced oxaliplatin-induced ROS generation. In addition, N-acetyl-L-cysteine and the superoxide scavengers butylated hydroxyanisole and dihydroxybenzene-3,5-disulfonic acid attenuated necrosis, indicating a critical role(s) of ROS in occurrence of necrotic death. Apoptosis induced by combined treatment appeared to be mediated by p53-caspase 8-caspase 3 pathway. In conclusion, UDCA switches oxaliplatin-induced necrosis to apoptosis via inhibition of ROS production and activation of the p53-caspase 8 pathway in HepG2 cells. As necrosis and subsequent inflammation are implicated in tumor progression and malignancy, our results imply a potential improved efficacy of UDCA-combined chemotherapy in HCC by reducing inflammatory responses that may be triggered by oxaliplatin.Hepatocellular carcinoma (HCC) is one of the most common malignancies and the leading causes of cancer-related mortality, and it generally represents highly resistant features to chemotherapy.1-3 Surgical resection and liver transplantation might be the most effective way to cure the cancer, but these approaches have limited applicability and advanced tumors frequently recur even after complete surgical resection. 4,5 Hence, chemotherapy remains an important option to treat HCC and developments of new chemotherapeutic strategies are necessary.Oxaliplatin, a third generation platinum-based chemotherapeutic agent, displays a broader spectrum of antitumor activity than cisplatin and carboplatin and no cross-resistance against some cisplatin-and carboplatin-resistant tumors. [6][7][8][9] Currently, it is widely used as a basis of combination regimens for various cancers including gastric, colorectal and advanced nasopharyngeal carcinoma. [10][11][12] In addition, several oxaliplatin-combined regimens have been used for patients with advanced HCC and these have shown a moderate but promising anti-tumor effect. 13,14

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confidence: 99%

Ursodeoxycholic acid switches oxaliplatin‐induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53‐caspase 8 pathway in HepG2 hepatocellular carcinoma

Lim

Choi

Kang

2010

Intl Journal of Cancer

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“…VEGF was reported to be a factor contributing to the poor prognosis of MPM. However, the level of VEGF expression varied among MPM (7,26,27). In the case of ) cells were orally treated with or without E7080 (10 mg/kg, daily) from day 7 to the end of the experiment.…”

Section: Discussionmentioning

confidence: 99%

E7080, a Multi–Tyrosine Kinase Inhibitor, Suppresses the Progression of Malignant Pleural Mesothelioma with Different Proangiogenic Cytokine Production Profiles

Ikuta

Yano²,

Hashimoto³

et al. 2009

Clinical Cancer Research

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Purpose: Malignant pleural mesothelioma (MPM) is a biologically heterogeneous malignant disease with a poor prognosis. We reported previously that the anti-vascular endothelial growth factor (VEGF) antibody, bevacizumab, effectively inhibited the progression of VEGF-high-producing (but not VEGF-low-producing) MPM cells in orthotopic implantation models, indicating the need for novel therapeutic strategies to improve the poor prognosis of this disease. Therefore, we focused on the multityrosine kinase inhibitor E7080 and assessed its therapeutic efficacy against MPM cells with different proangiogenic cytokine production profiles. Experimental Design: The efficacy of E7080 was assayed in orthotopic implantation of severe combined immunodeficient mouse models with three human MPM cell lines (MSTO-211H, NCI-H290, and Y-MESO-14). Results: With regard to proangiogenic cytokine production profiles, MSTO-211H and Y-MESO-14 cells were MPM cells producing high levels of fibroblast growth factor-2 and VEGF, respectively. NCI-H290 cells produced low levels of fibroblast growth factor-2 and VEGF compared with the other two cell lines. E7080 potently suppressed the phosphorylation of VEGF receptor-2 and FGF receptor 1 and, thus, inhibited proliferation of endothelial cells, but not that of the MPM cell lines, in vitro. Orthotopically inoculated MSTO-211H cells produced only thoracic tumors, whereas NCI-H290 and Y-MESO-14 cells also developed pleural effusions. Treatment with E7080 potently inhibited the progression of these three MPM cell lines and markedly prolonged mouse survival, which was associated with decreased numbers of tumor-associated vessels and proliferating MPM cells in the tumor. Conclusions: These results strongly suggest broad-spectrum activity of E7080 against MPM with different proangiogenic cytokine production profiles in humans. (Clin Cancer Res 2009;15(23):7229-37) Malignant pleural mesothelioma (MPM) is an aggressively growing tumor, which disseminates into the thoracic cavity and frequently produces a malignant pleural effusion (1). More than 60% of patients with MPM present with a pleural effusion associated with breathlessness, often accompanied by chest wall pain, which compromises their quality of life (2). This type of tumor was once considered rare, but its incidence is increasing worldwide, due primarily to exposure to asbestos and possibly to the SV40 tumor virus. MPM is refractory to conventional chemotherapy and radiotherapy, and also has a poor prognosis, with a median survival time from onset of ∼1 year. Although the multitargeted antifolate agent, pemetrexed, in combination with cisplatin, was recently approved as first-line treatment of MPM (3), the overall prognosis of patients with MPM remains very poor, indicating the need for effective novel therapies.Angiogenesis, the formation of new blood vessels to deliver oxygen and nutrients to the expanding tumor mass, is crucial for the growth and metastasis of solid tumors (4). In many types of cancer, including MPM, there is an ...

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“…Molecular and pathologic characterization of malignant pleural mesothelioma has resulted in reports of several potential prognostic factors; however, most are either unavailable in clinical practice or have not been validated adequately in conjunction with clinical factors (14)(15)(16)(17). Over the past 10 years, fluorodeoxyglucose positron emission tomography (FDG-PET) scanning has become commonly used.…”

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confidence: 99%

A Novel Prognostic Model for Malignant Mesothelioma Incorporating Quantitative FDG-PET Imaging with Clinical Parameters

Nowak

Francis

Phillips

et al. 2010

Clinical Cancer Research

111

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Purpose: Existing prognostic systems for malignant pleural mesothelioma do not incorporate imaging information. We aimed to identify the contribution of quantitative fluorodeoxyglucose positron emission tomography (FDG-PET) analysis to other prognostic variables in this disease.Experimental Design: Patients with malignant pleural mesothelioma underwent helical thoracoabdominal computed tomography and FDG-PET scans at baseline. Patients were treated as clinically indicated and followed for survival. FDG-PET variables derived included total glycolytic volume, a composite of tumor volume and glycolytic activity.Results: Ninety-three patients were accrued from 2003 to 2006. Of 89 eligible assessable patients, 28 had undergone pleurodesis before enrolment. Seventeen patients remained alive at analysis; median survival is 15.4 months. On univariate analysis, significant prognostic factors were: total glycolytic volume on FDG-PET (P = 0.003), sarcomatoid histology (P < 0.0005), weight loss (P = 0.031), computed tomography stage (P = 0.015), and European Organization for Research and Treatment of Cancer good prognostic score (P = 0.049). In patients with epithelioid or biphasic histology, baseline total glycolytic volume remained predictive of survival in patients with (P = 0.01) or without (P = 0.018) previous pleurodesis. In multivariate analysis, no variable other than histology contributed to the model in patients with sarcomatoid histology; total glycolytic volume and weight loss contributed to the models in patients with nonsarcomatoid histology. computed tomography-assessed tumor-node-metastasis stage did not contribute to the model. A nomogram, which incorporates quantitative PET parameters and pleurodesis into prognostic information, is presented.Conclusions: Sarcomatoid histology remains the strongest prognostic factor. In patients with non sarcomatoid disease, volumetric FDG-PET parameters are more predictive of survival than tumor-node-metastasis staging, suggesting that tumor volume and glycolytic activity may be more important determinants of prognosis in malignant pleural mesothelioma than anatomic extent of disease.

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Prognostic Significance of Vascular Endothelial Growth Factor, Tumor Necrosis, and Mitotic Activity Index in Malignant Pleural Mesothelioma

Cited by 87 publications

References 21 publications

Ursodeoxycholic acid switches oxaliplatin‐induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53‐caspase 8 pathway in HepG2 hepatocellular carcinoma

Ursodeoxycholic acid switches oxaliplatin‐induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53‐caspase 8 pathway in HepG2 hepatocellular carcinoma

E7080, a Multi–Tyrosine Kinase Inhibitor, Suppresses the Progression of Malignant Pleural Mesothelioma with Different Proangiogenic Cytokine Production Profiles

A Novel Prognostic Model for Malignant Mesothelioma Incorporating Quantitative FDG-PET Imaging with Clinical Parameters

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