Mesothelin Overexpression Promotes Autocrine IL-6/sIL-6R Trans-Signaling to Stimulate Pancreatic Cancer Cell Proliferation

Bharadwaj, Uddalak; Marín-Müller, Christian; Zhang, Y.; Li, M.; Chen, C.; Yao, Qizhi

doi:10.1016/j.jss.2009.11.450

Cited by 10 publications

(14 citation statements)

References 40 publications

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“…It promotes proliferation of pancreatic cancer cells through alteration of cyclin E as a result of constitutive activation of signal transducer and activator of transcription (STAT) protein 3 [12]. In addition, mesothelin overexpression results in upregulation of growth/ survival pathways through autocrine production of growth factors such as interleukin (IL)-6 [13]. Mesothelin also induces an increase in nuclear factor (NF)-kB activation, which leads to resistance to tumour necrosis factor-a-induced apoptosis [14], indicating a mechanism through which mesothelin may help increase survival of tumour cells in the highly inflammatory milieu, evident in pancreatic cancer through Akt/phosphoinositide 3-kinase/NF-kB activation and IL-6 overexpression.…”

Section: Mesothelinmentioning

confidence: 99%

“…Mesothelin also induces an increase in nuclear factor (NF)-kB activation, which leads to resistance to tumour necrosis factor-a-induced apoptosis [14], indicating a mechanism through which mesothelin may help increase survival of tumour cells in the highly inflammatory milieu, evident in pancreatic cancer through Akt/phosphoinositide 3-kinase/NF-kB activation and IL-6 overexpression. Mesothelin overexpression results in secretion of high levels of IL-6, which could be responsible for the cells' increased viability and proliferation under serum-reduced conditions through an IL-6/soluble IL-6 receptor trans-signalling mechanism and the induction of the IL-6-STAT3 pathway [12,13].…”

Section: Mesothelinmentioning

confidence: 99%

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Effectiveness of mesothelin family proteins and osteopontin for malignant mesothelioma

et al. 2012

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Malignant mesothelioma (MM) is an aggressive tumour with poor prognosis whose early diagnosis is difficult. Mesothelin, megakaryocyte potentiating factor (MPF) and osteopontin have attracted attention as biomarkers. The aim of the present review is to provide an overview regarding these candidate biomarkers for MM, and discuss their potential role in today's clinical practice.Mesothelin and MPF have good specificity but sub-optimal sensitivity for detection of MM, being negative both in the sarcomatoid histological sub-type and in almost half of epithelioid mesothelioma, especially in the early stages. Osteopontin is a marker of the duration of asbestos exposure, but lacks specificity for mesothelioma. Several patient characteristics influence the diagnostic accuracy of biomarkers and make the establishment of the ''optimal'' diagnostic threshold difficult. Mesothelin and MPF have proved useful in assessing response to treatment. Combining different markers together may lead to an improvement in diagnostic accuracy, but there is still need for research in this area. Extensive validation and further research is required to improve the use of serum markers in mesothelioma management. In the near future, their application in clinical practice is probably in monitoring response to therapy, rather than in guiding diagnostic decisions and risk assessment of asbestos-exposed populations.

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Section: Mesothelinmentioning

confidence: 99%

Section: Mesothelinmentioning

confidence: 99%

Effectiveness of mesothelin family proteins and osteopontin for malignant mesothelioma

et al. 2012

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“…Mesothelin may further contribute to metastasis by inducing the expression of matrix metalloproteinases 7 and 9 (13,14). In pancreatic cancer cells, mesothelin has been shown to contribute to tumorigenesis by inducing interleukin-6 expression and cell proliferation and by promoting resistance to TNF-a (15,16). Because of high expression in several cancers and a conversely restricted expression in normal tissues, mesothelin is an attractive target for anticancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Anetumab Ravtansine: A Novel Mesothelin-Targeting Antibody–Drug Conjugate Cures Tumors with Heterogeneous Target Expression Favored by Bystander Effect

Golfier

Kopitz

Kahnert

et al. 2014

Molecular Cancer Therapeutics

200

166

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Mesothelin is a tumor differentiation antigen frequently overexpressed in tumors such as mesothelioma, ovarian, pancreatic, and lung adenocarcinomas while showing limited expression in nonmalignant tissues. Mesothelin is therefore an attractive target for cancer therapy using antibody-drug conjugates (ADC). This study describes the detailed characterization of anetumab ravtansine, here referred to as BAY 94-9343, a novel ADC consisting of a human anti-mesothelin antibody conjugated to the maytansinoid tubulin inhibitor DM4 via a disulfide-containing linker. Binding properties of the anti-mesothelin antibody were analyzed using surface plasmon resonance, immunohistochemistry, flow cytometry, and fluorescence microscopy. Effects of BAY 94-9343 on cell proliferation were first studied in vitro and subsequently in vivo using subcutaneous, orthotopic, and patient-derived xenograft tumor models. The antibody binds to human mesothelin with high affinity and selectivity, thereby inducing efficient antigen internalization. In vitro, BAY 94-9343 demonstrated potent and selective cytotoxicity of mesothelin-expressing cells with an IC 50 of 0.72 nmol/L, without affecting mesothelin-negative or nonproliferating cells. In vivo, BAY 94-9343 localized specifically to mesothelin-positive tumors and inhibited tumor growth in both subcutaneous and orthotopic xenograft models. In addition, BAY 94-9343 was able to induce a bystander effect on neighboring mesothelin-negative tumor cells. Antitumor efficacy of BAY 94-9343 correlated with the amount of mesothelin expressed and was generally superior to that of standard-of-care regimen resulting in complete tumor eradication in most of the models. BAY 94-9343 is a selective and highly potent ADC, and our data support its development for the treatment of patients with mesothelin-expressing tumors. Mol Cancer Ther; 13(6); 1537-48. Ó2014 AACR.

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“…Subsequent studies by Bharadwaj et al NF-B activation which leads to resistance to TNF-α-induced apoptosis 23 , indicating a mechanism through which MSLN may help to increase survival of tumor cells in the highly inflammatory milieu evident in pancreatic cancer through Akt/PI3K/NF-B Activation and IL-6 overexpression. MSLN overexpression results in secretion of high levels of IL-6, which could in turn be responsible for the cells' increased viability and proliferation under serumreduced conditions through a IL-6/soluble IL-6R (sIL-6R) trans-signaling mechanism and the induction of the IL-6-STAT3 pathway 3,22 .…”

Section: Mesothelin In Pancreatic Cancersmentioning

confidence: 99%

The Role of Mesothelin in Pancreatic Cancer

Marín-Müller¹,

Chen²,

Yao³

2012

Pancreatic Cancer - Molecular Mechanism and Targets

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Mesothelin Overexpression Promotes Autocrine IL-6/sIL-6R Trans-Signaling to Stimulate Pancreatic Cancer Cell Proliferation

Cited by 10 publications

References 40 publications

Effectiveness of mesothelin family proteins and osteopontin for malignant mesothelioma

Effectiveness of mesothelin family proteins and osteopontin for malignant mesothelioma

Anetumab Ravtansine: A Novel Mesothelin-Targeting Antibody–Drug Conjugate Cures Tumors with Heterogeneous Target Expression Favored by Bystander Effect

The Role of Mesothelin in Pancreatic Cancer

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