Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion in an orthotopic mouse model and in epithelioid pleural mesothelioma patients Journal Article


Authors: Servais, E. L.; Colovos, C.; Rodriguez, L.; Bograd, A. J.; Nitadori, J. I.; Sima, C.; Rusch, V. W.; Sadelain, M.; Adusumilli, P. S.
Article Title: Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion in an orthotopic mouse model and in epithelioid pleural mesothelioma patients
Abstract: Purpose: Mesothelin (MSLN) is a tumor-associated antigen, being investigated as a biomarker and therapeutic target in malignant pleural mesothelioma (MPM). The biologic function of MSLN overexpression in MPM is unknown. We hypothesized that MSLN may promote tumor invasion in MPM, a tumor characterized primarily by regional aggressiveness and rare distant metastases. Experimental Design: Human and murine MPM cells with MSLN forced expression and short hairpin RNA knockdown were examined for proliferation, invasion, and matrix metalloproteinase (MMP) secretion. The influence of MSLN overexpression on MPM cell invasion was assessed in an orthotopic mouse model and in patient samples. Results: MSLN expression promotes MPM cell invasion and MMP secretion in both human and murine MPM cells. In an orthotopic MPM mouse model characterized by our laboratory, MPM cells with MSLN overexpression preferentially localized to the tumor invading edge, colocalized with MMP-9 expression, and promoted decreased survival without an increase in tumor burden progression. In a tissue microarray from epithelioid MPM patients (n = 139, 729 cores), MSLN overexpression correlated with higher MMP-9 expression at individual core level. Among stage III MPM patients (n = 72), high MSLN expression was observed in 26% of T2 tumors and 51% of T3 tumors. Conclusions: Our data provide evidence elucidating a biologic role for MSLN as a factor promoting tumor invasion and MMP-9 expression in MSLN expressing MPM. As regional invasion is the characteristic feature in MSLN expressing solid cancers (MPM, pancreas, and ovarian), our observations add rationale to studies investigating MSLN as a therapeutic target. ©2012 AACR.
Keywords: adult; cancer survival; controlled study; human tissue; protein expression; aged; aged, 80 and over; middle aged; human cell; overall survival; nonhuman; cancer staging; flow cytometry; neoplasm staging; protein function; cell proliferation; animal cell; mouse; animals; mice; apoptosis; gene expression profiling; gelatinase b; tumor markers, biological; animal experiment; animal model; in vivo study; in vitro study; molecular imaging; mice, inbred balb c; distant metastasis; cancer invasion; immunoenzyme techniques; survival time; blotting, western; reverse transcriptase polymerase chain reaction; rna, messenger; oligonucleotide array sequence analysis; pleura mesothelioma; mesothelioma; cell migration; cell movement; tumor model; neoplasm invasiveness; tissue microarray; tumor growth; disease models, animal; cell adhesion; enzyme release; cell invasion; short hairpin rna; pleural neoplasms; enzyme localization; epithelioid cells; mesothelin; tumor microenvironment; matrix metalloproteinase 9; real-time polymerase chain reaction; gpi-linked proteins
Journal Title: Clinical Cancer Research
Volume: 18
Issue: 9
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2012-05-01
Start Page: 2478
End Page: 2489
Language: English
DOI: 10.1158/1078-0432.ccr-11-2614
PROVIDER: scopus
PUBMED: 22371455
PMCID: PMC3759995
DOI/URL:
Notes: --- - "Export Date: 4 June 2012" - "CODEN: CCREF" - "Source: Scopus"
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MSK Authors
  1. Camelia S Sima
    204 Sima
  2. Valerie W Rusch
    655 Rusch
  3. Elliot Louis Servais
    17 Servais
  4. Adam Jason Bograd
    11 Bograd
  5. Michel W J Sadelain
    456 Sadelain
  6. Christos Colovos
    16 Colovos