Mesothelin: a new target for immunotherapy.

Mesothelin is a differentiation antigen present on normal mesothelial cells and overexpressed in several human tumors, including mesothelioma and ovarian and pancreatic adenocarcinoma. The mesothelin gene encodes a precursor protein that is processed to yield the 40-kDa protein, mesothelin, attached to the cell membrane by a glycosylphosphatidyl inositol linkage and a 31-kDa shed fragment named megakaryocyte-potentiating factor. The biological function of mesothelin is not known. Mesothelin is a promising candidate for tumor-specific therapy, given its limited expression in normal tissues and high expression in several cancers. SS1(dsFv)PE38 is a recombinant anti-mesothelin immunotoxin that is undergoing clinical evaluation in patients with mesothelin-expressing tumors. There is evidence that mesothelin is an immunogenic protein and could be exploited as a therapeutic cancer vaccine. A soluble mesothelin variant has been identified and could be a useful tumor marker for malignant mesotheliomas.

[1]  W. Renner,et al.  A Common 936 C/T Mutation in the Gene for Vascular Endothelial Growth Factor Is Associated with Vascular Endothelial Growth Factor Plasma Levels , 2000, Journal of Vascular Research.

[2]  R. Moon,et al.  The Tuberin-Hamartin Complex Negatively Regulates β-Catenin Signaling Activity* , 2003, The Journal of Biological Chemistry.

[3]  I. Pastan,et al.  Targeted therapy against human lung cancer in nude mice by high-affinity recombinant antimesothelin single-chain Fv immunotoxin. , 2002, Molecular cancer therapeutics.

[4]  I. Pastan,et al.  Stabilization of the Fv fragments in recombinant immunotoxins by disulfide bonds engineered into conserved framework regions. , 1994, Biochemistry.

[5]  D. Faigel,et al.  Novel Markers of Pancreatic Adenocarcinoma in Fine-Needle Aspiration: Mesothelin and Prostate Stem Cell Antigen Labeling Increases Accuracy in Cytologically Borderline Cases , 2003, Applied immunohistochemistry & molecular morphology : AIMM.

[6]  S. Takai,et al.  Mapping and determination of the cDNA sequence of the Erc gene preferentially expressed in renal cell carcinoma in the Tsc2 gene mutant (Eker) rat model. , 2000, Biochemical and biophysical research communications.

[7]  N. Yamaguchi,et al.  A novel cytokine exhibiting megakaryocyte potentiating activity from a human pancreatic tumor cell line HPC-Y5. , 1994, The Journal of biological chemistry.

[8]  M. Miettinen,et al.  Expression of Calretinin, Thrombomodulin, Keratin 5, and Mesothelin in Lung Carcinomas of Different Types: An Immunohistochemical Analysis of 596 Tumors in Comparison With Epithelioid Mesotheliomas of the Pleura , 2003, The American journal of surgical pathology.

[9]  R. Moon,et al.  Stromelysin-1 and mesothelin are differentially regulated by Wnt-5a and Wnt-1 in C57mg mouse mammary epithelial cells , 2003, BMC Developmental Biology.

[10]  A. Musk,et al.  Mesothelin-family proteins and diagnosis of mesothelioma , 2003, The Lancet.

[11]  I. Pastan,et al.  Anti-Tumor Activity of K1-LysPE38QQR, an Immunotoxin Targeting Mesothelin, a Cell-Surface Antigen Overexpressed in Ovarian Cancer and Malignant Mesothelioma , 2000, Journal of immunotherapy.

[12]  M. A. Davitz,et al.  How GPI-anchored proteins turnover: or where do they go after arrival at the plasma membrane. , 1994, Seminars in immunology.

[13]  I. Pastan,et al.  111Indium‐labeled monoclonal antibody K1: Biodistribution study in nude mice bearing a human carcinoma xenograft expressing mesothelin , 1999, International journal of cancer.

[14]  I. Pastan,et al.  Isolation of a high-affinity stable single-chain Fv specific for mesothelin from DNA-immunized mice by phage display and construction of a recombinant immunotoxin with anti-tumor activity. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[15]  C. Moskaluk,et al.  Large-scale molecular and tissue microarray analysis of mesothelin expression in common human carcinomas. , 2003, Human pathology.

[16]  Z. Ye,et al.  Soluble member(s) of the mesothelin/megakaryocyte potentiating factor family are detectable in sera from patients with ovarian carcinoma. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[17]  I. Pastan,et al.  Antitumor activity of SS(dsFv)PE38 and SS1(dsFv)PE38, recombinant antimesothelin immunotoxins against human gynecologic cancers grown in organotypic culture in vitro. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[18]  I. Pastan,et al.  Functional domains of pseudomonas exotoxin identified by deletion analysis of the gene expressed in E. coli , 1987, Cell.

[19]  N. Ordóñez,et al.  Application of Mesothelin Immunostaining in Tumor Diagnosis , 2003, The American journal of surgical pathology.

[20]  I. Pastan,et al.  Functional analysis of domains II, Ib, and III of Pseudomonas exotoxin. , 1989, The Journal of biological chemistry.

[21]  I. Pastan,et al.  Monoclonal Antibody K1 Reacts With Epithelial Mesothelioma but not With Lung Adenocarcinoma , 1992, The American journal of surgical pathology.

[22]  I. Pastan,et al.  Vascular Endothelial Growth Factor in Predicting Outcome in Breast Cancer , 2004, Clinical Cancer Research.

[23]  I. Pastan,et al.  Improving antibody affinity by mimicking somatic hypermutation in vitro , 1999, Nature Biotechnology.

[24]  N. Yamaguchi,et al.  Molecular Cloning and Expression of Megakaryocyte Potentiating Factor cDNA (*) , 1995, The Journal of Biological Chemistry.

[25]  I. Pastan,et al.  Isolation and characterization of a monoclonal antibody, K1, reactive with ovarian cancers and normal mesothelium , 1992, International journal of cancer.

[26]  N. Ordóñez.  Value of Mesothelin Immunostaining in the Diagnosis of Mesothelioma , 2003, Modern Pathology.

[27]  N. Umesaki,et al.  Binding of Ovarian Cancer Antigen CA125/MUC16 to Mesothelin Mediates Cell Adhesion* , 2004, Journal of Biological Chemistry.

[28]  Ji Huang,et al.  [Serial analysis of gene expression]. , 2002, Yi chuan = Hereditas.

[29]  I. Pastan,et al.  Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[30]  J. Cameron,et al.  Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE). , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[31]  B. Paulweber,et al.  A common 936 C/T gene polymorphism of vascular endothelial growth factor is associated with decreased breast cancer risk , 2003, International journal of cancer.

[32]  I. Bauerfeind,et al.  Association between HER-2/neu and Vascular Endothelial Growth Factor Expression Predicts Clinical Outcome in Primary Breast Cancer Patients , 2004, Clinical Cancer Research.

[33]  R. Bast,et al.  Status of tumor markers in ovarian cancer screening. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  I. Pastan,et al.  Mesothelin Is Not Required for Normal Mouse Development or Reproduction , 2000, Molecular and Cellular Biology.

[35]  T. Strong,et al.  Characterization of human mesothelin transcripts in ovarian and pancreatic cancer , 2004, BMC Cancer.

[36]  I. Pastan,et al.  Frequent expression of the tumor antigen cak1 in squamous‐cell carcinomas , 1992, International journal of cancer.

[37]  L. Grochow,et al.  Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.