Immunobiology of human mucin 1 in a preclinical ovarian tumor model

R. A. Budiu, E. Elishaev, J. Brozick, M. Lee, R. P. Edwards, P. Kalinski, A. M. Vlad

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Epithelial ovarian cancer is an aggressive malignancy, with a low 5-year median survival. Continued improvement on the development of more effective therapies depends in part on the availability of adequate preclinical models for in vivo testing of treatment efficacy. Mucin 1 (MUC1) glycoprotein is a tumor-associated antigen overexpressed in ovarian cancer cells, making it a potential target for immune therapy. To create a preclinical mouse model for MUC1-positive ovarian tumors, we generated triple transgenic (Tg) mice that heterozygously express human MUC1 +/-as a transgene, and carry the conditional K-rasG12D oncoallele (loxP-Stop-loxP-K-ras G12D/+) and the floxed Pten gene (Pten/loxP/loxP). Injection of Cre recombinase-encoding adenovirus (AdCre) in the ovarian bursa of triple (MUC1KrasPten) Tg mice triggers ovarian tumors that, in analogy to human ovarian cancer, express strongly elevated MUC1 levels. The tumors metastasize loco-regionally and are accompanied by high serum MUC1, closely mimicking the human disease. Compared with the KrasPten mice with tumors, the MUC1KrasPten mice show increased loco-regional metastasis and augmented accumulation of CD4+Foxp3+ immune-suppressive regulatory T cells. Vaccination of MUC1KrasPten mice with type 1 polarized dendritic cells (DC1) loaded with a MUC1 peptide (DC1-MUC1) can circumvent tumor-mediated immune suppression in the host, activate multiple immune effector genes and effectively prolong survival. Our studies report the first human MUC1-expressing, orthotopic ovarian tumor model, reveal novel MUC1 functions in ovarian cancer biology and demonstrate its suitability as a target for immune-based therapies.

Original languageEnglish (US)
Pages (from-to)3664-3675
Number of pages12
JournalOncogene
Volume32
Issue number32
DOIs
StatePublished - Aug 8 2013
Externally publishedYes

Keywords

  • Kras
  • MUC1
  • Pten
  • dendritic cells
  • ovarian cancer

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Fingerprint Dive into the research topics of 'Immunobiology of human mucin 1 in a preclinical ovarian tumor model'. Together they form a unique fingerprint.

Cite this