Advertisement

Immunologic Research

, Volume 50, Issue 2–3, pp 261–268 | Cite as

Importance of MUC1 and spontaneous mouse tumor models for understanding the immunobiology of human adenocarcinomas

  • Olivera J. FinnEmail author
  • Kira R. Gantt
  • Andrew J. Lepisto
  • Sharmila Pejawar-Gaddy
  • Jia Xue
  • Pamela L. Beatty
UNIVERSITY OF PITTSBURGH IMMUNOLOGY 2011

Abstract

Many important aspects of cancer biology, such as cancer initiation, progression, and metastasis, have been studied in animal models, mostly mice. As long as cancer was considered primarily a genetic disease, the study of transplantable mouse tumors, or even human tumor xenografts in immunocompromised mice, appeared to suffice. Many important genetic events that lead to transformation and in vivo tumor growth were elucidated. However, many even more important factors that determine whether or not the genetic potential of a tumor cell will be realized, such as the host response to the tumor and the tumor microenvironment that influences this response over a long period of time of tumor development, remained untested and unappreciated. This is slowly changing with the advent of molecular techniques that have spurred efforts to engineer better mouse models of human tumors. In this review, we show results of our efforts to combine a genetic mouse model of spontaneous human adenocarcinomas based on a Kras mutation, with an important human molecule MUC1 that is abnormally expressed on human adenocarcinomas, promoting oncogenesis, proinflammatory tumor microenvironment, and immunosurveillance.

Keywords

Lung cancer Pancreatic cancer Cancer vaccine Tumor-associated antigens Mucin 

Notes

Acknowledgments

This work was supported by grants 2P01 CA073743 (to OJF), 1F32 CA119780 (to KRG) and T32 CA802084 (to AJL).

References

  1. 1.
    Tuveson DA, Shaw AT, Willis NA, Silver DP, Jackson EL, Chang S, Mercer KL, Grochow R, Hock H, Crowley D, Hingorani SR, Zaks T, King C, Jacobetz MA, Wang L, Bronson RT, Orkin SH, DePinho RA, Jacks T. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell. 2004;5:375–87.PubMedCrossRefGoogle Scholar
  2. 2.
    Vlad AM, Kettel JC, Alajez NM, Carlos CA, Finn OJ. MUC1 immunobiology: from discovery to clinical applications. Adv Immunol. 2004;82:249–93.PubMedCrossRefGoogle Scholar
  3. 3.
    Li Y, Bharti A, Chen D, Gong J, Kufe D. Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-associated antigen and beta-catenin. Mol Cell Biol. 1998;18:7216–24.PubMedGoogle Scholar
  4. 4.
    Li Y, Kuwahara H, Ren J, Wen G, Kufe D. The c-Src tyrosine kinase regulates signaling of the human DF3/MUC1 carcinoma-associated antigen with GSK3 beta and beta-catenin. J Biol Chem. 2001;276:6061–4.PubMedCrossRefGoogle Scholar
  5. 5.
    Li Y, Ren J, Yu W, Li Q, Kuwahara H, Yin L, Carraway KL 3rd, Kufe D. The epidermal growth factor receptor regulates interaction of the human DF3/MUC1 carcinoma antigen with c-Src and beta-catenin. J Biol Chem. 2001;276:35239–42.PubMedCrossRefGoogle Scholar
  6. 6.
    Ren J, Li Y, Kufe D. Protein kinase C delta regulates function of the DF3/MUC1 carcinoma antigen in beta-catenin signaling. J Biol Chem. 2002;277:17616–22.PubMedCrossRefGoogle Scholar
  7. 7.
    Ren J, Raina D, Chen W, Li G, Huang L, Kufe D. MUC1 oncoprotein functions in activation of fibroblast growth factor receptor signaling. Mol Cancer Res. 2006;4:873–83.PubMedCrossRefGoogle Scholar
  8. 8.
    Pandey P, Kharbanda S, Kufe D. Association of the DF3/MUC1 breast cancer antigen with Grb2 and the Sos/Ras exchange protein. Cancer Res. 1995;55:4000–3.PubMedGoogle Scholar
  9. 9.
    Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 2000;19:3159–67.PubMedCrossRefGoogle Scholar
  10. 10.
    Yin L, Huang L, Kufe D. MUC1 oncoprotein activates the FOXO3a transcription factor in a survival response to oxidative stress. J Biol Chem. 2004;279:45721–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Ren J, Agata N, Chen D, Li Y, Yu WH, Huang L, Raina D, Chen W, Kharbanda S, Kufe D. Human MUC1 carcinoma-associated protein confers resistance to genotoxic anticancer agents. Cancer Cell. 2004;5:163–75.PubMedCrossRefGoogle Scholar
  12. 12.
    Carlos CA, Dong HF, Howard OM, Oppenheim JJ, Hanisch FG, Finn OJ. Human tumor antigen MUC1 is chemotactic for immature dendritic cells and elicits maturation but does not promote Th1 type immunity. J Immunol. 2005;175:1628–35.PubMedGoogle Scholar
  13. 13.
    Wei X, Xu H, Kufe D. Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response. Cancer Cell. 2005;7:167–78.PubMedCrossRefGoogle Scholar
  14. 14.
    Thompson EJ, Shanmugam K, Hattrup CL, Kotlarczyk KL, Gutierrez A, Bradley JM, Mukherjee P, Gendler SJ. Tyrosines in the MUC1 cytoplasmic tail modulate transcription via the extracellular signal-regulated kinase 1/2 and nuclear factor-kappaB pathways. Mol Cancer Res. 2006;4:489–97.PubMedCrossRefGoogle Scholar
  15. 15.
    Tsutsumida H, Swanson BJ, Singh PK, Caffrey TC, Kitajima S, Goto M, Yonezawa S, Hollingsworth MA. RNA interference suppression of MUC1 reduces the growth rate and metastatic phenotype of human pancreatic cancer cells. Clin Cancer Res. 2006;12:2976–87.PubMedCrossRefGoogle Scholar
  16. 16.
    Engelmann K, Shen H, Finn OJ. MCF7 side population cells with characteristics of cancer stem/progenitor cells express the tumor antigen MUC1. Cancer Res. 2008;68:2419–26.PubMedCrossRefGoogle Scholar
  17. 17.
    Hikita ST, Kosik KS, Clegg DO, Bamdad C. MUC1* mediates the growth of human pluripotent stem cells. PLoS One. 2008;3:e3312.PubMedCrossRefGoogle Scholar
  18. 18.
    Rowse GJ, Tempero RM, VanLith ML, Hollingsworth MA, Gendler SJ. Tolerance and immunity to MUC1 in a human MUC1 transgenic murine model. Cancer Res. 1998;58:315–21.PubMedGoogle Scholar
  19. 19.
    Beatty PL, Narayanan S, Gariepy J, Ranganathan S, Finn OJ. Vaccine against MUC1 antigen expressed in inflammatory bowel disease and cancer lessens colonic inflammation and prevents progression to colitis-associated colon cancer. Cancer Prev Res. 2010;3:438–46.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Olivera J. Finn
    • 1
    Email author
  • Kira R. Gantt
    • 1
  • Andrew J. Lepisto
    • 1
  • Sharmila Pejawar-Gaddy
    • 1
  • Jia Xue
    • 1
  • Pamela L. Beatty
    • 1
  1. 1.Department of ImmunologyUniversity of Pittsburgh School of MedicinePittsburghUSA

Personalised recommendations