While mucins are found on normal cell surfaces, and are proposed to have multiple roles such as providing protection from environmental exposures and carcinogens, and involvement in cell adhesion and migration, altered forms of the MUC1 glycoprotein have been found heavily expressed in human breast cancer tissue, and other tumors. In our laboratory mammary tumor cells expressing the transmembrane isoform of MUC1 develop tumors in vivo and lead to death of the host. In contrast, tumor cells expressing a MUC1 secreted isoform fail to develop tumors by an immunologically regulated mechanism. Furthermore, MUC1 secreting mammary tumor cells confer protection in mice against the parental mammary tumor line, which does not secrete MUC1, and other highly tumorigenic cell lines unrelated to the mammary tumor line. The following proposal aims to dissect some of the molecular mechanisms involved in this phenomenon.
The first aim will examine characteristics of the MUC1 secreting tumor cells which may lead to rejection in vivo or failure to grow. Immunological surface molecules, and production of tumor derived factors, such as chemoattractant molecules and extracellular matrix degrading proteins, will be screened by various assays such as flow cytometry, ELISA, and zymography assays. These techniques will identify if there is a variable expression of these molecules by the tumor lines, which may aid in immunoregulation of tumor growth or elimination.
The second aim will dissect the effect of these tumor cells differing in MUC1 expression on various immunological parameters including among others migration and activation of different types of lymphoreticular cells, dendritic cell maturation and function, monocyte migration, expansion of immature myeloid suppressor cells and their ability to inhibit anti-tumor immune responses, and induction of immunological tolerance to tumors.
This aim will be achieved by different assays including but not limited to flow cytometry, gel matrix cellular recruitment in vivo, T cell activation and proliferation, and use of cellular migration chambers. Furthermore, the purified secreted isoform of MUC1 or an Immuno Enhancing Peptide (IEP) only found in the secreted isoform will be used in parallel experiments to test the ability of changing the parameters analyzed in the two aims. The objective of this proposal is to investigate the immunological and cellular mechanisms involved in the growth of tumors, and examine the immunoregulatory characteristics of the MUC1 glycoprotein, which may have immunoenhancing and anti-tumor properties. Understanding how MUC1 is involved in tumor immunoregulation may potentially lead to its use as an immunotherapeutic agent against various cancers.
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| Ilkovitch, Dan; Handel-Fernandez, Mary Ellen; Herbert, Lynn M et al. (2008) Antitumor effects of Mucin 1/sec involves the modulation of urokinase-type plasminogen activator and signal transducer and activator of transcription 1 expression in tumor cells. Cancer Res 68:2427-35 |
