The development of breast cancer can be modulated by actions of the immune system. Reciprocally, tumors appear to cause profound alterations of the immunologically relevant cells either directly, via tumor cell derived factors, or in an indirect manner. Dr. Lopez proposes to continue studies using the well-characterized murine mammary tumor model to elucidate the interactions between the growing neoplasms and the immune effector cells. The DI -DMBA-3 tumor, and the DA-3 tumor cell line derived in vitro from the former, are syngeneic to BALB/c mice and grow in vivo in the host of origin. She will focus especially on elucidating the phenotypic and functional alterations observed in the T cell compartment of tumor bearing mice.
The aims are to (1) delineate the interactions between thymocytes and the thymic microenvironment leading to thymic involution during mammary tumorigenesis; (2) analyze the basis of down-regulation of IEL-12 production by macrophages and the altered T cell responsiveness to this cytokine in the tumor bearing mice; (3) elucidate the molecular events leading to the over-expression of matrix metalloproteinase-9 (MMP-9) in T cells from tumor bearers and its role in the infiltration of these lymphocytes into mammary tumors; and (4) determine the mechanisms by which DA-3 mammary tumor cells transfected with a secreted form of the human MUCI gene fail to grow in intact BALB/c mice, while they develop in immunodeficient mice. An under- standing of the causes for the immune deviations occurring during mammary tumorigenesis, at the cellular and molecular levels, will help devise rational new therapeutic approaches for the eventual control of breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA025583-22S1
Application #
6255139
Study Section
Experimental Immunology Study Section (EI)
Project Start
1979-04-01
Project End
2004-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
22
Fiscal Year
2000
Total Cost
$88,178
Indirect Cost
Name
University of Miami School of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33146
Ilkovitch, Dan; Carrio, Roberto; Lopez, Diana M (2012) uPA and uPA-receptor are involved in cancer-associated myeloid-derived suppressor cell accumulation. Anticancer Res 32:4263-70
Carrio, Roberto; Torroella-Kouri, Marta; Iragavarapu-Charyulu, Vijaya et al. (2011) Tumor-induced thymic atrophy: alteration in interferons and Jak/Stats signaling pathways. Int J Oncol 38:547-53
Carrio, Roberto; Torroella-Kouri, Marta; Libreros, Stephania et al. (2011) Decreased accumulation of immune regulatory cells is correlated to the antitumor effect of IFN-ýý overexpression in the tumor. Int J Oncol 39:1619-27
Carrio, Roberto; Altman, Norman H; Lopez, Diana M (2009) Downregulation of interleukin-7 and hepatocyte growth factor in the thymic microenvironment is associated with thymus involution in tumor-bearing mice. Cancer Immunol Immunother 58:2059-72
Torroella-Kouri, Marta; Silvera, Risset; Rodriguez, Dayron et al. (2009) Identification of a subpopulation of macrophages in mammary tumor-bearing mice that are neither M1 nor M2 and are less differentiated. Cancer Res 69:4800-9
Carrio, Roberto; Lopez, Diana M (2009) Impaired thymopoiesis occurring during the thymic involution of tumor-bearing mice is associated with a down-regulation of the antiapoptotic proteins Bcl-XL and A1. Int J Mol Med 23:89-98
Ilkovitch, Dan; Lopez, Diana M (2009) Urokinase-mediated recruitment of myeloid-derived suppressor cells and their suppressive mechanisms are blocked by MUC1/sec. Blood 113:4729-39
Ilkovitch, Dan; Lopez, Diana M (2009) The liver is a site for tumor-induced myeloid-derived suppressor cell accumulation and immunosuppression. Cancer Res 69:5514-21
Handel-Fernandez, Mary Ellen; Ilkovitch, Dan; Iragavarapu-Charyulu, Vijaya et al. (2009) Decreased levels of both Stat1 and Stat3 in T lymphocytes from mice bearing mammary tumors. Anticancer Res 29:2051-8
Calderon, Cesar L; Torroella-Kouri, Marta; Dinapoli, Michael R et al. (2008) Involvement of protein kinase C and not of NF kappa B in the modulation of macrophage nitric oxide synthase by tumor-derived phosphatidyl serine. Int J Oncol 32:713-21

Showing the most recent 10 out of 38 publications