The broad, long term objective of this proposal is to understand the role of adhesion molecules in the pathogenesis of lymphoid malignancies. This proposal will focus on the regulatory and functional mechanisms of integrins that control cell adhesion and the processes of cell migration and localization. The major hypotheses of this proposal are (1) although levels of integrin expression have obvious implications in the development of cancer, it is the alterations in the regulation of integrin receptor function that result in the major pathophysiological consequences, and (2) unique regulatory alterations will characterize distinctly differentiated normal lymphocyte subpopulations and malignant lymphocytes with different histopathological sybtypes and grades. The major observations that provide much of the foundation of this proposal are (1) integrin-mediated adhesion of lymphoid cells is subject to a regulatory cycle of """"""""off"""""""" and """"""""on"""""""" signals, (2) integrin triggering induces the rapid morphological changes in lymphocytes that result in pseudopodial extension and motility, and (3) normal resting lymphocytes, normal activated lymphocytes, indolent non-Hodgkin's lymphoma cells, chronic lymphocytic leukemia, and acute lymphoblastic leukemia cells all apparently have different alterations in these processes.
The specific aims will employ a combination of quantitative cellular adhesion and spreading assays, digital color microscopy, biochemical assays, and immunochemical techniques to analyze the roles of different structural and signal transduction molecules in the initiation and maintenance of integrin-mediated adhesion, pseudopodial extension, and transendothelial migration. The health relatedness of this research is that an understanding of normal integrin regulation versus that found in disease states and function may have diagnostic or prognostic value to the clinician and will lay the foundation for the development of novel therapeutic methods for controlling the growth and metastasis of leukemia and lymphoma cells, potentially allowing normal integrin functions to be maintained.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA062596-05
Application #
2752158
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mufson, R Allan
Project Start
1993-09-01
Project End
2001-12-30
Budget Start
1999-01-01
Budget End
1999-12-30
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Diaz-Montero, C Marcela; Wygant, James N; McIntyre, Bradley W (2006) PI3-K/Akt-mediated anoikis resistance of human osteosarcoma cells requires Src activation. Eur J Cancer 42:1491-500
Diaz-Montero, C Marcela; McIntyre, Bradley W (2005) Acquisition of anoikis resistance in human osteosarcoma cells does not alter sensitivity to chemotherapeutic agents. BMC Cancer 5:39
Qin, Chunlin; Brunn, Jan C; Baba, Otto et al. (2003) Dentin sialoprotein isoforms: detection and characterization of a high molecular weight dentin sialoprotein. Eur J Oral Sci 111:235-42
Marco, Rex A W; Diaz-Montero, C Marcela; Wygant, James N et al. (2003) Alpha 4 integrin increases anoikis of human osteosarcoma cells. J Cell Biochem 88:1038-47
Miyamoto, Yuko J; Mitchell, Jason S; McIntyre, Bradley W (2003) Physical association and functional interaction between beta1 integrin and CD98 on human T lymphocytes. Mol Immunol 39:739-51
Woodside, Darren G; Wooten, David K; Teague, T Kent et al. (2003) Control of T lymphocyte morphology by the GTPase Rho. BMC Cell Biol 4:2
Diaz-Montero, C M; McIntyre, B W (2003) Acquisition of anoikis resistance in human osteosarcoma cells. Eur J Cancer 39:2395-402
Lee, Lawrence Y; Miyamoto, Yuko J; McIntyre, Bradley W et al. (2002) The Staphylococcus aureus Map protein is an immunomodulator that interferes with T cell-mediated responses. J Clin Invest 110:1461-71
Mitchell, Jason S; Kanca, Oguz; McIntyre, Bradley W (2002) Lipid microdomain clustering induces a redistribution of antigen recognition and adhesion molecules on human T lymphocytes. J Immunol 168:2737-44
Caruso, D A; McIntyre, B W (2001) In an adhesion dependent human gastric adenocarcinoma cell line, integrin ligation without adhesion rescues from anoikis but is not sufficient for cell cycle progression. Cell Death Differ 8:665-78

Showing the most recent 10 out of 29 publications