The Role of Tumor Cell Surface Lectin in Metastases

Wayne State University, Detroit MI

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Abstract

DESCRIPTION (provided by applicant): Metastasis, the epitome of cancer progression, is a pathophysical process of profound significance, because much of the lethality is from malignant neoplasms. Carbohydrate-mediated recognition leads to the formation of multi-cell emboli in the circulation, a process directly related to the development of metastases. The role of galectin-3 in the process is now established through the efforts of this continued research. Galectin-3 is a chimeric gene product with monomer subunit of ~30,000 daltons, and is an unusual protein, in that it is localized and functions in the cytoplasm, cell membrane, nucleus and the extracellular millieu. Galectin-3 is an antiapoptotic molecule that contains the NWGR anti-death motif of the bcl-2 family members and is a novel binding partner of B-catenin. The results shown here indicate that galectin-3 regulates, in part, the intersection between cell-cell adhesion and signaling during cancer progression and metastasis. It has distinct functions and recognition sites involving different cell lineages at different developmental and pathological stages including cell growth, apoptosis-resistance, adhesion, differentiation, inflammation, transformation, angiogenesis, invasion and metastasis. We now propose to define in greater detail the structural-functional relationship of galectin-3 as it relates to cellular localization, cell growth, apoptosis- resistance, cell-cell recognition, angiogenesis, tumor growth and hematogenous spread of tumor cells. To this end we propose the following: 1) Determine the pathway for shuttling gal-3 between the cytoplasm and nucleus and its effect on tumor progression and metastasis. 2) Delineate the molecular role of gal-3 in Wnt signaling pathway during breast cancer progression and the impact of pathway inhibitors on breast cancer tumor growth and metastasis. 3) a) Establish the functional role of cleaved gal-3 in angiogenesis, invasion and metastasis, using cellular and genetic approaches both in vitro and in vivo, and b) Explore the feasibility of utilizing differential anti-gal-3 antibodies (specifically recognizing intact versus cleaved gal-3) as possible surrogate prognostic/diagnostic marker for MMPs activity in human cancers. It is expected that the results obtained from this study will provide a better understanding of galectin-3 and its interacting ligands in tumor progression and metastasis and will further the developments of specific reagents for the detection and interventions in these processes.