Metastasis, the epitome of cancer progression, is a pathophysical process of profound significance, because much of the lethality from malignant neoplasms is attributed directly to their ability to develop metastasis in distant organs. 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 this process is now established through the efforts of this continued research. Galectin-3 is a member of the galectin gene family, composed of at least twelve members. Galectin-3 is a chimeric gene product with monomer subunit of about 30,000 daltons, composed of three distinct structural motifs, a short NH2-origin preceding an amino half-domain containing Gly-X-Y tandem repeats characteristic of collagens and carboxy-terminal half which encompasses the N-acetyllactosamine (Galbeta-4GlcNac)-binding site. Galectin-3 is an unusual protein, in that it is localized and functions in the cytoplasm, cell membrane, nucleus and the extracellular milieu and undergoes for function a non-covalent homodimerization and post-translation phosphorylation that regulate carbohydrate-recognition. It contains the NWGR anti-death motif of the BH1 domain of the bcl-2 family members. Galectin-3 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) To determine the molecular basis of the anti-apoptotic property of galectin-3; 2) To determine the functional consequence of galectin-3 phosphorylation on cell regulation and apoptosis; 3) To study the effect of antigalectin-3 therapy on cancer progression and metastasis. It is expected that the results to be 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.
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