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, apoptosisresistance, 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 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA046120-26
Application #
8636404
Study Section
Special Emphasis Panel (NSS)
Program Officer
Woodhouse, Elizabeth
Project Start
1987-07-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
26
Fiscal Year
2014
Total Cost
$340,849
Indirect Cost
$116,606
Name
Wayne State University
Department
Pathology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Funasaka, Tatsuyoshi; Raz, Avraham; Nangia-Makker, Pratima (2014) Galectin-3 in angiogenesis and metastasis. Glycobiology 24:886-91
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Balan, Vitaly; Wang, Yi; Nangia-Makker, Pratima et al. (2013) Galectin-3: a possible complementary marker to the PSA blood test. Oncotarget 4:542-9
Wang, Y; Balan, V; Kho, D et al. (2013) Galectin-3 regulates p21 stability in human prostate cancer cells. Oncogene 32:5058-65
Levy, Ran; Biran, Anat; Poirier, Francoise et al. (2011) Galectin-3 mediates cross-talk between K-Ras and Let-7c tumor suppressor microRNA. PLoS One 6:e27490
Kobayashi, Tsutomu; Shimura, Tatsuo; Yajima, Toshiki et al. (2011) Transient gene silencing of galectin-3 suppresses pancreatic cancer cell migration and invasion through degradation of ?-catenin. Int J Cancer 129:2775-86
Balan, Vitaly; Nangia-Makker, Pratima; Jung, Young Suk et al. (2010) Galectin-3: A novel substrate for c-Abl kinase. Biochim Biophys Acta 1803:1198-205

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