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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA046120-22
Application #
7780451
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Mohla, Suresh
Project Start
1987-07-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
22
Fiscal Year
2010
Total Cost
$361,245
Indirect Cost
Name
Wayne State University
Department
Pathology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Nakajima, Kosei; Kho, Dhong Hyo; Yanagawa, Takashi et al. (2016) Galectin-3 Cleavage Alters Bone Remodeling: Different Outcomes in Breast and Prostate Cancer Skeletal Metastasis. Cancer Res 76:1391-402
Harazono, Yosuke; Kho, Dhong Hyo; Balan, Vitaly et al. (2015) Extracellular galectin-3 programs multidrug resistance through Na+/K+-ATPase and P-glycoprotein signaling. Oncotarget 6:19592-604
Harazono, Yosuke; Kho, Dhong Hyo; Balan, Vitaly et al. (2014) Galectin-3 leads to attenuation of apoptosis through Bax heterodimerization in human thyroid carcinoma cells. Oncotarget 5:9992-10001
Funasaka, Tatsuyoshi; Raz, Avraham; Nangia-Makker, Pratima (2014) Galectin-3 in angiogenesis and metastasis. Glycobiology 24:886-91
Funasaka, Tatsuyoshi; Raz, Avraham; Nangia-Makker, Pratima (2014) Nuclear transport of galectin-3 and its therapeutic implications. Semin Cancer Biol 27:30-8
Harazono, Y; Nakajima, K; Raz, A (2014) Why anti-Bcl-2 clinical trials fail: a solution. Cancer Metastasis Rev 33:285-94
Nakajima, Kosei; Kho, Dhong Hyo; Yanagawa, Takashi et al. (2014) Galectin-3 inhibits osteoblast differentiation through notch signaling. Neoplasia 16:939-49
Funasaka, Tatsuyoshi; Balan, Vitaly; Raz, Avraham et al. (2013) Nucleoporin Nup98 mediates galectin-3 nuclear-cytoplasmic trafficking. Biochem Biophys Res Commun 434:155-61
Wang, Y; Balan, V; Kho, D et al. (2013) Galectin-3 regulates p21 stability in human prostate cancer cells. Oncogene 32:5058-65
Nangia-Makker, Pratima; Raz, Tirza; Tait, Larry et al. (2013) Ocimum gratissimum retards breast cancer growth and progression and is a natural inhibitor of matrix metalloproteases. Cancer Biol Ther 14:417-27

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