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 #
2R37CA046120-19
Application #
7192984
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
2007-04-01
Budget End
2008-03-31
Support Year
19
Fiscal Year
2007
Total Cost
$346,620
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
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Funasaka, Tatsuyoshi; Raz, Avraham; Nangia-Makker, Pratima (2014) Galectin-3 in angiogenesis and metastasis. Glycobiology 24:886-91
Harazono, Y; Nakajima, K; Raz, A (2014) Why anti-Bcl-2 clinical trials fail: a solution. Cancer Metastasis Rev 33:285-94
Funasaka, Tatsuyoshi; Balan, Vitaly; Raz, Avraham et al. (2013) Nucleoporin Nup98 mediates galectin-3 nuclear-cytoplasmic trafficking. Biochem Biophys Res Commun 434:155-61
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
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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