The dramatic changes in glycolipid composition and metabolism associated with cellular differentiation and oncogenesis suggest a specific role of membrane glycolipids in these processes. Previous studies have revealed that many tumor-associated antigens as well as developmentally-regulated antigens are glycolipids. Some of these antigens are modified or incompatible blood group antigens. On the other hand, ubiquitous gangliosides such as GM3 or GM1 may have a basic function in regulating cell proliferation and cell adhesing. Some evidence has been provided for a possible effect of membranes gangliosides on growth factor receptors such as EGF, PDGF, FGF, and transferrin. GM3 or GM1 inhibit tyrosine phosphorylation of the PDGF receptor, while GM3 inhibits that of the EGF receptor. Based on these findings, we propose to study the following projects: (1) A search for new glycolipid tumor-associated markers and their expression as related to various stages of cancer progression. (2) Specificities of blood group determinants as influenced by their carrier carbohydrates. (3) Oncofetal alteration of blood group determinants and their carrier carbohydrates, particularly expression of the globo-series blood group antigens and incompatible A-like antigens in human cancer. (4) A possible role of glycolipids in cell recognition during embryogenesis and differentiation of teratocarcinoma. (5) Cell growth inhibition and differentiation induction by exogenous addition of gangliosides, and the mechanism of such effects. (6) The effect of anti-carbohydrate antibodies on cell growth and differentiation. These studies may greatly enrich our knowledge of: (1) the molecular basis of tumor markers, their heterogeneity as related to phenotypic variation of human tumor cell population, and the steps of cancer progression; and (2) the molecular basis of cell recognition and adhesion through glycolipids, and the mechanism of aberrant cell proliferation of cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA042505-06
Application #
3479310
Study Section
Project Start
1987-09-01
Project End
1993-05-31
Budget Start
1990-06-01
Budget End
1991-05-31
Support Year
6
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Biomembrane Institute
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98119
Hakomori, Sen-Itiroh; Handa, Kazuko (2015) GM3 and cancer. Glycoconj J 32:1-8
Handa, Kazuko; Hakomori, Sen-Itiroh (2012) Carbohydrate to carbohydrate interaction in development process and cancer progression. Glycoconj J 29:627-37
Hakomori, Sen-itiroh (2008) Structure and function of glycosphingolipids and sphingolipids: recollections and future trends. Biochim Biophys Acta 1780:325-46
Hakomori, Senitiroh (2004) Carbohydrate-to-carbohydrate interaction in basic cell biology: a brief overview. Arch Biochem Biophys 426:173-81
Hakomori, Senitiroh (2004) Carbohydrate-to-carbohydrate interaction, through glycosynapse, as a basis of cell recognition and membrane organization. Glycoconj J 21:125-37
Hakomori Si, Sen-itiroh (2002) Inaugural Article: The glycosynapse. Proc Natl Acad Sci U S A 99:225-32
Yu, Song; Kojima, Naoya; Hakomori, Sen-itiroh et al. (2002) Binding of rainbow trout sperm to egg is mediated by strong carbohydrate-to-carbohydrate interaction between (KDN)GM3 (deaminated neuraminyl ganglioside) and Gg3-like epitope. Proc Natl Acad Sci U S A 99:2854-9
Hakomori, S (2001) Tumor-associated carbohydrate antigens defining tumor malignancy: basis for development of anti-cancer vaccines. Adv Exp Med Biol 491:369-402
Handa, K; Kojima, N; Hakomori, S (2000) Analysis of glycolipid-dependent cell adhesion based on carbohydrate-carbohydrate interaction. Methods Enzymol 312:447-58
Iwabuchi, K; Handa, K; Hakomori, S (2000) Separation of glycosphingolipid-enriched microdomains from caveolar membrane characterized by presence of caveolin. Methods Enzymol 312:488-94

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