開幕典禮及大會特別演講(一)

P-3
Glycobiology of Cancer and Inflammation: Roles of Galectins
Fu-Tong Liu, Institute of Biomedical Sciences, Academia Sinica; Department of Dermatology, University of California, Davis, School of Medicine, Sacramento, CA

  Galectins are β-galactoside-binding animal lectins. Presently seventeen members have been identified in mammals. Members are defined by shared consensus amino acid sequences in the carbohydrate-recognition domain (CRD) and affinity for -galactosides. None of the galectin family members contain a classical signal sequence; however, they are found in extracellular space. Galectins can function both extracellularly (through binding to cell surface glycans) or intracellularly (which may not be dependent on carbohydrate binding).

  A number of galectins have been shown to play important roles in the immune and inflammatory responses. Recombinant galectin-1 and -9 can induce apoptosis in T cells, by engaging cell surface glycoproteins. They can suppress the immune and inflammatory responses when administered in vivo.

  Recombinant galectin-3 has been shown to activate various leukocytes, induce migration of monocytes/macrophages, and also induce apoptosis in T cells. Various intracellular functions have also been documented for galectin-3, including anti-apoptosis, promotion of phagocytosis by macrophages, positive regulation of histamine release and IL-4 production by mast cells, and suppression of IL-12 production by dendritic cells.
The role of galectin-3 in the inflammatory response in vivo has been documented by using galectin-3-deficient mice, including airway inflammation in a model of asthma and skin inflammation in a model of atopic dermatitis. Also, galectin-3 is critical for the development of the Th2 response by functioning through both T cells and dendritic cells. In general, galectin-3 promotes the inflammatory response and may thus be a target for treatment of various inflammatory diseases.

  Galectin-1 binds to oncogenic H-Ras, a transforming oncogene, and can potentially contribute to neoplastic transformation. Galectin-1 has been shown to participate in tumor aggressiveness, possibly by enhancing cell migration and invasivenes. Galectin-1 also plays a role in immune evasion by tumor cells: galectin-1 secreted by the mouse melanoma cells induces apoptosis in cytolytic T cells directed to these cancer cells.

  The role of galectin-3 in tumor growth, progression and metastasis has been comprehensively documented. There is evidence that its expression is necessary for the initiation of the transformed phenotype of tumors, possibly related to the ability of the protein to interact with oncogenic K-Ras. The most extensively studied function of galectin-3 is its inhibition of apoptosis in a range of tumor cell types exposed to diverse apoptotic stimuli.
Galectin-3 may also regulate tumor development by controlling the levels of regulators of cell cycle progression, such as cyclin D1 and c-myc. In addition, galectin-3 can promote motility and invasiveness of tumor cells and affect tumor metastasis by exerting its effect in the tumor microenvironment, including angiogenesis and fibrosis. Moreover, tumor-associated galectin-3 may contribute to tumor immune escape by killing tumor-targeting T cells or by rendering them nonreactive. By studying gal3-/- keratinocytes, we found that galectin-3 regulates cell surface expression of epidermal growth factor receptor (EGFR) in keratinocytes. Galectin-3 thus may contribute to tumorigenesis by regulating cell surface expression of EGFR. Thus, the existing information suggests that galectin-3 is a target for treatment of cancers and this has been demonstrated in a number of reports.

  Galectin-7 is a proapoptotic protein. We found that tumor formation from galectin-7-transfected tumor cells was dramatically reduced compared to control transfectants when these cells were inoculated subcutaneously into mice. Thus, galectin-7 has a suppressive effect on tumor growth. Galectin-7 gene transfer or means to specifically induce galectin-7 expression may be a new approach for treatment of cancers.