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Tumor Malignancy Defined by Aberrant Glycosylation and Sphingo(glyco)lipid Metabolism¹

Pacific Northwest Research Foundation, Biomembrane Division, Seattle, Washington 98122, and Departments of Pathobiology and Microbiology, University of Washington, Seattle, Washington 98195

Aberrant glycosylation expressed in glycosphingolipids and glycoproteins in tumor cells has been implicated as an essential mechanism in defining stage, direction, and fate of tumor progression. This general concept is supported by results from three lines of study:

(a) Numerous clinicopathological studies have shown a clear correlation between aberrant glycosylation status of primary tumor and invasive/metastatic potential of human cancer as reflected by 5- or 10-year survival rates of patients.

(b) Carbohydrates expressed in tumor cells are either adhesion molecules per se or modulate adhesion receptor function. Some are directly involved in cell adhesion. They are recognized by selectins or other carbohydrate-binding proteins or by complementary carbohydrates (through carbohydrate-carbohydrate interaction). N- or O-glycosylation of functionally important membrane components may alter tumor cell adhesion or motility in a direction that either promotes or inhibits invasion and metastasis. Examples of such receptors are E-cadherin, integrins, immunoglobulin family receptors (e.g., CD44), and lysosome-associated membrane protein.

(c) Gangliosides and sphingolipids modulate transmembrane signaling essential for tumor cell growth, invasion, and metastasis. The transducer molecules susceptible to gangliosides and sphingolipids include integrin receptors, tyrosine kinase-linked growth factor receptors, protein kinase C, and G-protein-linked receptor affecting protein kinase A. Some glycosphingolipids (e.g., Gb3Cer, Le^y), ceramide, and sphingosine induce tumor cell differentiation and subsequent apoptosis. Shedded gangliosides may block immunogenicity of tumor cells, providing conditions favorable for "escape" from immunological suppression of tumor growth by the host.

Various reagents that block carbohydrate-mediated tumor cell adhesion or block glycosylation processing have been shown to inhibit tumor cell metastasis. This provides the basis for further development of "anti-adhesion therapy." Ganglioside analogues and sphingolipid analogues that inhibit protein kinase C and receptor-associated tyrosine kinase have been applied for inhibition of metastasis. A crucial mechanism for inhibition of metastasis by these reagents may involve blocking of transmembrane signaling for expression of P- and E-selectin. This provides the basis for development of "ortho-signaling therapy."

¹ The author's own studies cited in this paper were supported by National Cancer Institute Outstanding Investigator Grant CA42505.

² To whom requests for reprints should be addressed, at Pacific Northwest Research Foundation, Biomembrane Division, 720 Broadway, Seattle, WA 98122. Phone: (206) 726-1222; Fax: (206) 726-1212.

Received 9/ 9/96. Accepted 9/27/96.

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				K. Kumamoto, Y. Goto, K. Sekikawa, S. Takenoshita, N. Ishida, M. Kawakita, and R. Kannagi Increased Expression of UDP-Galactose Transporter Messenger RNA in Human Colon Cancer Tissues and Its Implication in Synthesis of Thomsen-Friedenreich Antigen and Sialyl Lewis A/X Determinants Cancer Res., June 1, 2001; 61(11): 4620 - 4627. [Abstract] [Full Text] [PDF]

				L. Borsig, R. Wong, J. Feramisco, D. R. Nadeau, N. M. Varki, and A. Varki Heparin and cancer revisited: Mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis PNAS, March 13, 2001; 98(6): 3352 - 3357. [Abstract] [Full Text] [PDF]

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				E. Machida, J. Nakayama, J. Amano, and M. Fukuda Clinicopathological Significance of Core 2 {beta}1,6-N-Acetylglucosaminyltransferase Messenger RNA Expressed in the Pulmonary Adenocarcinoma Determined by in Situ Hybridization Cancer Res., March 1, 2001; 61(5): 2226 - 2231. [Abstract] [Full Text]

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				M. Meichenin, J. Rocher, O. Galanina, N. Bovin, N. Nifant’ev, A. Sherman, E. Cassagnau, M. F. Heymann, J. Bara, R. H. Fraser, et al. Tk, a New Colon Tumor-associated Antigen Resulting from Altered O-Glycosylation Cancer Res., October 1, 2000; 60(19): 5499 - 5507. [Abstract] [Full Text]

				K.-A. Karlsson The human gastric colonizer Helicobacter pylori: a challenge for host-parasite glycobiology Glycobiology, August 1, 2000; 10(8): 761 - 771. [Abstract] [Full Text] [PDF]

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				S. Mao, C. Gao, C.-H. L. Lo, P. Wirsching, C.-H. Wong, and K. D. Janda Phage-display library selection of high-affinity human single-chain antibodies to tumor-associated carbohydrate antigens sialyl Lewisx and Lewisx PNAS, June 8, 1999; 96(12): 6953 - 6958. [Abstract] [Full Text] [PDF]

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				T. Sugiyama and Y. Sadzuka Combination of Theanine with Doxorubicin Inhibits Hepatic Metastasis of M5076 Ovarian Sarcoma Clin. Cancer Res., February 1, 1999; 5(2): 413 - 416. [Abstract] [Full Text] [PDF]

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