BIOSYNTHESIS AND SHEDDING OF MURINE LYMPHOMA GANGLIOSIDES

Ganglioside biosynthesis and subsequent shedding are a potential mecha nism contributing to tumor cell escape from the host immune response. As a first step in identifying active molecular species, structural ch aracterization and quantification of the purified individual cellular and shed gangliosides of YAC-1 murine lymphoma cells were undertaken. These studies uncovered three striking changes in ganglioside metaboli sm in cells passaged in vivo, compared with cells cultured in vitro. ( i) Marked inhibition of GalNAcG(M1b) synthesis: G(M1b) was present in an equal proportion to its biosynthetic product GalNAcG(M1b) in vitro, but was present in a 6-fold higher concentration in vivo. (ii) Marked inhibition of NeuGc synthesis: NeuGc, present in vitro in an up to 7- fold higher concentration than its biosynthetic precursor NeuAc, was d ecreased in relative concentration in vivo (1:1). (iii) Selectivity of shedding: ganglioside shedding in vitro was generalized with respect to both carbohydrate structure and ceramide structure (mainly d18:1-C2 4:1 and d18:1-C16:0), while in vivo, there was selective shedding of g angliosides containing NeuGc and the shorter chain fatty acid. The red uced synthesis of NeuGc and of GalNAcG(M1b) in vivo, and the selective shedding of more polar ganglioside species, also in vivo, show that t he extracellular environment can markedly affect cellular ganglioside metabolism.