Roles of GalNAc-disialyl Lactotetraosyl Antigens in Renal Cancer Cells

Abstract

GalNAc-disialyl Lc4 (GalNAc-DSLc4) was reported as a novel antigen that associated with malignant features of renal cell cancers (RCCs). To clarify roles of GalNAc-DSLc4 in malignant properties of RCCs, we identified B4GalNAc-T2 as a responsible gene for the synthesis of GalNAc-DSLc4, and prepared stable transfectants of GalNAc-T2 cDNA using VMRC-RCW cells, resulting in the establishment of high expressants of GalNAc-DSLc4. They showed increased proliferation and invasion, and specific adhesion to laminin. In the transfectants, PI3K/Akt signals were highly activated by serum stimulation or adhesion to laminin. GalNAc-DSLc4 was co-localized in lipid rafts with integrin β1 and caveolin-1 in both immunoblotting of fractionated detergent extracts and immunocytostaining, particularly when stimulated with serum. Masking of GalNAc-DSLc4 with antibodies as well as PI3K inhibitor suppressed malignant properties of the transfectants. These results suggested that GalNAc-DSLc4 is involved in malignant properties of RCCs by forming a molecular complex with integrins in lipid rafts.

Sphingolipid metabolism in the development and progression of cancer: one cancer's help is another's hindrance

“…GalNAc‐DSLc4, a ganglioside with a hybrid structure between the ganglio‐ and the lacto‐series (Fig. 1 , insert) isolated from a renal carcinoma cell line [ 126 ], was found to recruit integrin β1 to lipid rafts, where they cooperate to adhere to metastatic sites, potentially also implicating GalNAc‐DSLc4 in the promotion of distant metastasis [ 127 ]. In a murine lymphoma model, treatment with a monoclonal antibody against GD2 was sufficient to suppress tumor micrometastasis [ 128 ], while anti‐GM2 antibodies inhibited multiple organ metastasis of small‐cell lung cancer [ 129 ] (Table 1 ).…”

Renal Cell Carcinoma-Infiltrating CD3low Vγ9Vδ1 T Cells Represent Potentially Novel Anti-Tumor Immune Players

“…In the context of cancer, Vδ1 γδ T cells recognize altered-self lipids presented by CD1d [10]. The abundance of lipid sulfatide and glycosphingolipids contributing to RCC progression [10,[22][23][24][25] led us to hypothesize that these molecules present on CD1d in RCC may play an important role in activating CD3 low Vγ9δ1 T cells. A greater understanding of the relationship between different Vγ9Vδ1 TCR ligands, their mode of recognition, tissue expression, and regulation/dysregulation will undoubtedly provide novel therapeutic avenues and insights into RCC [21].…”

Cholesterol and Sphingolipid Enriched Lipid Rafts as Therapeutic Targets in Cancer

“…In renal cell cancers, GalNAc-disialyl Lc4 forms a molecular complex with integrin β1 and caveolin-1 in lipid rafts and increases malignant properties that can be reverted by antibodies [ 148 ].…”

“… Schematic representation of the main cancers in which lipid rafts are involved. Lipid rafts are involved in liquid [ 117 , 130 , 132 ] and solid tumors [ 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 131 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 ] including tumors of breast [ 118 , 119 , 120 , 121 , 122 , 133 , 134 , 135 , 136 , 137 , 138 , 139 ], stomach [ 123 , 124 ], liver [ 125 , 126 , 131 , 140 , 141 ], pancreas [ 127 , 142 , 143 ...…”

“…A proteomic study on lipid rafts purified from breast cancer cells showed an abundance of groups of proteins specific for the progression toward malignancy [133]. [117,130,132] and solid tumors [118][119][120][121][122][123][124][125][126][127][128][129]131,[133][134][135][136][137][138][139][140][141][142][143][144][145][146][147][148] including tumors of breast [118][119][120][121][122][133][134][135][136][137][138][139], stomach [123,124], liver [125,126,…”