Tumor immunity has a two-stage defense system consisting of natural killer (NK) immunity for primary tumor and cytotoxic T lymphocyte (CTL) immunity for the metastatic lesions. However, cancer exerts the versatile immune evasion strategies to predominate over this two-stage defense. A series of our studies revealed that bladder cancer cells evade each tumor immune system by different evasion strategies using altered O-glycosylation. β-1,6-N-acetylglucosaminyltransferase (C2GnT) which adds N-acetylglucosamine to N-acetylgalactosamine forms a branched structure called core 2 O-glycans on cell-surface glycoproteins. To elucidate the roles of core 2 O-glycans in bladder cancer metastasis, we analyzed C2GnT expression in cancer cells in bladder (primary tissue) and cancer cells in lymph node (target organ). We showed that bladder cancer cells evade NK tumor immunity by upregulating C2GnT expression and CTL immunity by downregulating C2GnT expression. C2GnT-positive cancer cells survive NK cell attack in the primary tissue, resulting in acquiring a high-metastatic phenotype. On the other hand, C2GnT-negative cancer cells evade CTL attack, resulting in indefinite proliferation in the target organs such as lymph node. This review highlights two opposite roles of core 2 O-glycans in the evasion mechanisms of the attack by different effector cells.

We previously analyzed the cell-surface glycans of human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs) using lectin microarrays and mass spectrometry. We demonstrated that H type3 (Fucα1-2Galβ1-3GalNAc) is highly expressed in hESCs/hiPSCs compared with human somatic cells. Furthermore, we generated a lectin–drug conjugate (LDC) by fusing rBC2LCN with Pseudomonas aeruginosa exotoxin A as a cytotoxic agent for the selective elimination of hESCs/hiPSCs. Recently, we found that rBC2LCN strongly binds to a pancreatic cancer cell line Capan-1 with the cancer stem cell like property. rBC2LCN stained all of the pancreatic ductal adenocarcinoma (PDAC) tissues obtained from 69 patients. We therefore perceived LDC as a potential anticancer drug. The half maximal effective concentration (EC₅₀) of LDC to Capan-1 was 1.04 pg/mL (0.0195 pM), which was 1,000-fold lower than that reported for conventional immunotoxins. Furthermore, the intraperitoneal or intravenous administration of LDC reduced the tumor weight in orthotopic and peritoneal dissemination mouse models. In this review, the development of LDC as a novel modality and its application to pancreatic cancer therapy are mainly described.

Keratan sulfate is a sulfated polysaccharide classified as a glycosaminoglycan, which has the structurally unique characteristics of diversity in the linker oligosaccharides connecting to the core protein, the existence of both an intrachain fucose branch and a “capping” monosaccharide at the nonreducing end, and diversity of the sulfation patterns. The function(s) of this newest glycosaminoglycan, keratan sulfate, remain mostly unclear. In this minireview, we describe the structures and known functions of keratan sulfate as well as cutting-edge methods to enable the synthesis of keratan sulfate with complex structures.

Tumor immunity has a two-stage defense system consisting of natural killer (NK) immunity for primary tumor and cytotoxic T lymphocyte (CTL) immunity for the metastatic lesions. However, cancer exerts the versatile immune evasion strategies to predominate over this two-stage defense. A series of our studies revealed that bladder cancer cells evade each tumor immune system by different evasion strategies using altered O-glycosylation. β-1,6-N-acetylglucosaminyltransferase (C2GnT) which adds N-acetylglucosamine to N-acetylgalactosamine forms a branched structure called core 2 O-glycans on cell-surface glycoproteins. To elucidate the roles of core 2 O-glycans in bladder cancer metastasis, we analyzed C2GnT expression in cancer cells in bladder (primary tissue) and cancer cells in lymph node (target organ). We showed that bladder cancer cells evade NK tumor immunity by upregulating C2GnT expression and CTL immunity by downregulating C2GnT expression. C2GnT-positive cancer cells survive NK cell attack in the primary tissue, resulting in acquiring a high-metastatic phenotype. On the other hand, C2GnT-negative cancer cells evade CTL attack, resulting in indefinite proliferation in the target organs such as lymph node. This review highlights two opposite roles of core 2 O-glycans in the evasion mechanisms of the attack by different effector cells.

We previously analyzed the cell-surface glycans of human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs) using lectin microarrays and mass spectrometry. We demonstrated that H type3 (Fucα1-2Galβ1-3GalNAc) is highly expressed in hESCs/hiPSCs compared with human somatic cells. Furthermore, we generated a lectin–drug conjugate (LDC) by fusing rBC2LCN with Pseudomonas aeruginosa exotoxin A as a cytotoxic agent for the selective elimination of hESCs/hiPSCs. Recently, we found that rBC2LCN strongly binds to a pancreatic cancer cell line Capan-1 with the cancer stem cell like property. rBC2LCN stained all of the pancreatic ductal adenocarcinoma (PDAC) tissues obtained from 69 patients. We therefore perceived LDC as a potential anticancer drug. The half maximal effective concentration (EC₅₀) of LDC to Capan-1 was 1.04 pg/mL (0.0195 pM), which was 1,000-fold lower than that reported for conventional immunotoxins. Furthermore, the intraperitoneal or intravenous administration of LDC reduced the tumor weight in orthotopic and peritoneal dissemination mouse models. In this review, the development of LDC as a novel modality and its application to pancreatic cancer therapy are mainly described.

Keratan sulfate is a sulfated polysaccharide classified as a glycosaminoglycan, which has the structurally unique characteristics of diversity in the linker oligosaccharides connecting to the core protein, the existence of both an intrachain fucose branch and a “capping” monosaccharide at the nonreducing end, and diversity of the sulfation patterns. The function(s) of this newest glycosaminoglycan, keratan sulfate, remain mostly unclear. In this minireview, we describe the structures and known functions of keratan sulfate as well as cutting-edge methods to enable the synthesis of keratan sulfate with complex structures.