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Reduced expression of E-cadherin has been regarded as one of the main molecular events involved in dysfunction of the cell-cell adhesion system, triggering cancer invasion and metastasis. However, even with a sufficient amount of E-cadherin, cell-cell adhesion is sometimes lost in "diffusely invasive" human carcinomas. Ten human cancer cell lines, showing growth characterized morphologically by loose cell-cell adhesion, were analyzed for possible structural abnormalities of their expressed E-cadherin. Four of the cell lines showed strong mRNA and protein expression with no nudeotide sequence abnormalities, and mRNA was absent in four other cell lines. mRNA sequence was abnormal in the remaining two gastric carcinoma cell lines. In MKN45 (poorly differentiated adenocarcinoma), this involved a 12-bp in-frame deletion with strong expression of mRNA and protein. In KATO-HI (signet ring cell carcinoma), there were four mRNA species with insertions of different sizes, among which the major transcripts (with a 7-bp insertion) caused a frameshift, and expression of both mRNA and protein was markediy reduced. In these two cell lines, DNA mutations were detected around exon-intron junctions, revealing that aberrant RNA splicing was the cause ofthe mRNA abnormalities. In addition, the wild-type allele of the E-cadherin locus was lost, suesting that the E-cadherin gene had been inactivated by two hits (mutation and allele loss), similar to the mechanism for inactivation of tumor suppressor genes.Elucidation of the molecular events involved in cancer invasion and metastasis, which determine the clinical prognosis of cancer patients, is of the utmost importance in cancer research. These phenomena should be triggered by the dissociation of cancer cells from the primary tumor through breakdown of the cell-cell adhesion system, of which one of the main component molecules is E-cadherin (for review, see ref.

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Platelets promote LSEC proliferation and induce IL-6 and VEGF production. Direct contact between the platelets and LSECs and S1P, that are contained in platelets, were involved in the excretion of IL-6 from LSECs. IL-6 from LSECs induced proliferation of parenchymal hepatocytes.

The onset symptom of patients with pancreatic carcinoma closely correlates with prognosis.

Various cancers, including pancreatic ductal adenocarcinoma (PDAC), remain intractable even with costly tumor-targeting antibody drugs. Because the outermost coatings of cancer cells are composed of cell-specific glycan layers (glycocalyx), lectins, proteins with glycan-binding potential, were evaluated for possible use as drug carriers in PDAC treatment. A human PDAC cell line with well-to-moderately differentiated properties (Capan-1) was subjected to lectin microarray analysis to identify specific lectin-glycan pairs. The selected lectin was fused with a bacterial exotoxin for the construction of a lectin-drug conjugate (LDC), and its safety and antitumor effects were evaluated. A specific affinity between a recombinant bacterial C-type lectin (rBC2LC-N) and Capan-1 was identified, and its positivity was confirmed in 69 human samples. In contrast to the belief that all lectins mediate harmful hemagglutination, rBC2LC-N did not cause hemagglutination with human erythrocytes and was safely administered to mice. The 50% inhibitory concentration of LDC to Capan-1 (1.04 pg/mL ¼ 0.0195 pmol/L) was 1/1,000 lower than that reported for conventional immunotoxins. The intraperitoneal administration of LDC reduced the tumor weight from 390 to 130.8 mg (P < 0.01) in an orthotopic model and reduced the number of nodules from 48 to 3 (P < 0.001) and improved survival from 62 to 105 days in a peritoneal dissemination model (P < 0.0001). In addition, the effect of LDC was reproduced in nodules from patient-derived PDAC xenografts through intravenous injection. Herein, we show the concept of utilizing lectins as drug carriers to target glycans on the cancer cell surface, highlighting new insights into cancer treatments.

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