The relationship between the expressions of the cell adhesion molecule CD44H, CD44v3, and CD44v6 and metastases in gastric cancer

Expression of CD44 variants in some tissues appears to relate to tumor progression, and particularly to the metastatic potential of some cancers. The aim of this study was to clarify the relation between the expression of CD44 splice variants and tumor metastasis by using CD44v-specific gastric cancer monoclonal antibodies. A total of 110 patients with primary gastric cancer were studied. Histological samples of 70 of the 110 (63.6%) were stained with three monoclonal antibodies directed against the CD44H and CD44 variants (CD44v3, CD44v6) in gastric cancer. The incidence of lymph node metastasis was higher in the CD44H strongerexpression group than in the weaker expression group. No significant correlation could be found between CD44H, CD44V3, or CD44v6 expression and liver metastasis or histological types (differentiated vs.undifferentiated) . Lymph node metastasis correlated with CH44H rather than CD44v3 or CD44v6. These results suggested that CD44H might be a useful marker for lymph node metastasis in resected gas-tric cancer. The 5-year survival rate was 57.3% in the group positively ex-pressing CD44 and 52.4% in the group with negative expression of CD44. Concerning prognosis, we found here that the expression of CD44 is not sig-nificantly associated with increased mortality. Further study of the expression of specific isoforms may help elucidate in more detail the mechanisms of these findings

Tumorigenicity, Motility and Liver Metastasis of Human Gastric Carcinoma Lines with High Metastatic Potential in the Liver of Nude Mice

To analyze the human gastric carcinoma metastasis to the liver, a human gastric carcinoma line, AZ521 was injected into the spleens of nude mice. Cells from the few liver metastatic foci of injected AZ521 were expanded in vitro and subsequently injected into the spleens of nude mice. By repeating these proce-dures five times, we were able to obtain a cell line, designated AZ-H5c, with high metastatic potential in nude mice. It was observed that animals had liver metastasis in 10 of 12 (83%) cases injected with AZ-H5c, whereas only 14% with parental AZ521. The growth activity in vivo of AZ-H5c cells is much more rapid than that of AZ521 cells, but its growth activity in vitro is slower. The mortile activity in vitro of AZ-H5c is stronger than that of AZ521. These results suggest that our model can provide a new approach to basic and clinical studies of cancer metastasis

Evidence for increased DNA damage repair in the postmortem brain of the high stress-response group of schizophrenia

BackgroundSchizophrenia (SZ) is a disorder diagnosed by specific symptoms and duration and is highly heterogeneous, clinically and pathologically. Although there are an increasing number of studies on the association between genetic and environmental factors in the development of SZ, the actual distribution of the population with different levels of influence of these factors has not yet been fully elucidated. In this study, we focused on stress as an environmental factor and stratified SZ based on the expression levels of stress-responsive molecules in the postmortem prefrontal cortex.MethodsWe selected the following stress-responsive molecules: interleukin (IL) -1β, IL-6, IL-10, tumor necrosis factor-α, interferon-γ, glucocorticoid receptor, brain-derived neurotrophic factor, synaptophysin, S100 calcium-binding protein B, superoxide dismutase, postsynaptic density protein 95, synuclein, apolipoprotein A1 (ApoA1), ApoA2, and solute carrier family 6 member 4. We performed RNA sequencing in the prefrontal gray matter of 25 SZ cases and 21 healthy controls and conducted a hierarchical cluster analysis of SZ based on the gene expression levels of stress-responsive molecules, which yielded two clusters. After assessing the validity of the clusters, they were designated as the high stress-response SZ group and the low stress-response SZ group, respectively. Ingenuity Pathway Analysis of differentially expressed genes (DEGs) between clusters was performed, and Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining was conducted on four cases each in the high and low stress-response SZ groups to validate DNA damage.ResultsWe found higher prevalence of family history of SZ in the low stress-response SZ group (0/3 vs. 5/4, p = 0.04). Pathway analysis of DEGs between clusters showed the highest enrichment for DNA double-strand break repair. TUNEL staining showed a trend toward a lower percentage of TUNEL-positive cells in the high stress-response SZ group.ConclusionOur results suggest that there are subgroups of SZ with different degrees of stress impact. Furthermore, the pathophysiology of these subgroups may be associated with DNA damage repair. These results provide new insights into the interactions and heterogeneity between genetic and environmental factors

Anti-Tumor Effect against Human Cancer Xenografts by a Fully Human Monoclonal Antibody to a Variant 8-Epitope of CD44R1 Expressed on Cancer Stem Cells

BACKGROUND: CD44 is a major cellular receptor for hyaluronic acids. The stem structure of CD44 encoded by ten normal exons can be enlarged by ten variant exons (v1-v10) by alternative splicing. We have succeeded in preparing MV5 fully human IgM and its class-switched GV5 IgG monoclonal antibody (mAb) recognizing the extracellular domain of a CD44R1 isoform that contains the inserted region coded by variant (v8, v9 and v10) exons and is expressed on the surface of various human epithelial cancer cells. METHODS AND PRINCIPAL FINDINGS: We demonstrated the growth inhibition of human cancer xenografts by a GV5 IgG mAb reshaped from an MV5 IgM. The epitope recognized by MV5 and GV5 was identified to a v8-coding region by the analysis of mAb binding to various recombinant CD44 proteins by enzyme-linked immunosorbent assay. GV5 showed preferential reactivity against various malignant human cells versus normal human cells assessed by flow cytometry and immunohistological analysis. When ME180 human uterine cervix carcinoma cells were subcutaneously inoculated to athymic mice with GV5, significant inhibition of tumor formation was observed. Furthermore, intraperitoneal injections of GV5markedly inhibited the growth of visible established tumors from HSC-3 human larynx carcinoma cells that had been subcutaneously transplanted one week before the first treatment with GV5. From in vitro experiments, antibody-dependent cellular cytotoxicity and internalization of CD44R1 seemed to be possible mechanisms for in vivo anti-tumor activity by GV5. CONCLUSIONS: CD44R1 is an excellent molecular target for mAb therapy of cancer, possibly superior to molecules targeted by existing therapeutic mAb, such as Trastuzumab and Cetuximab recognizing human epidermal growth factor receptor family