Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A diversity of adhesive interactions occur between the cancer cell and host extracellular matrix which potentiate neoplastic expansion and metastatic dissemination. In miscellaneous malignant diseases, tumour progression has been observed to be associated with alterations in adhesion molecule expression. Recently, circulating soluble intercellular adhesion molecules have been identified. In this study, serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble E-selectin (sE-selectin) were determined in patients with gastric cancer. The study group consisted of 27 patients with previously untreated gastric adenocarcinoma. Four patients had stage II, two patients stage III and 21 patients stage IV disease according to the TNM classification. Nineteen patients had distant metastasis. The sera obtained from 18 healthy volunteers served as controls. Serum sICAM-1 and sE-selectin concentrations were determined by enzyme-linked immunosorbent assay (ELISA). In addition, we also studied other tumour-associated antigens, i.e. CEA and CA 19-9. Serum sICAM-1 levels were significantly increased in patients with gastric cancer (P < 0.0001). However, sE-selectin levels did not differ from the controls. sICAM-1 concentrations were also significantly higher in patients with distant metastasis and peritoneal spread (P = 0.0045 and P = 0.0157 respectively), whereas sE-Selectin levels were elevated only in patients with peritoneal metastasis (P = 0.033). Serum concentrations of sICAM-1 and sE-selectin correlated with CEA levels (P = 0.0013 and P = 0.003 respectively). Elevated levels of sE-selectin were associated with poorer prognosis (P = 0.0099), whereas sICAM-1 had no significant impact on survival. Our results suggest that increased sICAM-1 serum levels may reflect widespread disease and contribute directly to the progression of gastric cancer. Further investigation of the molecular mechanisms of adhesive tumour-host interactions may lead to a better understanding of the natural history of gastric cancer.
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PMID:Circulating intercellular adhesion molecule-1 and E-selectin levels in gastric cancer. 968 5

For tumor progression, a cascade of linked sequential biological events is essential. We tried to test whether biological therapy can modulate specific biological phenotypes and increase the anti-tumor effect when combined with chemotherapy. Five human gastric cancer cell lines (YCC-1, YCC-2, YCC-3, YCC-7, AGS) were used in these studies. Pentosan polysulfate (PPS) as a heparin-binding growth factor inhibitor, Tranexamic acid as a plasmin inhibitor, Lovastatin as an adhesion inhibitor and Adriamycin as a chemotherapeutic agent were selected. The effects of each drug on colony formation and tumor cell proliferation were evaluated by soft agar assay and cell proliferation assay, respectively to test direct anti-tumor effect. The expression of uPA, PAI-1 was determined by ELISA, while MMPs activity was evaluated by zymography. PPS suppressed the colony-forming activity as much as Adriamycin did, but it showed only cytostatic effects in cell proliferation assay. Migration capacity using Boyden chamber assay was more closely correlated with adhesive capacity than uPA or MMP-2 expression. The motility inhibitory effect of Tranexamic acid was observed in the YCC-7 cell line, which expressed all the required biological phenotypes for migration. In AGS, with high cell motility and adhesiveness, the adhesion was inhibited by Lovastatin and most of the inhibitory effect was recovered by Mevalonate. When PPS was combined with Adriamycin on the Adriamycin-resistant, midkine (MK) gene expressing YCC-7 cell line, the growth inhibition rate increased up to 84%, while that for a single treatment of PPS or Adriamycin was 40% and 22%, respectively (p=0.001). When we combined Tranexamic acid and Adriamycin, we observed the synergistic effect in YCC-3 and YCC-7, while no combined effect was found in YCC-1. The combination of Lovastatin and Adriamycin did not show any combined effects in any of the cell lines. In conclusion, a synergistic anti-proliferative effect (chemo-sensitization) with combined chemo-biotherapy was found in cancer cells with specific biological target, MK. The anti-motility effect was the greatest when the gastric cancer cells expressed all the specific biological phenotypes.
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PMID:Modulation of biological phenotypes for tumor growth and metastasis by target-specific biological inhibitors in gastric cancer. 1040 90

Metabolic stress usually occurs in rapidly growing gastric cancer (GC) when the energy demand exceeds the supply. Interestingly, cancer cells can somehow escape this stress. Some small Rho GTPases regulating cell migration can be activated by metabolic stress. DLC3 is a RhoA-specific GTPase-activating protein of unclear function in cancer. We hypothesized that it participated in metabolic stress escape. Methods: Metabolic stress in GC cells was induced by glucose deprivation, and DLC3 expression was detected. Based on the prognostic value, cell viability, motility and glycolysis were detected in DLC3 differently expressed GC cells in vitro and in vivo. DLC3 downstream targets were screened and verified. Chemotactic ability was evaluated to study DLC3 and its downstream signaling on metabolic stress escape. In addition, therapeutic strategies targeting DLC3 were explored. Results: DLC3 expression was lowered by metabolic stress in GC cells. DLC3 downregulation indicated poor cancer prognosis, and silencing DLC3 promoted GC cell proliferation and invasion. MACC1, an oncogene promoting GC growth and metastasis, was proved to be the downstream target of DLC3. Low DLC3 expression and high MACC1 expression indicated high recurrence rate after GC resection. DLC3 transcriptionally inhibited MACC1 expression via RhoA/JNK/AP-1 signaling, and subsequently suppressed GC cell glycolysis and survival under metabolic stress. The DLC3/MACC1 axis modulated the chemotaxis of GC cells from energy deficient area to glucose abundant area. Finally, lovastatin was found to be a promising therapeutic drug targeting the DLC3/MACC1 axis. Conclusions: The DLC3/MACC1 axis modulates GC glycolysis and chemotaxis to escape glucose deprivation. Lovastatin may inhibit GC by targeting the DLC3/MACC1 axis.
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PMID:Gastric cancer cells escape metabolic stress via the DLC3/MACC1 axis. 3103 59

Human epidermal growth factor receptor 2 (HER2) is used as a tumor biomarker and therapeutic target. Pertuzumab is an anti-HER2 antibody, and its binding to tumor cells requires HER2 to be present at the cell membrane. However, the cellular distribution of HER2 protein in gastric tumors is dynamic, and HER2 internalization decreases antibody binding to tumor cells. These features preclude the use of pretargeted strategies for molecular imaging and therapy. We explored the pharmacological modulation of HER2 endocytosis as a strategy to improve pertuzumab uptake in HER2-positive gastric tumors and allow the use of a pretargeted imaging approach. Methods: We conducted in vitro and in vivo studies with NCI-N87 gastric cancer cells to determine how HER2 endocytosis affects pertuzumab binding to tumor cells. Lovastatin, a clinically approved cholesterol-lowering drug, was used to modulate caveolae-mediated HER2 endocytosis. Results: Administration of lovastatin to NCI-N87 cancer cells resulted in significant accumulation of non-activated HER2 dimers at the cell surface. Pretreatment of NCI-N87 cells with lovastatin increased in vitro specific accumulation of membrane-bound 89Zr-labeled pertuzumab. Lovastatin-enhanced pertuzumab tumor uptake was also observed in NCI-N87 gastric cancer xenografts, allowing tumor detection as early as 4 h and high-contrast images at 48 h after tracer administration via PET. Temporal enhancement of HER2 membrane availability by lovastatin allowed imaging of cell surface HER2 with transcyclooctene-conjugated antibodies and 18F-labeled tetrazine. Conclusion: Temporal pharmacological modulation of membrane HER2 may be clinically relevant and exploitable for pretargeted molecular imaging and therapy in gastric tumors.
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PMID:Temporal Modulation of HER2 Membrane Availability Increases Pertuzumab Uptake and Pretargeted Molecular Imaging of Gastric Tumors. 3117 98