Human epidermal growth factor receptor 2 (HER2)-directed treatment using trastuzumab has shown clinical benefit in HER2-positive gastric cancer. Clinical trials using lapatinib in HER2-positive gastric cancer are also currently underway. As with other molecularly targeted agents, the emergence of acquired resistance to HER2-directed treatment is an imminent therapeutic problem for HER2-positive gastric cancer. In order to investigate the mechanisms of acquired resistance to HER2-directed treatment in gastric cancer, we generated lapatinib-resistant gastric cancer cell lines (SNU216 LR) in vitro by chronic exposure of a HER2-positive gastric cancer cell line (SNU216) to lapatinib. The resultant SNU216 LR cells were also resistant to gefitinib, cetuximab, trastuzumab, afatinib and dacomitinib. Interestingly, SNU216 LR cells displayed an epithelial-mesenchymal transition (EMT) phenotype and maintained the activation of MET, HER3, Stat3, Akt and mitogen-activated protein kinase signaling in the presence of lapatinib. Using gene expression arrays, we identified the upregulation of a variety of EMT-related genes and extracellular matrix molecules, such as Testican-1, in SNU216 LR cells. We showed that the inhibition of Testican-1 by small interfering RNA decreased Testican-1-induced, MET-dependent, downstream signaling, and restored sensitivity to lapatinib in these cells. Furthermore, treatment with XAV939 selectively inhibited β-catenin-mediated transcription and Testican-1-induced EMT signaling, leading to G1 arrest. Taken together, these data support the potential role of EMT in acquired resistance to HER2-directed treatment in HER2-positive gastric cancer, and provide insights into strategies for preventing and/or overcoming this resistance in patients.

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In South Korea, the need for periodontal scaling was associated with socio-economic factors, such as low levels of education, low incomes, employment as a service and sales worker and employment as a manual worker. Consequently, clinical and community dental hygienists should consider adults with these risk factors as belonging to high-priority subgroups to whom they should respond first.

Transplantation of a murine mammary carcinoma (CE maca) into mice induces marked granulocytosis and hypercalcemia secondary to excessive bone resorption. Such responses are not induced by another murine mammary carcinoma Bc66. In order to understand the mechanisms of these unique phenomena, we analyzed mRNA of tumor cells for expression of murine granulopoietic growth factors and studied interactions of tumor- derived factors using antiserum to a growth factor in vitro and in vivo. The Northern blot analysis of CE tumor clones revealed the expression of granulocyte colony stimulating factor (G-CSF) and macrophage colony stimulating factor (M-CSF), but no other CSF genes, while the Bc66 clone expressed only M-CSF. The G-CSF and M-CSF gene expression in CE tumor clones was accompanied by secretion of these proteins in culture. The granulocyte stimulating activity of CE tumor- derived G-CSF or recombinant human G-CSF was markedly enhanced by purified M-CSF in vitro. Significant but variable neutrophilia was observed in mice inoculated with CE tumor clones. Anti-M-CSF treatment of CE tumor-bearing mice significantly reduced neutrophilia, but did not affect hypercalcemia. These studies document that G-CSF and M-CSF are produced constitutively from the CE maca, and G-CSF is likely responsible for granulocytosis induced by this tumor. G-CSF and M-CSF function synergistically in granulocyte stimulation in vitro and this synergism may also play a role in marked granulocytosis of tumor- bearing animals, providing further evidence of the effect of CSFs in vivo.