Tsunehiro Oyama

Bio: Tsunehiro Oyama is an academic researcher from Hyogo College of Medicine. The author has contributed to research in topics: Lung cancer & Adenocarcinoma. The author has an hindex of 38, co-authored 144 publications receiving 5652 citations. Previous affiliations of Tsunehiro Oyama include University of Occupational and Environmental Health Japan.

Mutations of the p53 Gene as a Predictor of Poor Prognosis in Patients With Non-Small-Cell Lung Cancer

Abstract: Background Inactivation of the p53 tumor suppressor gene (also known as TP53) through a point mutation and/or loss of heterozygosity is one of the most common genetic changes found in various types of human tumors. Purpose Our purpose was to investigate the relationship between the presence of p53 gene mutations and survival of patients with non-small-cell lung cancer (NSCLC) of all stages who underwent surgery with preoperative curative intent as a routine therapeutic intervention. The prognostic significance of factors like sex, age, tumor histology, and the stage of the disease was also evaluated. Methods We analyzed 120 tumor specimens from patients with histologically confirmed NSCLC for p53 mutations occurring in exons 5 through 8 by polymerase chain reaction-single-strand conformation polymorphism assay of genomic DNA. Univariate and multivariate analyses were performed to assess the association between p53 mutations and the survival of the NSCLC patients. Results Fifty-one (43%) of 120 tumor specimens showed p53 mutations. Overall, the p53 mutations did not correlate with sex, age, or the clinical stage of the disease but showed frequent association with tumors of squamous cell histology. Univariate analysis revealed that the patients with p53 mutations survived for a significantly shorter period of time after surgery than those without the mutations (P = .0100, logrank test). The presence of p53 mutations was a significant prognostic factor in the patients with advanced disease (stages IIIA through IV) (P = .0091) but not in those with early disease (stages I and II) (P = .2837). Multivariate analysis using the Cox proportional hazards model found independent prognostic significance for p53 mutations (hazards ratio [HR] = 1.84; P = .018) and advanced disease stage (HR = 2.20; P = .003). The model also predicted the lower risk for female patients (HR = 0.51; P = .040). Conclusion The occurrence of p53 mutations in some NSCLC tumors may be independently associated with a shortened overall survival and may be of somewhat more prognostic significance in patients with advanced stage than in those with early stage of the disease. Implication Detection of p53 mutations may help in the selection of NSCLC patients suitable for appropriate investigational therapeutic strategies in view of improving their survival and quality of life.

Monocarboxylate transporters 1 and 4 are involved in the invasion activity of human lung cancer cells.

Abstract: Cancer cells show constitutive upregulation of glycolysis, and the concentration of lactate thus produced correlates with prognosis. Here, we examined whether lactate concentration and lactate transporter expression are related to migration and invasion activity. We found that the expression of the monocarboxylate transporters MCT1 and MCT4, but not MCT5, in human lung cancer cell lines was significantly correlated with invasiveness. To clarify the effects of MCT1 and MCT4 expression on invasion, we performed migration and invasion assays after transfection with siRNA specific for MCT1 or MCT4. Knockdown of MCT1 or MCT4 did not influence cell migration but reduced invasion; this was also observed for knockdown of the lactate transporter-associated protein basigin. We also demonstrated that both expression and activity of MMP9 and MMP2 were not correlated with invasion activity and not regulated by MCT1, MCT4 and basigin. Furthermore, the addition of lactate did not increase migration and invasion activity, but low concentration of 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS), a general anion channel blocker, as well as other MCT inhibitors quercetin and simvastatin, inhibited cell invasion without influencing migration activity and the cellular expression of MCT1 and MCT4. This is the first report suggesting that lactate transporters are involved in human cancer cell invasiveness. As such, these proteins may be promising targets for the prevention of cancer invasion and metastasis.

Defective Function of Langerhans Cells in Tumor-Bearing Animals Is the Result of Defective Maturation from Hemopoietic Progenitors

Abstract: Langerhans cells (LC), the APCs in the skin, serve as a model for investigation of dendritic cell (DC) function in tissues. DC play a crucial role in the generation of antitumor immune responses. In this study, we investigated the effect of the presence of tumor in vivo on the ability of LC to take up Ag, migrate to draining lymph nodes, and stimulate primary T cell responses. In two animal models, these functions were substantially inhibited. This effect was not restricted to LC located in the skin near a tumor but was also seen at sites distant from the tumor. The duration of tumor exposure, and not its ultimate size, were found to be important, suggesting that tumors could be inhibiting the maturation of LC rather than directly inhibiting their function. Model experiments with radiation chimeras supported this hypothesis. To investigate the potential role of vascular endothelial growth factor (VEGF) in these effects we used anti-VEGF-neutralizing Ab to treat animals bearing tumors. Treatment with the Ab at a dose of 10 μg i.p. per mouse, twice a week for 4 wk, significantly improved the number and function of LC as measured by their ability to migrate to lymph nodes and stimulate primary T cell responses, even at doses that do not affect the growth of these established poorly immunogenic tumors. Thus, inhibition of VEGF signaling may improve DC function in tumor-bearing hosts and possibly serve to improve the efficacy of cancer immunotherapy.

Epithelial-mesenchymal transition in EGFR-TKI acquired resistant lung adenocarcinoma.

Abstract: Background: The epithelial to mesenchymal transition (EMT) may well play a part in determining the sensitivity to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). However to date, no study has investigated the association between the EMT status and acquired resistance using cancer specimens. Patients and Methods: Immunohistochemical (IHC) staining was used to analyse the protein expression of epithelial and mesenchymal markers in tumour samples from lung adenocarcinoma patients. Mutations in the EGFR and K-ras gene were also examined. Results: All patients showed a positive expression of epithelial markers in sensitive tumours. Tumour in 4 (44.4%) out of 9 patients showed down-regulation of epithelial markers or up-regulation of mesenchymal markers. The change in the EMT status between pre-and post-treatment was shown in 2 cases each with and without the T790M mutation. Conclusion: EMT plays a role in approximately half of the cases of resistance to EGFR-TKI, independent of T790M mutation.

Myeloid-derived suppressor cells as regulators of the immune system.

Abstract: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand during cancer, inflammation and infection, and that have a remarkable ability to suppress T-cell responses. These cells constitute a unique component of the immune system that regulates immune responses in healthy individuals and in the context of various diseases. In this Review, we discuss the origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit.

Vascular endothelial growth factor: basic science and clinical progress.

Abstract: Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen in vitro and an angiogenic inducer in a variety of in vivo models. Hypoxia has been shown to be a major inducer of VEGF gene transcription. The tyrosine kinases Flt-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2) are high-affinity VEGF receptors. The role of VEGF in developmental angiogenesis is emphasized by the finding that loss of a single VEGF allele results in defective vascularization and early embryonic lethality. VEGF is critical also for reproductive and bone angiogenesis. Substantial evidence also implicates VEGF as a mediator of pathological angiogenesis. In situ hybridization studies demonstrate expression of VEGF mRNA in the majority of human tumors. Anti-VEGF monoclonal antibodies and other VEGF inhibitors block the growth of several tumor cell lines in nude mice. Clinical trials with various VEGF inhibitors in a variety of malignancies are ongoing. Very recently, an anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the Food and Drug Administration as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy. Furthermore, VEGF is implicated in intraocular neovascularization associated with diabetic retinopathy and age-related macular degeneration.

Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors

Abstract: Lung cancers harboring mutations in the epidermal growth factor receptor (EGFR) respond to EGFR tyrosine kinase inhibitors, but drug resistance invariably emerges. To elucidate mechanisms of acquired drug resistance, we performed systematic genetic and histological analyses of tumor biopsies from 37 patients with drug-resistant non–small cell lung cancers (NSCLCs) carrying EGFR mutations. All drug-resistant tumors retained their original activating EGFR mutations, and some acquired known mechanisms of resistance including the EGFR T790M mutation or MET gene amplification. Some resistant cancers showed unexpected genetic changes including EGFR amplification and mutations in the PIK3CA gene, whereas others underwent a pronounced epithelial-to-mesenchymal transition. Surprisingly, five resistant tumors (14%) transformed from NSCLC into small cell lung cancer (SCLC) and were sensitive to standard SCLC treatments. In three patients, serial biopsies revealed that genetic mechanisms of resistance were lost in the absence of the continued selective pressure of EGFR inhibitor treatment, and such cancers were sensitive to a second round of treatment with EGFR inhibitors. Collectively, these results deepen our understanding of resistance to EGFR inhibitors and underscore the importance of repeatedly assessing cancers throughout the course of the disease.

Hormones and endocrine-disrupting chemicals: Low-dose effects and nonmonotonic dose responses

Abstract: For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from...