ABSTRACT
Predicting bladder cancer progression is important in selecting the optimal treatment for bladder cancer. Because current diagnostic factors regarding progression are lacking, new factors are needed to further stratify the curative potential of bladder cancer. Glycoprotein-130 (GP130), a transmembrane protein, is central to a number of signal transduction pathways involved in tumor aggressiveness, making it an attractive target. We hypothesize that if GP130 is found in an aggressive population of bladder tumors, then blocking GP130 expression may inhibit bladder cancer growth. Herein, we quantitatively show, using 11 patient samples and four bladder cancer cell lines, that GP130 is expressed in the aggressive human bladder tumors and in high-grade bladder cancer cell lines. Moreover, GP130 is significantly correlated with tumor grade, node category, tumor category, and patient outcome. We demonstrated a tumor-specific GP130 effect by blocking GP130 expression in bladder tumor cells, which resulted in decreased cell viability and reduced cell migration. Furthermore, we reduced tumor volume by approximately 70% compared with controls by downregulating GP130 expression using chitosan-functionalized nanoparticles encapsulating GP130 siRNA in an in vivo bladder cancer xenograft mouse model. Our results indicate that GP130 expression is linked to the aggressiveness of bladder tumors, and blocking GP130 has therapeutic potential in controlling tumor growth.
Subject(s)
Cytokine Receptor gp130/metabolism , RNA, Small Interfering/administration & dosage , Up-Regulation , Urinary Bladder Neoplasms/pathology , Animals , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Cytokine Receptor gp130/genetics , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Male , Mice , Nanoparticles , Neoplasm Grading , Neoplasm Transplantation , RNA, Small Interfering/pharmacology , Up-Regulation/drug effects , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/metabolismABSTRACT
BACKGROUND: A highly selected subset of patients with oligometastatic non-small cell lung cancer (NSCLC) will be cured after all sites of established disease (primary and metastases) have been eliminated by surgery or radiation (ie, "curative intent" approach). Mediastinal lymph node metastases (N2) have been found retrospectively to predict a poor prognosis in this setting (5-year survival of 4% for N2-positive versus 31% for N2-negative). Hence, our institution has programmatically limited the use of curative intent local therapy to oligometastatic NSCLC patients confirmed to be free of N2 disease. However, it is unclear whether the exclusion of N2-positive patients is an effective prospective selection step to aggressively treat oligometastatic NSCLC. METHODS: A prospectively maintained institutional tumor registry was reviewed for oligometastatic stage IV NSCLC patients evaluated for curative intent treatment from 2005 to 2014. RESULTS: All synchronous oligometastatic NSCLC cases were evaluated by invasive mediastinal staging before treatment. Twenty-two patients without N2 disease underwent curative intent treatment, and 13 patients with N2 disease were treated palliatively. The groups were similar by bivariate analyses. The N2-negative patients treated with curative intent had a superior 5-year survival compared with N2-positive patients treated palliatively (58% versus 0%, respectively; p = 0.028). CONCLUSIONS: Using invasive mediastinal staging to exclude N2 disease has a role in surgical decision making and achieving long-term survival among oligometastatic NSCLC patients. Further study is warranted to determine whether a subset of patients with N2 disease also have the potential for long-term survival with local therapy.