Growth Of Human Lung Tumors Research Articles

The choline acetyltransferase inhibitor BW813U inhibits angiogenesis and tumor growth in human lung adenocarcinoma

Angiogenesis refers to the development of new blood vessels from preexisting blood vessels. The angiogenic pathway is essential for the growth and progression of almost every kind of human cancer. Nicotine, the addictive component of tobacco smoke is known to accelerate the growth of human lung tumors by stimulating tumor angiogenesis. The pro‐angiogenic effects of nicotine are mediated by nicotinic acetylcholine receptors (nAChRs). The endogenous ligand for nicotine is the neurotransmitter acetylcholine (ACh). Published reports show that ACh acts as growth factor for human lung cancers. Almost all lung tissues (including fetal lung) express signaling proteins involved in the synthesis, transport of the ACh‐signaling pathway. These include choline acetyl transferase enzyme (ChAT), vesicular acetylcholine transporter (VAChT), acetylcholine esterase (AChE) and choline transporter (ChT). The primary objective of our studies was to determine if disruption of ChAT could inhibit angiogenesis and suppress the growth of human LACs. We used a small molecule inhibitor of ChAT namely BW813U for our studies. BW813U robustly suppressed angiogenesis in Matrigel assays and chicken chorioallantoic membrane (CAM) assays. The administration of BW813U potenetly decreased the growth rate of H838 tumors xenotransplanted in SCID mice. Immunohistochemical staining experiments revealed that the anti‐tumor activity of BW813U was correlated with decrease of CD31 angiogenic biomarker in H813 tumor sections. The anti‐angiogenic activity of BW813U was mediated by the alpha7‐nAChR pathway and involved the nitric oxide pathway. Taken together, our studies show that ChAT antagonists like BW813U may have applications in the treatment of LAC.

MiR-574-5p as RNA decoy for CUGBP1 stimulates human lung tumor growth by mPGES-1 induction.

MicroRNAs (miRs) are important posttranscriptional regulators of gene expression. Besides their well-characterized inhibitory effects on mRNA stability and translation, miRs can also activate gene expression. In this study, we identified a novel noncanonical function of miR-574-5p. We found that miR-574-5p acts as an RNA decoy to CUG RNA-binding protein 1 (CUGBP1) and antagonizes its function. MiR-574-5p induces microsomal prostaglandin E synthase-1 (mPGES-1) expression by preventing CUGBP1 binding to its 3'UTR, leading to an enhanced alternative splicing and generation of an mPGES-1 3'UTR isoform, increased mPGES-1 protein expression, PGE2 formation, and tumor growth in vivo. miR-574-5p-induced tumor growth in mice could be completely inhibited with the mPGES-1 inhibitor CIII. Moreover, miR-574-5p is induced by IL-1β and is strongly overexpressed in human nonsmall cell lung cancer where high mPGES-1 expression correlates with a low survival rate. The discovered function of miR-574-5p as a CUGBP1 decoy opens up new therapeutic opportunities. It might serve as a stratification marker to select lung tumor patients who respond to the pharmacological inhibition of PGE2 formation.-Saul, M. J., Baumann, I., Bruno, A., Emmerich, A. C., Wellstein, J., Ottinger, S. M., Contursi, A., Dovizio, M., Donnini, S., Tacconelli, S., Raouf, J., Idborg, H., Stein, S., Korotkova, M., Savai, R., Terzuoli, E., Sala, G., Seeger, W., Jakobsson, P.-J., Patrignani, P., Suess, B., Steinhilber, D. miR-574-5p as RNA decoy for CUGBP1 stimulates human lung tumor growth by mPGES-1 induction.

Novel antimicrobial peptides with high anticancer activity and selectivity.

We describe a strategy to boost anticancer activity and reduce normal cell toxicity of short antimicrobial peptides by adding positive charge amino acids and non-nature bulky amino acid β-naphthylalanine residues to their termini. Among the designed peptides, K4R2-Nal2-S1 displayed better salt resistance and less toxicity to hRBCs and human fibroblast than Nal2-S1 and K6-Nal2-S1. Fluorescence microscopic studies indicated that the FITC-labeled K4R2-Nal2-S1 preferentially binds cancer cells and causes apoptotic cell death. Moreover, a significant inhibition in human lung tumor growth was observed in the xenograft mice treated with K4R2-Nal2-S1. Our strategy provides new opportunities in the development of highly effective and selective antimicrobial and anticancer peptide-based therapeutics.

Abstract B79: TIMP-2 mediated growth inhibition of human glioma U87MG is accompanied by elevated IGFBP7 and FSP-1/S100A4 expression at the tumor/stroma interface

Abstract The tissue inhibitor of matrix metalloproteinase–2 (TIMP-2) belongs to a small family of multifunctional secreted proteins that inhibit matrix metalloproteases (MMPs), proteases principally associated with promoting tumor invasion and metastasis. We have previously shown that forced TIMP-2 expression inhibits human lung tumor growth through MMP-independent mechanisms including tumor cell apoptosis and upregulation of insulin growth factor binding protein-7 (IGFPB7), a protein reported to function as a potential tumor suppressor in a variety of tumor types including human glioma. In the current study, we used immunohistochemistry, TUNEL assay, and dual immunofluorescence to assess the growth inhibitory effects of TIMP-2 in human glioma xenografts generated using U87MG cells lentivirally transfected to overexpress the human TIMP-2 cDNA sequence (U87MG-T2) or vector alone (U87MG-EV). Compared to EV controls, U87MG-T2 xenografts demonstrated a significant inhibition of tumor growth, accompanied by increased tumor cell apoptosis at the tumor edge. Moreover, a dramatic increase in IGFBP7 and fibroblast specific protein-1 (FSP1)/S100A4 was detected in distinct subpopulations of non-tumor cells at the tumor/stroma interface, whereas both markers were sparsely observed in U87MG-EV controls. In an effort to determine the origin of IGFBP7 positive cells, we performed dual immunofluorescence using antibodies to the blood vessel marker CD34, FSP-1/S100A4, and human mitochondria (clone 113-1). IGFBP7 positive cells did not co-express any of the three markers analyzed, indicating that IGFBP7 positive cells are host derived and consist of cells other than blood vessels or stromal fibroblasts. We conclude that endogenous TIMP-2 significantly inhibits human glioma tumor growth in vivo through tumor cell apoptosis and tumor-host interactions involving discrete subsets of non-tumor cells in the adjacent tumor microenvironment. Citation Format: Sandra Jensen-Taubman, Dimitra Bourboulia, Huiying Han, Laurie Shuman Moss, Beiyang Wei, William G. Stetler-Stevenson. TIMP-2 mediated growth inhibition of human glioma U87MG is accompanied by elevated IGFBP7 and FSP-1/S100A4 expression at the tumor/stroma interface. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B79. doi:10.1158/1538-7445.CHTME14-B79

Enhanced efficacy of local etoposide delivery by poly(ether-anhydride) particles against small cell lung cancer in vivo

Drug carrier particles composed of poly(ethylene glycol)-co-poly(sebacic acid) (PEG–PSA) have been shown capable of efficient aerosolization into model lungs and the ability to rapidly penetrate human mucus. Here, we develop PEG–PSA particles (Etop/PEG–PSA) that encapsulate up to 40% etoposide by weight in a one step process, release it continuously for 6 days in vitro, and maintain its cytotoxic activity against a human lung tumor cell line in vitro. We further show that Etop/PEG–PSA injected intratumorally effectively suppress human lung tumor growth in a xenograft mouse model, with 100% survival after 31 days. In contrast, 0% survival was observed by day 24 in animals that received free etoposide (either intratumoral or intraperitoneal administration) or placebo particles intratumorally. These findings support PEG–PSA as a drug delivery platform for improved local therapy of cancer.

Transgenic overexpression of IGF-II induces spontaneous lung tumors: a model for human lung adenocarcinoma.

Elevated levels of insulin-like growth factor (IGF)-II are associated with a poor prognosis in human pulmonary adenocarcinoma; however, a causal role for IGF-II in pulmonary adenocarcinoma has not been demonstrated. Here, we show that transgenic overexpression of IGF-II in lung epithelium induces lung tumors in 69% of mice older than 18 months of age. These tumors displayed morphological characteristics of human pulmonary adenocarcinoma such as their epithelial origin, tubulo-acinar architecture and expression of TTF-1, SP-B and proSP-C. Examination of signaling molecules downstream of the IGF-IR showed the activation of either the Erk1/Erk2 or p38 MAPK pathways, but not both, within the lung tumors. Notably, all lung tumors contained high levels of phosphorylated CREB, suggesting that both the Erk1/Erk2 and p38 MAPK pathways converged on this transcription factor. Moreover, IGF-II induced proliferation and CREB phosphorylation in human lung cancer cell lines, suggesting that IGF-II and CREB also contribute to the growth of human lung tumors. Thus, IGF-II is an important genetic factor in the development of lung tumorigenesis, in which activation of CREB is a ubiquitous event. The MMTV-IGF-II transgenic mice provide a critical model for elucidating the role of IGF-II in this fatal human disease.

Cyclooxygenase-2 expression influences the growth of human large and small cell lung carcinoma lines in athymic mice: Impact of an organoselenium compound on growth regulation

Increased expression of cyclooxygenase-2 (COX-2) significantly enhances carcinogenesis and inflammatory reactions. Regulation of COX-2 overexpression may be a reasonable target for cancer chemoprevention. We have tested the hypothesis that levels of COX-2 expression determine the growth of human lung cancer cells in nude mice. Two cell lines, NCI-H460 (non-small cell lung cancer) and NCI-H69 (small cell lung cancer) were selected because the former expresses high levels of COX-2 protein and the latter has no detectable levels. We also examined the effects of 1,4-phenylenebis(methylene)selenocyanate (p-XSC), a highly effective chemopreventive organoselenium compound and known inhibitor of COX-2 expression, in vivo, on cell growth and COX-2 expression in vitro in the NCI-H460 cancer cell line. Cells were exposed to p-XSC at levels between 10 and 100 microM for six days and showed toxicity at approximately 50 microM. Pre-exposure of NCI-H460 to non-toxic levels of p-XSC suppressed COX-2 protein expression in a dose-dependent manner. At 40 microM, p-XSC suppressed phorbol myristate acetate (PMA)-induced COX-2 expression in NCI-H460 cells by more than 66%. In vivo studies in athymic mice showed a significant difference in tumor volume between cell lines. Pre-treatment of NCI-H460 cells with a non-toxic dose of p-XSC, prior to their injection into nude mice, significantly suppressed tumor growth when compared to untreated cells. Collectively, the outcome of our in vitro and in vivo studies supports the hypothesis that levels of COX-2 expression determine the extent of human lung tumor growth in athymic mice. Therefore, inhibition of COX-2 expression by agents such as p-XSC provides a strong rationale for the development of future clinical prevention trials.

Expression of transferrin- and interleukin-2- receptors, and HLA-DR in human lung carcinoma

The expression of HLA-DR and of the receptors for transferrin and interleukin-2 was histochemically analyzed for 27 human lung carcinomas, 3 mesotheliomas, and 3 thymomas by use of the monoclonal antibodies CLONAB Tf-R, Il-2R, and LN3. In addition, a pan B-cell antibody (CD-19) and a pan T-cell antibody (CD3) were applied. The transferrin receptor was found to be expressed in all cases of adenocarcinoma, in 12/17 cases of epidermoid carcinoma, and in a similar percentage of the thymoma cases (2/3). The interleukin-2 receptor specific antibody stained positively only for 3 cases (1 mesothelioma, 1 adenocarcinoma, and 1 epidermoid carcinoma). The expression of HLA-DR could be demonstrated in a similar small percentage of adenocarcinoma and of epidermoid carcinoma, however in 2/3 cases of mesothelioma and thymoma, respectively. The CD-19 antibody stained negatively for all tumor cases, the pan T-antibody positive in 2/10 adenocarcinoma and in 1/3 thymoma. The data suggest that the transferrin receptor may play an important role in human lung tumor growth. In addition, it may be used as diagnostic aid for distinguishing mesothelioma from metastatic adenocarcinoma of lung into the pleura.