1538-4047 Cancer Biology & Therapy cbt Austin, Tx Landes Bioscience biweekly January/February 2002 - http://dx.doi.org/10.4161/cbt http://www.landesbioscience.com/journals/cbt/ 1538-4047 Casey Trimmer Federica Sotgia Diana Whitaker-Menezes Renee M. Balliet Gregory Eaton Ubaldo E. Martinez-Outschoorn Stephanos Pavlides Anthony Howell Renato V. Iozzo Richard G. Pestell Philipp E. Scherer Franco Capozza and Michael P. Lisanti cbt Caveolin-1 and mitochondrial SOD2 (MnSOD) function as tumor suppressors in the stromal microenvironment: A new genetically tractable model for human cancer associated fibroblasts Landes Bioscience 2011-02-15 383 - 394 Cancer Biology & Therapy 11-4 Landes Bioscience We have recently proposed a new model for understanding tumor metabolism, termed: "The Autophagic Tumor Stroma Model of Cancer Metabolism". In this new paradigm, catabolism (autophagy) in the tumor stroma fuels the anabolic growth of aggressive cancer cells. Mechanistically, tumor cells induce autophagy in adjacent cancer-associated fibroblasts via the loss of caveolin-1 (Cav-1), which is sufficient to promote oxidative stress in stromal fibroblasts. To further test this hypothesis, here we created human Cav-1 deficient immortalized fibroblasts using a targeted sh-RNA knock-down approach. Relative to control fibroblasts, Cav-1 deficient fibroblasts dramatically promoted tumor growth in xenograft assays employing an aggressive human breast cancer cell line, namely MDA-MB-231 cells. Co-injection of Cav-1 deficient fibroblasts, with MDA-MB-231 cells, increased both tumor mass and tumor volume by ~4-fold. Immuno-staining with CD31 indicated that this paracrine tumor promoting effect was clearly independent of angiogenesis. Mechanistically, proteomic analysis of these human Cav-1 deficient fibroblasts identified > 40 protein biomarkers that were upregulated, most of which were associated with i) myofibroblast differentiation, or ii) oxidative stress/hypoxia. In direct support of these findings, the tumor promoting effects of Cav-1 deficient fibroblasts could be functionally suppressed (nearly 2-fold) by the recombinant over-expression of SOD2 (superoxide dismutase 2), a known mitochondrial enzyme that de-activates superoxide, thereby reducing mitochondrial oxidative stress. In contrast, cytoplasmic soluble SOD1 had no effect, further highlighting a specific role for mitochondrial oxidative stress in this process. In summary, here we provide new evidence directly supporting a key role for a loss of stromal Cav-1 expression and oxidative stress in cancer-associated fibroblasts, in promoting tumor growth, which is consistent with "The Autophagic Tumor Stroma Model of Cancer". The human Cav-1 deficient fibroblasts that we have generated are a new genetically tractable model system for identifying other suppressors of the cancer-associated fibroblast phenotype, via a genetic "complementation" approach. This has important implications for understanding the pathogenesis of triple negative and basal breasts cancers, as well as tamoxifen-resistance in ER+ breast cancers, which are all associated with a Cav-1 deficient "lethal" tumor micro-environment, driving poor clinical outcome. http://dx.doi.org/10.4161/cbt.11.4.14101 http://www.landesbioscience.com/journals/cbt/article/14101/ article Research Paper 1538-4047 Greta Garrido Ilia A. Tikhomirov Ailem Rabasa Eric Yang Elías Gracia Normando Iznaga Luis E. Fernández Tania Crombet Robert S. Kerbel and Rolando Pérez cbt Bivalent binding by intermediate affinity of nimotuzumab: A contribution to explain antibody clinical profile Landes Bioscience 2011-02-15 373 - 382 Cancer Biology & Therapy 11-4 Landes Bioscience Nimotuzumab is an EGFR-targeting antibody that has demonstrated encouraging clinical results in the absence of severe side-effects observed with other approved anti-EGFR antibodies. We investigated whether different clinical behavior of nimotuzumab is related to its bivalent/monovalent binding profile. Binding properties of nimotuzumab and cetuximab, the most development of anti-EGFR antibodies, were studied in vitro using chip surfaces and cells with varying EGFR expression levels. Experimental observations demonstrated that in contrast to cetuximab, the intrinsic properties of nimotuzumab required bivalent binding for stable attachment to the cellular surface, leading to nimotuzumab selectively binding to cells that express moderate to high EGFR expression levels. At these conditions, both antibodies bound bivalently, and accumulated to similar degrees. When EGFR density is low, nimotuzumab monovalent interaction was transient, whereas cetuximab continued to interact strongly with the receptors. We compared the in vitro anti-tumor efficacy of nimotuzumab and cetuximab. Cetuximab decreased the cell viability and induced apoptosis for all the tested cell lines, effects which did not depend on EGFR expression level. In contrast, nimotuzumab also provoked significant anti-cellular effects, but its anti-tumor capacity decreased together with EGFR expression level. Cetuximab Fab fragment was able to impact tumor cell survival, whereas nimotuzumab fragment totally lost this effect. Tumor-xenograft experiments using cells with a high EGFR expression revealed similar tumor growth inhibiting effects for both antibodies. This study suggests an explanation for nimotuzumab clinical profile, whereby antitumor activity is obtained in absence of severe toxicities due to its properties of bivalent binding to EGFR. See commentary: <a href="http://www.landesbioscience.com/journals/cbt/article/14920/">Don’t jump to rash conclusions</a> http://dx.doi.org/10.4161/cbt.11.4.14097 http://www.landesbioscience.com/journals/cbt/article/14097/ article Research Paper 1538-4047 Zheng-Cai Jia Yi Tian Ze-Min Huang Jing-Xue Wang Xiao-Lan Fu Bing Ni and Yu-Zhang Wu cbt Identification of a new MAGE-A10 antigenic peptide presented by HLA-A*0201 on tumor cells Landes Bioscience 2011-02-15 395 - 400 Cancer Biology & Therapy 11-4 Landes Bioscience MAGE-A antigens belong to cancer/testis (CT) antigens that are expressed in tumors but not in normal tissues with the exception of testis and placenta. Among MAGE-A antigens, MAGE-A10 is extensively expressed in various histological types of tumors, representing an attractive target for tumor immunotherapy. Cytotoxic T lymphocytes (CTLs) play a key role in anti-tumor immune responses, so the identification of CTL epitopes derived from MAGE-A10 would contribute a lot to the design of epitope-based vaccines for tumor patients. In this study, we predicted HLA-A*0201-restricted CTL epitope peptides of MAGE-A10, followed by peptide/HLA-A*0201 binding affinity and complex stability assays, and induced peptide-specific CTL immune responses. Of the selected three peptides (designated P1, P2 and P3), P1 (MAGE-A10310-318, SLLKFLAKV) could elicit peptide-specific CTLs both in vitro from HLA-A*0201-positive PBMCs and in HLA-A*0201/Kb transgenic mice. And, the induced CTLs could lyse MAGE-A10-expressing tumor cells in a HLA-A*0201-restricted fashion but not MAGE-A10-negative tumor cells. Our results demonstrate that the peptide MAGE-A10310-318 is a HLA-A*0201-restricted CTL epitope of MAGE-A10 and could serve as a target for therapeutic antitumoral vaccination. http://dx.doi.org/10.4161/cbt.11.4.14100 http://www.landesbioscience.com/journals/cbt/article/14100/ article Research Paper 1538-4047 Hongxin Deng Qingyuan Jiang Yang Yang Shuang Zhang Yongping Ma Gang Xie Xiang Chen Zhiyong Qian Yanjun Wen Jiong Li Jinliang Yang Lijuan Chen Xia Zhao and Yuquan Wei cbt Intravenous liposomal delivery of the short hairpin RNAs against Plk1 controls the growth of established human hepatocellular carcinoma Landes Bioscience 2011-02-15 401 - 409 Cancer Biology & Therapy 11-4 Landes Bioscience Polo-like kinase 1 (Plk1) is a key cell cycle regulator that is frequently overexpressed in human hepatocellular carcinomas. Blockade of the Plk1 pathway has been reported to be capable of inducing anti-tumor effect. Here, plasmids containing U6 promoter-driven shRNAs against human Plk1 were constructed and transfected in human hepatocellular carcinoma cell line HepG2. ShRNA targeting Plk1 almost completely reduced Plk1 expression in HepG2 hepatocellular carcinoma cells, as confirmed by RT-PCR and Western blot. As a consequence, HepG2 cells exhibited reduced proliferation and enhanced apoptosis in vitro. Most importantly, Treatment with Plk shRNA-DOTAP:Chol complex significantly suppressed the growth of HepG2 xenografts, accompanied with phenotypic changes in tumor cells, including proliferation inhibition and apoptosis induction. Our study suggested that shRNA-mediated silencing of Plk1 might be a novel therapeutic approach against human hepatocellular carcinoma by inhibiting tumor cells proliferation and inducing apoptosis. http://dx.doi.org/10.4161/cbt.11.4.14178 http://www.landesbioscience.com/journals/cbt/article/14178/ article Research Paper 1538-4047 Ahmed A. Mohamed Shyh-Han Tan Chen Sun Syed Shaheduzzaman Ying Hu Gyorgy Petrovics Yongmei Chen Isabell A. Sesterhenn Hua Li Taduru Sreenath David G. McLeod Albert Dobi and Shiv Srivastava cbt ERG oncogene modulates prostaglandin signaling in prostate cancer cells Landes Bioscience 2011-02-15 410 - 417 Cancer Biology & Therapy 11-4 Landes Bioscience Androgen dependent induction of the ETS related gene (ERG) expression in more than half of all prostate cancers results from gene fusions involving regulatory sequence of androgen regulated genes (i.e. TMPRSS2, SLC45A3 and NDRG1) and protein coding sequence of the ERG. Emerging studies in experimental models underscore the functions of ERG in prostate tumorigenesis. However, biological and biochemical functions of ERG in prostate cancer (CaP) remain to be elucidated. This study suggests that ERG activation plays a role in prostaglandin signaling because knockdown of ERG expression in TMPRSS2-ERG fusion containing CaP cells leads to altered levels of the 15-hydroxy-prostaglandin dehydrogenase (HPGD), a tumor suppressor and prostaglandin catabolizing enzyme, and prostaglandin E2 (PGE2) . We demonstrate that HPGD expression is regulated by the binding of the ERG protein to the core promoter of this gene. Moreover, prostaglandin E2 dependent cell growth and urokinase-type plasminogen activator (uPA) expression are also affected by ERG knockdown. Together, these data imply that the ERG oncoprotein in CaP cells positively influence prostaglandin mediated signaling, which may contribute to tumor progression. See commentary: <a href="http://www.landesbioscience.com/journals/cbt/article/14499/">Gene fusions find an ERG-way to tumor inflammation </a> http://dx.doi.org/10.4161/cbt.11.4.14180 http://www.landesbioscience.com/journals/cbt/article/14180/ article Research Paper 1538-4047 James C. Forde Elaina N. Maginn Gillian McNamara Lynn M. Martin Guiseppe Campiani D. Clive Williams Daniela Zisterer Anthony M. McElligott Mark Lawler Thomas H. Lynch Donal Hollywood and Laure Marignol cbt Microtubule-targeting-compound PBOX-15 radiosensitizes cancer cells in vitro Landes Bioscience 2011-02-15 421 - 428 Cancer Biology & Therapy 11-4 Landes Bioscience Background We proposed to investigate the radiosensitizing properties of PBOX-15, a novel microtubule-disrupting agent, in a panel of cancer cell lines. Results PBOX-15 treatment was associated with significant cell kill and increased radiosensitivity in all three cell lines tested. The number of surviving cells in response to the combined treatment was significantly less than PBOX -15 alone in 22Rv1 cells. In these cells, radiosensitisation correlated with induction of G2/M cell cycle arrest by PBOX-15. The compound sustained its activity and increased HIF-1Α expression under hypoxic conditions. PBOX-15 prevented onset of hypoxia-induced radioresistance in hypoxic prostate cells and reduced the surviving fraction of irradiated hypoxic cells to levels similar to those achieved under aerobic conditions. Methods Clonogenic assays were used to determine sensitivity of a panel of cancer cell lines (22Rv1, A549, U87) to PBOX-15 alone or in combination with a single 2Gy dose fraction. Induction of cell cycle arrest and apoptosis was investigated in 22Rv1 prostate cancer cells. The cytotoxic properties of the compound under hypoxic conditions were correlated with Hypoxia Inducible Factor 1 alpha (HIF-1Α) gene and protein expression levels and its radiosensitisation potential was investigated in hypoxic 22Rv1 using clonogenic assays. Conclusions This preliminary data identifies the potential of PBOX-15 as a novel radiosensitising agent for the management of solid tumours and eradication of hypoxic cells. http://dx.doi.org/10.4161/cbt.11.4.14183 http://www.landesbioscience.com/journals/cbt/article/14183/ article Research Paper 1538-4047 Sarah K. Martin and Natasha Kyprianou cbt Gene fusions find an ERG-way to tumor inflammation Landes Bioscience 2011-02-15 418 - 420 Cancer Biology & Therapy 11-4 Landes Bioscience Commentary to: <a href="http://www.landesbioscience.com/journals/cbt/article/14180/">ERG oncogene modulates prostaglandin signaling in prostate cancer cells</a> Ahmed A. Mohamed, Shyh-Han Tan, Chen Sun, Syed Shaheduzzaman, Ying Hu, Gyorgy Petrovics, Yongmei Chen, Isabell A. Sesterhenn, Hua Li, Taduru Sreenath, David G. McLeod, Albert Dobi and Shiv Srivastava http://dx.doi.org/10.4161/cbt.11.4.14499 http://www.landesbioscience.com/journals/cbt/article/14499/ article Commentary