Cancer Letters RSS feed: Articles in Press. CANCER LETTERS is an international journal that considers full-length articles and Mini Reviews in the broad area of basic and translational oncology. Additionally, Special Issues highlight topical areas in cancer research. Basic areas of interest to a broad readership of Cancer Letters include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal places emphasis on experimental therapeutics, particularly targeted therapies for personalized cancer medicine. Cancer Letters now offers online submission for authors. Please submit manuscripts at http://www.ees.elsevier.com/can and follow the instructions on the site. http://www.cancerletters.info//inpress?rss=yesElsevier Inc.en © 2012 Elsevier Ireland Ltd. All rights reserved. Cancer Letters0304-38352012-05-17 © 2012 Elsevier Ireland Ltd. All rights reserved. healthpermissions@elsevier.comhttp://www.cancerletters.info/article/PIIS0304383512002194/abstract?rss=yesAbstract: Epigenetic upregulation of voltage-gated sodium channels (VGSCs) has been reported in a number of carcinoma cell lines and tissues. Furthermore, a large body of experimental evidence suggested that functional VGSC expression enhances various in vitro cell behaviours, such as directional motility, that would be involved in the metastatic cascade. However, it is not known if VGSC activity promotes metastasis in vivo. Here, using the Copenhagen rat model of prostate cancer and blocking VGSC activity in primary tumours with tetrodotoxin, we show (1) that the number of lung metastasis is reduced by >40% and (2) that lifespan is significantly improved.Voltage-gated sodium channel activity promotes prostate cancer metastasis in vivo - Corrected ProofSenay Yildirim, Seyhan Altun, Hatice Gumushan, Anup Patel, Mustafa B.A. Djamgoz10.1016/j.canlet.2012.03.036Cancer Letters (2012)2012-05-17Cancer Letters2012-05-17http://www.cancerletters.info/article/PIIS0304383512002558/abstract?rss=yesAbstract: The extrinsic apoptotic pathway can be activated by the endogenous ligand TRAIL (Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand) by binding to the death receptors TRAIL-R1 and TRAIL-R2 on the cell surface. This pathway is currently evaluated as an anticancer treatment strategy. Both recombinant human TRAIL and several agonistic antibodies against TRAIL-R1 and R2 have been studied in single agent and combination studies and proved to be safe and well tolerated. In this article, the clinical studies published to date will be reviewed. Also, future perspectives and biomarker studies for selecting patients that will benefit from these agents will be discussed.Translating TRAIL-receptor targeting agents to the clinic - Corrected ProofMartha W. den Hollander, Jourik A. Gietema, Steven de Jong, Annemiek M.E. Walenkamp, Anna K.L. Reyners, Corina N.A.M. Oldenhuis, Elisabeth G.E. de Vries10.1016/j.canlet.2012.04.007Cancer Letters (2012)2012-05-17Cancer Letters2012-05-17MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512002595/abstract?rss=yesAbstract: Statins are inhibitors of 3-hydroxy-methylglutaryl (HMG) CoA reductase. They exhibit effects beyond cholesterol reduction, including anticancer activity. This review presents the effects of statins in vitro and their possible molecular anticancer mechanisms and critically discusses the data regarding the role of statins in cancer prevention. Finally, this review focuses on the use of statins combined with other chemotherapeutics to increase the effectiveness of cancer treatments. Despite rare and inconclusive clinical data, the preclinical results strongly suggest that such combined treatment could be a promising new strategy for the treatment of certain tumor types.Statins and cancer: Current and future prospects - Corrected ProofMaja Osmak10.1016/j.canlet.2012.04.011Cancer Letters (2012)2012-05-17Cancer Letters2012-05-17MINI-REVIEWhttp://www.cancerletters.info/article/PIIS030438351200256X/abstract?rss=yesAbstract: Aberrant epigenetic landscapes and their involvement in genesis and progression of tumors, as well as in treatment responses and prognosis, indicate one of the most emerging fields in cancer research. In gliomas, the most common human primary brain tumors, and in particular in glioblastoma, the most malignant and devastating brain tumor entity in adults, the elucidation of distinct patterns of aberrant DNA methylation, histone modification, and miRNA expression and their interrelationship has fundamentally changed our point of view on these highly heterogeneous tumors. In the current review article, we address the basic principles of epigenetic control in gliomas, their current and putative future role in prognostic and predictive models and possible interactions within the epigenetic network. We discuss diagnostic and therapeutic opportunities appearing at horizon of epigenetic research. Moreover, we present current and propose future clinical workflow models for molecular characterization of malignant gliomas.Epigenetics in human gliomas - Corrected ProofSimone Kreth, Niklas Thon, Friedrich W. Kreth10.1016/j.canlet.2012.04.008Cancer Letters (2012)2012-05-16Cancer Letters2012-05-16MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512001164/abstract?rss=yesAbstract: Interleukin-12 (IL-12) is a potent immunomodulatory cytokine with unknown direct effect on the property of cancer stem cells (CSCs). In this study, we investigated the capacity of IL-12 to regulate the self-renewal and differentiation of human colon CSCs in vitro, as well as the effect of IL-12 on the growth of tumors initiated by CSCs in mice. After over-expression of IL-12 with lentiviral transfection, CSCs exhibited reduced invasiveness and tumorsphere formation in association with increased apoptosis in vitro. After injection into NOD/SCID mice, tumors initiated by CSCs transfected with IL-12 showed markedly reduced rate of growth. Mechanistic studies revealed that over-expression of IL-12 reduced the expression of IL-4 and STAT6 in CSCs. Thus, our study demonstrates a potentially beneficial role of IL-12 in directly limiting the malignant phenotype of CSCs.Interleukin-12 inhibits the survival of human colon cancer stem cells in vitro and their tumor initiating capacity in mice - Corrected ProofXiao-ling Yin, Ning Wang, Xing Wei, Gan-feng Xie, Jian-jun Li, Hou-jie Liang10.1016/j.canlet.2012.02.015Cancer Letters (2012)2012-05-14Cancer Letters2012-05-14http://www.cancerletters.info/article/PIIS030438351200239X/abstract?rss=yesAbstract: With growing epidemiologic and molecular evidence linking the pathogenesis of diabetes mellitus and oncogenesis, the role of anti-diabetic drugs as antineoplastic agents becomes a subject of intense investigation. Several trials are underway assessing the effect of adding metformin to the existing chemotherapy regimen in the treatment of cancers. This review has a focus on other commonly used drugs classified into two broad groups, incretins and thiazolidinediones. The aim of this review is to discuss the common genetic polymorphisms implicated in the pathogenesis of type 2 diabetes mellitus (type 2 DM) and how they are linked to molecular pathways involved in carcinogenesis.Incretins and thiazolidinediones in glucose homeostasis and cancer: Role of common polymorphisms - Corrected ProofShitij Arora, Anurag Mehrotra, Subhash C. Gulati10.1016/j.canlet.2012.04.002Cancer Letters (2012)2012-05-14Cancer Letters2012-05-14MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512002546/abstract?rss=yesAbstract: Based on cancer stem cell (CSC) concept of carcinogenesis, tumors represent complex heterogeneous organ-like systems with a hierarchical cellular organization, and only minority phenotypic subpopulations with stem-like properties possess a dual ability to self-renew indefinitely and produce all the heterogeneous cell phenotypes comprising the bulk tumor cells. Large experimental and clinical data indicate that conventional anti-cancer therapies cannot eradicate CSCs, and moreover, they usually increase their number leading to cancer recurrence and further drug resistance. In this review, several current controversies in the CSC field and recent studies, which help to shed light on their origin, are discussed. The emerging necessity for the development of complex, multimodal CSC-targeted treatment strategies, which combine conventional therapeutics with promising pathway-specific modulators, and natural compounds, which can improve the efficacy of conventional anti-cancer therapeutics and decrease their undesirable side effects is presented. Also, novel requirements and criteria necessary for evaluation of the CSC-targeted drug efficacy and relevant experimental models are discussed.Colon cancer stem cells – From basic to clinical application - Corrected ProofGalina Botchkina10.1016/j.canlet.2012.04.006Cancer Letters (2012)2012-05-14Cancer Letters2012-05-14MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512001024/abstract?rss=yesAbstract: Cancer stem cells are rare chemotherapy resistant cells within a tumor which can serve to populate the bulk of a tumor with more differentiated daughter cells and potentially contribute to recurrent disease. Ovarian cancer is a disease for which at the time of initial treatment we can obtain complete clinical remission in the majority of patients. Unfortunately, most will relapse and succumb to their disease. This clinical course is in line with the cancer stem cell model. In the past 5years a significant amount of work has been done to identify cells with characteristics of ovarian cancer stem cells. This review will focus specifically on the markers used to define human ovarian cancer stem cells, the prognostic implications of the expression of these cancer stem cell markers in patient’s primary tumors, and the potential of these cancer stem cell markers to serve as therapeutic targets.Ovarian cancer stem cell markers: Prognostic and therapeutic implications - Corrected ProofDaniela Burgos-Ojeda, Bo R. Rueda, Ronald J. Buckanovich10.1016/j.canlet.2012.02.002Cancer Letters (2012)2012-05-09Cancer Letters2012-05-09MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512001590/abstract?rss=yesAbstract: In carcinomas the expression of thrombomodulin (TM) is inversely correlated with tumour progression and metastasis. In the present study a decreased TM expression in human prostate cancer cell lines, LNCaP, DU-145, and PC-3, in relation to normal prostate epithelial cells (PrEC) is shown. Sequencing and methylation-specific high resolution melting (MS-HRM) analyses of bisulphite-modified genomic DNA indicates a high degree of methylation in DU-145 cells and lesser degrees in PC-3 and LNCaP cells, whereas in PrEC the TM promoter is unmethylated. The expression of TM is negatively regulated by NF-κB- and GSK3-β-dependent signalling pathways and positively regulated by retinoic acid and transcription factor Sp1 in PrEC, LNCaP and PC-3 cells, but not in DU-145 cells. However, exposure of DU-145 cells to the demethylating agent, 5-aza-2′deoxycytidine, restores the TM expression and its control by retinoic acid, NF-κB- and GSK3-β-dependent signalling. In conclusion, the study establishes that in prostate cancer cell lines relative to PrEC the TM is down-regulated and that the TM promoter is hypermethylated, which seems to be responsible for the down-regulation and failed regulation of TM expression in DU-145 cells.Regulation of thrombomodulin expression in prostate cancer cells - Corrected ProofMario Menschikowski, Albert Hagelgans, Oliver Tiebel, Margot Vogel, Graeme Eisenhofer, Gabriele Siegert10.1016/j.canlet.2012.03.001Cancer Letters (2012)2012-05-07Cancer Letters2012-05-07http://www.cancerletters.info/article/PIIS0304383512001693/abstract?rss=yesAbstract: Pancreatic cancer (PC) is one of the most malignant cancers worldwide. We describe a novel gene, NOP14, which plays significant roles in PC cell proliferation and migration. Inhibition or overexpression of NOP14 expression in PC cells can reduce or promote motility, proliferation and metastatic capacity in vivo. In parallel, we observed changes in proteins related to migration, such as E-cadherin, vimentin, MMP9, RhoA and p53, along with proteins involved in proliferation, such as MAPK3 and CDK2. Taken together, our study provides new evidence for NOP14 in regulating PC cell proliferation and migration, and may provide new insights for clinical diagnosis and therapy.NOP14 promotes proliferation and metastasis of pancreatic cancer cells - Corrected ProofBin Zhou, Qiao Wu, Ge Chen, Tai-Ping Zhang, Yu-Pei Zhao10.1016/j.canlet.2012.03.010Cancer Letters (2012)2012-05-07Cancer Letters2012-05-07http://www.cancerletters.info/article/PIIS0304383512002169/abstract?rss=yesAbstract: It has been proposed that p16INK4A qualifies as a surrogate marker for viral oncogene activity in head and neck cancer (HNSCC). By analyzing 78 HNSCC we sought to validate the accuracy of p16INK4A as a reliable marker of active HPV infections in HNSCC. To this end we determined HPV DNA (HPVD) and E6*I mRNA (HPVR) expression status and correlated these results with p16INK4A staining. In tonsillar SCC 12/20 were HPVD+ and 12/12 of these showed active HPV infections whereas in non-tonsillar SCC 10/58 were HPVD+ and 5/10 showed active HPV infections. Thus, we prove about 8% of non-tonsillar SCC to be also correlated with HPV-associated carcinogenesis. Strikingly, 3/14 (21.4%) of tonsillar and non-tonsillar HPVD+/HPVR+ cases did not show p16INK4A overexpression and these cases would have been missed when applying initial p16INK4A staining only. However, in 13 cases negative for HPV, DNA p16INK4A was overexpressed. In conclusion, our data confirm tonsillar SCC to be predominantly but not only associated with active HPV infections. Furthermore, our data show that p16INK4A overexpression is not evident in a subgroup of HNSCC with active HPV infection. Definitive HPV data should therefore be utilized in diagnostics and treatment modalities of HPV positive and HPV negative HNSCC patients, resulting in a paradigm shift regarding these obviously different tumor entities.HPV DNA, E6*I-mRNA expression and p16INK4A immunohistochemistry in head and neck cancer – How valid is p16INK4A as surrogate marker? - Corrected ProofMarkus Hoffmann, Silke Tribius, Elgar Susanne Quabius, Hannes Henry, Saskia Pfannenschmidt, Claudia Burkhardt, Tibor Görögh, Gordana Halec, Anna Sophie Hoffmann, Tomas Kahn, Christoph Röcken, Jochen Haag, Tim Waterboer, Markus Schmitt10.1016/j.canlet.2012.03.033Cancer Letters (2012)2012-05-07Cancer Letters2012-05-07http://www.cancerletters.info/article/PIIS0304383512002339/abstract?rss=yesAbstract: Recurrent metastatic breast cancer may arise in part due to the presence of drug resistant adult stem cells such as Side Population (SP) cells, whose phenotype has been demonstrated to be due to the expression of ABCG2. We hypothesised that SP may be identified in Fine Needle Aspirates (FNAs) and their presence may be determined by expression of ABCG2 in breast tumours. SP and non-side population cells (NSP) were isolated using dual wavelength flow cytometry combined with Hoechst 33342 dye efflux and analysed for expression of ABCG2 and chemoresistance. FNA samples used in SP analysis were matched with paraffin-embedded tissue which was used in immunohistochemical analysis to assess ABCG2 expression. Results were correlated to the pathobiology of the tumour. MCF7 and MDA-MB-231 cell lines contain SP cells. MCF7 SP have increased expression of ABCG2 and increased resistance to mitoxantrone compared to NSP cells. The presence of SP in FNAs were significantly associated with ER-negative (p=0.008) and with triple negative breast cancers (p=0.011) which were also found to have a significant increase in ABCG2 protein expression. ABCG2 transcript was detected in some but not all SP cell populations isolated from FNA samples.Breast cancer, side population cells and ABCG2 expression - Corrected ProofK.M. Britton, R. Eyre, I.J. Harvey, K. Stemke-Hale, D. Browell, T.W.J. Lennard, A.P. Meeson10.1016/j.canlet.2012.03.041Cancer Letters (2012)2012-05-07Cancer Letters2012-05-07http://www.cancerletters.info/article/PIIS0304383512002388/abstract?rss=yesAbstract: Patients with castration-resistant prostate cancer (CRPC) frequently have metastases to the bone, which may cause pain and lead to a deterioration in quality-of-life. Bone-seeking radiopharmaceuticals are agents which, when administered systemically, localize to the site of bone metastases and deliver focal radiation there. In this review, we will summarize the current literature on bone-targeting radiopharmaceuticals for CRPC, focusing on strontium-89, samarium-153, rhenium-186 and radium-223. We will discuss their indications, clinical efficacy, and toxicities and highlight some of the challenges in optimizing treatment with these agents. Historically, clinical trials with these drugs have failed to demonstrate survival improvements, restricting their use for palliative purposes only. Radium-223 is the first agent in this class to show an overall survival advantage in CRPC patients with bone metastases. This landmark finding will likely have a considerable impact on the treatment paradigm of bone-metastatic CRPC, and will pave the way for further developments in the future.Bone-targeting radiopharmaceuticals for the treatment of prostate cancer with bone metastases - Corrected ProofJatinder Goyal, Emmanuel S. Antonarakis10.1016/j.canlet.2012.04.001Cancer Letters (2012)2012-05-07Cancer Letters2012-05-07MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512002406/abstract?rss=yesAbstract: IL-6 is a multifunctional cytokine that is important for immune responses, cell survival, apoptosis, and proliferation. However, little is known about the correlation between the IL-6 signaling pathway and DNA damage in human tumors. The present study demonstrates the role of the IL-6/STAT3 signaling pathway in human tumor cells exposed to DNA damage. Tumor cells exposed to DNA damage increase the expression and secretion of IL-6 and the phosphorylation of JAK1 and STAT3. The activation of the JAK1–STAT3 signaling pathway is inhibited by knockdown of gp130 or neutralization of soluble IL-6, implying that DNA damage induces the phosphorylation of JAK1 and STAT3 by autocrine IL-6. Interestingly, inhibition of the IL-6/STAT3 signaling pathway impairs the growth of tumor cells exposed to DNA damage and results in the induction of senescence. Therefore, the present study suggests that IL-6 inhibits senescence but promotes the survival and proliferation of tumor cells exposed to DNA damage through the activation of the JAK1–STAT3 signaling pathway.DNA damage induces the IL-6/STAT3 signaling pathway, which has anti-senescence and growth-promoting functions in human tumors - Corrected ProofUn Jung Yun, Sang Eun Park, Yong Sam Jo, Jungbin Kim, Deug Y. Shin10.1016/j.canlet.2012.04.003Cancer Letters (2012)2012-05-07Cancer Letters2012-05-07http://www.cancerletters.info/article/PIIS0304383512002418/abstract?rss=yesAbstract: A relatively novel paradigm in tumor biology hypothesizes that cancer growth is driven by tumor cells with stem-like properties. However, direct proof of a population of stem cells in small cell lung cancer (SCLC) remains elusive. In this study, we enriched for stem-like cells from the SCLC cell line H446 by growing them as spheres in a defined serum-free medium. Sphere-derived cells have increased in vitro clonogenic and in vivo tumorigenic potentials as well as drug-resistant properties. After enrichment for stem-like cells, we used multiple candidate stem cell markers to examine the expression profile and found that the sphere-derived cells contained a higher proportion of cells expressing the stem cell surface markers uPAR and CD133 when compared with parental cells. To identify a selectable marker for the sphere-forming cells, we evaluated the sphere-forming abilities of uPAR+ and uPAR− cells as well as the sphere-forming abilities of CD133+ and CD133− cells. Both CD133+ and CD133− cell fractions were capable of forming spheres, and no statistically significant difference was observed in the sphere-forming efficiency between these two populations. In contrast, cells derived from the uPAR+ fraction were capable of forming spheres, whereas cells derived from the uPAR− fraction remained as single cells. Moreover, uPAR+ cells efficiently formed transplantable tumors, whereas uPAR− cells were unable to initiate tumors when transplanted at equivalent cell numbers. In addition, uPAR+ cells could differentiate into CD56+cells, CK+ cells, and uPAR− cells. These data support the existence of a population of tumor sphere-forming cells with stem cell properties in the H446 SCLC cell line. Furthermore, the stem cell population may be enriched in cells expressing the uPAR cell surface marker.Characterization of sphere-forming cells with stem-like properties from the small cell lung cancer cell line H446 - Corrected ProofXiaofei Qiu, Zhengyan Wang, Yanlei Li, Yajing Miao, Yu Ren, Yajing Luan10.1016/j.canlet.2012.04.004Cancer Letters (2012)2012-05-07Cancer Letters2012-05-07http://www.cancerletters.info/article/PIIS0304383512001759/abstract?rss=yesAbstract: Identification of tumor-suppressor genes (TSGs) silenced by aberrant methylation of promoter CpG islands (CGIs) is important, but hampered by a large number of genes methylated as passengers of carcinogenesis. To overcome this issue, we here took advantage of the fact that the vast majority of genes methylated in cancers lack, in normal cells, RNA polymerase II (Pol II) and have trimethylation of histone H3 lysine 27 (H3K27me3) in their promoter CGIs. First, we demonstrated that three of six known TSGs in breast cancer and two of three in colon cancer had Pol II and lacked H3K27me3 in normal cells, being outliers to the general rule. BRCA1, HOXA5, MLH1, and RASSF1A had high Pol II, but were expressed only at low levels in normal cells, and were unlikely to be identified as outliers by their expression statuses in normal cells. Then, using epigenome statuses (Pol II binding and H3K27me3) in normal cells, we made a genome-wide search for outliers in breast cancers, and identified 14 outlier promoter CGIs. Among these, DZIP1, FBN2, HOXA5, and HOXC9 were confirmed to be methylated in primary breast cancer samples. Knockdown of DZIP1 in breast cancer cell lines led to increases of their growth, suggesting it to be a novel TSG. The outliers based on their epigenome statuses contained unique TSGs, including DZIP1, compared with those identified by the expression microarray data. These results showed that the epigenome-based outlier approach is capable of identifying a different set of TSGs, compared to the expression-based outlier approach.Development of a novel approach, the epigenome-based outlier approach, to identify tumor-suppressor genes silenced by aberrant DNA methylation - Corrected ProofMizuho Kikuyama, Hideyuki Takeshima, Takayuki Kinoshita, Eriko Okochi-Takada, Mika Wakabayashi, Sadako Akashi-Tanaka, Toshihisa Ogawa, Yasuyuki Seto, Toshikazu Ushijima10.1016/j.canlet.2012.03.016Cancer Letters (2012)2012-05-04Cancer Letters2012-05-04http://www.cancerletters.info/article/PIIS0304383512001401/abstract?rss=yesAbstract: We generated a fusion protein Bax345/BLyS containing the truncated form of Bax (Bax345) at the N-terminus followed by a 218 linker to the B lymphocyte stimulator (BLyS). Bax345/BLyS was cytotoxic to a panel of diffuse large B cell lymphoma and mantle cell lymphoma lines expressing the BLyS receptors. Specific delivery of Bax345/BLyS to malignant B cells drove cells into apoptosis by mitochondrial dysfunction and treatment of cells with Bax345/BLyS induced down-regulation of Mcl-1, X-IAP, and survivin. Bax345/BLyS represents a new class of targeted therapeutic agents with a unique mechanism of action and may have therapeutic potential for malignant B cells.Bax345/BLyS: A novel, completely human fusion protein targeting malignant B cells and delivering a unique mitochondrial toxin - Corrected ProofMi-Ae Lyu, Lawrence H. Cheung, Walter N. Hittelman, Yuying Liu, John W. Marks, Min-Jeong Cho, Michael G. Rosenblum10.1016/j.canlet.2012.02.029Cancer Letters (2012)2012-04-30Cancer Letters2012-04-30http://www.cancerletters.info/article/PIIS0304383512001449/abstract?rss=yesAbstract: Breast cancer (BC) is an aggressive and high mortality cancer that can be classified into five molecular subtypes, based on gene expression profiling. The extreme heterogeneity poses difficulties for understanding and treating BC. Among many risk factors, inflammation plays a causal role in BC progression and recurrence, wherein NFkB and glucocorticoid receptor (GR) are critical transcription factors in regulating inflammation. NFkB is generally pro-inflammatory, and GR is anti-inflammatory, constituting a Yin–Yang mode in regulation. Thus, the crosstalk between these two transcription factors exerts even more important functions in determining the survival or apoptosis of BC cells. NFkB is widely involved in the initiation and progression of BC; its inhibitors are emerging as a potent primary or adjuvant therapy. On the other hand, glucocorticoids (GCs) are already used as neo-adjuvant and adjuvant therapies to treat various cancers with remarkable effects to induce apoptosis in leukemia and lymphoma. However, GCs unexpectedly promote cancer cell survival and induce chemo-resistance in BC. To understand this unique transcriptional interplay in BC, in this review we discuss the functions of NFkB and GR in BC development and progression by emphasizing their cross talk at cell signaling and protein interaction levels; and the future perspectives are proposed for the development of new therapeutic approaches for BC based on these signaling pathways.Crosstalk between NFkB and glucocorticoid signaling: A potential target of breast cancer therapy - Corrected ProofJun Ling, Raj Kumar10.1016/j.canlet.2012.02.033Cancer Letters (2012)2012-04-30Cancer Letters2012-04-30MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512001632/abstract?rss=yesAbstract: Cyclin D1, an oncogenic G1 cyclin which can be induced by environmental carcinogens and whose over-expression may cause dysplasia and carcinoma, has been shown to be a target for cancer chemoprevention and therapy. In this study, we investigated the effects and underlying mechanisms of action of a polyprenylated xanthone, gambogenic acid (GEA) on gefitinib-sensitive and -resistant lung cancer cells. We found that GEA inhibited proliferation, caused G1 arrest and repressed colony-forming activity of lung cancer cells. GEA induced degradation of cyclin D1 via the proteasome pathway, and triggered dephosphorylation of GSK3β which was required for cyclin D1 turnover, because GSK3β inactivation by its inhibitor or specific siRNA markedly attenuated GEA-caused cyclin D1 catabolism. GEA induced autophagy of lung cancer cells, possibly due to activation of GSK3β and inactivation of AKT/mTOR signal pathway. These results indicate that GEA is a cyclin D1 inhibitor and a GSK3β activator which may have chemopreventive and therapeutic potential for lung cancer.Gambogenic acid induces G1 arrest via GSK3β-dependent cyclin D1 degradation and triggers autophagy in lung cancer cells - Corrected ProofXian-Jun Yu, Quan-Bin Han, Zhe-Sheng Wen, Liang Ma, Jin Gao, Guang-Biao Zhou10.1016/j.canlet.2012.03.004Cancer Letters (2012)2012-04-30Cancer Letters2012-04-30http://www.cancerletters.info/article/PIIS0304383512002091/abstract?rss=yesAbstract: The involvement of insulin in endometrial carcinoma (EC) was investigated using radioimmunoassay, Western blot, immunoprecipitation, MTT, and Annexin V-FITC/PI assays in tissue samples and cultured cells. Serum levels of insulin, p-p52Shc, p-p46Shc, Shc·Grb2 complexes, p-MEK, p-ERK, and cyclin D1 were elevated in patients with EC. Expression of key proteins in the MEK/ERK pathway, including p-p52Shc, Shc·Grb2 complexes, p-MEK, p-ERK, and cyclin D1, was significantly higher in patients with advanced FIGO stage, high grade, and lymph-node metastasis and correlated positively with serum insulin concentration. Insulin promotes Ishikawa 3-H-12 cell proliferation, survival, and invasion, and these effects induced by insulin were significantly blocked by MEK inhibitor PD98059. Insulin thus promotes EC cell proliferation, survival, and invasion via the MEK/ERK pathway.Insulin promotes proliferation, survival, and invasion in endometrial carcinoma by activating the MEK/ERK pathway - Corrected ProofYingmei Wang, Yuanxi Zhu, Lizhi Zhang, Wenyan Tian, Shaofang Hua, Jing Zhao, Huiying Zhang, Fengxia Xue10.1016/j.canlet.2012.03.026Cancer Letters (2012)2012-04-30Cancer Letters2012-04-30http://www.cancerletters.info/article/PIIS0304383512002133/abstract?rss=yesAbstract: Nasopharyngeal carcinoma (NPC) is a highly metastatic cancer. The 2-year survival rate of patients with stage III or IV disease is only about 50%. Due to its high radiosensitivity, radiotherapy is the standard treatment for early-stage of NPC. However, the radioresistance observed in some patients can cause distant metastases and local recurrence after radiotherapy. Special emphasis has been given to the discovery of effective radiosensitizers. Oncogenic proteins encoded by EBV genomes may serve as part of targeted radiosensitization, such as NF кB-mediated expression of latent membrane protein-1. We here review the major nucleic acid-based options currently used in cancer therapeutic approaches and the selected candidate genes that can be targeted for NPC radiosensitization.Potential use of nucleic acid-based agents in the sensitization of nasopharyngeal carcinoma to radiotherapy - Corrected ProofLu Zhang, Lifang Yang, Jian Jian Li, Lunquan Sun10.1016/j.canlet.2012.03.030Cancer Letters (2012)2012-04-27Cancer Letters2012-04-27MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512002145/abstract?rss=yesAbstract: Pancreatic tumors are resistant to conventional chemotherapies. The present study was aimed at evaluating the potential of a novel plant-derived product as a therapeutic agent for pancreatic cancer (PC). The effects of an extract from the tropical tree Annona Muricata, commonly known as Graviola, was evaluated for cytotoxicity, cell metabolism, cancer-associated protein/gene expression, tumorigenicity, and metastatic properties of PC cells. Our experiments revealed that Graviola induced necrosis of PC cells by inhibiting cellular metabolism. The expression of molecules related to hypoxia and glycolysis in PC cells (i.e. HIF-1α, NF-κB, GLUT1, GLUT4, HKII, and LDHA) were downregulated in the presence of the extract. In vitro functional assays further confirmed the inhibition of tumorigenic properties of PC cells. Overall, the compounds that are naturally present in a Graviola extract inhibited multiple signaling pathways that regulate metabolism, cell cycle, survival, and metastatic properties in PC cells. Collectively, alterations in these parameters led to a decrease in tumorigenicity and metastasis of orthotopically implanted pancreatic tumors, indicating promising characteristics of the natural product against this lethal disease.Graviola: A novel promising natural-derived drug that inhibits tumorigenicity and metastasis of pancreatic cancer cells in vitro and in vivo through altering cell metabolism - Corrected ProofMaría P. Torres, Satyanarayana Rachagani, Vinee Purohit, Poomy Pandey, Suhasini Joshi, Erik D. Moore, Sonny L. Johansson, Pankaj K. Singh, Apar K. Ganti, Surinder K. Batra10.1016/j.canlet.2012.03.031Cancer Letters (2012)2012-04-27Cancer Letters2012-04-27http://www.cancerletters.info/article/PIIS030438351200211X/abstract?rss=yesAbstract: Breast cancer stem cells (BCSCs) initiate and sustain breast cancers, and several putative markers have been proposed to prospectively isolate BCSC from the non-cancer stem cell population. The candidate BCSC marker Sca-1 is a GPI-linked membrane protein expressed on activated lymphocytes, hematopoietic stem cells and mammary stem cells. Sca-1+ cells were purified from the murine mammary tumour cell line 4T1. However, this did not enrich for a stem-like, tumour initiating or metastatic cell population in vitro or in vivo. Sphere formation, which induced high levels of Sca-1, reduced BCSC gene expression with near complete loss of spontaneous metastasis from sphere-derived tumours. This was associated with decreased expression of TGFB2 and reduced activation of the TGFβ signalling pathway in spheres. Both TGFB2 expression in vitro and spontaneous metastasis in vivo could be restored upon re-differentiation of sphere cells by exposure to serum, and this occurred with retention of the majority of Sca-1 expression. We conclude that while putative BCSC, including spheres, can have high Sca-1 expression, Sca-1 itself is not a marker of BCSC in established 4T1 tumours or the cell line.Sphere formation reverses the metastatic and cancer stem cell phenotype of the murine mammary tumour 4T1, independently of the putative cancer stem cell marker Sca-1 - Corrected ProofHeli Matilainen, Xiao-Wen Yu, Ching-Wen Tang, Michael V. Berridge, Melanie J. McConnell10.1016/j.canlet.2012.03.028Cancer Letters (2012)2012-04-26Cancer Letters2012-04-26http://www.cancerletters.info/article/PIIS0304383512002327/abstract?rss=yesAbstract: Matrix metalloproteinases (MMPs) are proteases responsible for remodeling the extracellular matrix (ECM) and enabling spreading and metastasis of tumor cells, a common phenomenon in oral squamous cell carcinomas (OSCC). They are strongly blocked by several inhibitors, among which we must highlight, for their specificity and potency, the endogenous tissue inhibitors of metalloproteinases (TIMP-1, -2, -3 and -4). The goal of this paper is to describe the expression of TIMPs in OSCC, determining their relation with clinical, histological and prognostic factors, delving into OSCC regulation mechanisms and discussing the use of exogenous TIMPs to treat this type of tumors. Expression of TIMPs in OSCC is higher in tumors than in normal tissue, which correlates with an increase of metastatic risk and regional lymph node affectation. Although some metalloproteinases inhibitors (MMIs) have shown promising results in the treatment of these tumors, their use in OSCC has not been widely tested; and although some indirect MMIs, like COX-2 inhibitors, flavonoids and endostatin seem to have beneficial effects on the invasive capacity of OSCC through regulation of MMPs and TIMP levels, routine clinical use has not been accepted yet.Tissue inhibitor of metalloproteinases in oral squamous cell carcinomas – A therapeutic target? - Corrected ProofMario Pérez-Sayáns García, José Manuel Suárez-Peñaranda, Pilar Gayoso-Diz, Francisco Barros-Angueira, José Manuel Gándara-Rey, Abel García-García10.1016/j.canlet.2012.03.040Cancer Letters (2012)2012-04-26Cancer Letters2012-04-26MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512002042/abstract?rss=yesHighlights: ► At the last follow-up of IRIS trial, about 40% of patients did not reach a favorable result. ► High dose imatinib or association with IFN did not improve the results of standard dose imatinib. ► Second generation TKIs used as front-line treatment induced rapid decrease of disease burden, with reduced rate of progression. ► Further researches are needed to identify potential candidates to discontinuation of therapy.Abstract: Imatinib has revolutionized treatment strategies for chronic myeloid leukemia patients: long-term overall survival was reported to be up to 80% at 8years of follow-up in respondent patients. Despite the straightforward results obtained, it has been estimated a failure rate per year of 2–4%. Several attempts to improve response have been made with high-dose of imatinib and with combination of standard dose with interferon, but both failed to ameliorate cytogenetic and molecular responses and long-term event-free and overall survival and no advantages were reported in high-risk patients. The introduction of second generation tyrosine kinase inhibitors in clinical practice allowed to rescue more than 50% of patients resistant or intolerant to imatinib. Both dasatinib and nilotinib were tested as single agent in first-line and then tested against imatinib standard dose: the results of phases II and III trials showed early and maintained complete cytogenetic response, rapid reduction of molecular burden and significant reduction of progression rate. At the present time, after FDA approval of both agents in first-line, several points of discussion are still unresolved.How to treat CML patients in the tyrosine kinase inhibitors era? From imatinib standard dose to second generation drugs front-line: Unmet needs, pitfalls and advantages - Corrected ProofMassimo Breccia, Giuliana Alimena10.1016/j.canlet.2012.03.021Cancer Letters (2012)2012-04-25Cancer Letters2012-04-25MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512002054/abstract?rss=yesAbstract: The prognosis of pancreatic cancer is extremely poor, mainly because of its aggressive biological behavior and late onset of symptoms for clinical diagnosis; these impose limitations on therapeutic intervention. Deeper genomic sequencing analyses of pancreatic cancers revealed 12 core pathways and a long duration, nearly 20years from initiation to distant metastases. This evidence will offer a broader aspect and time window of opportunity for early detection, thus preventing deaths from this cruel cancer. Epigenetic biomarkers can be utilized for assessing cancer risk, early detection, and predicting prognosis and therapeutic responses. In this review, we briefly summarize relevant issues associated with pancreatic cancer progression and recent advances in epigenetic biomarkers such as DNA methylation, miRNAs, satellite repeats, and histone modifications for early diagnosis.Road to early detection of pancreatic cancer: Attempts to utilize epigenetic biomarkers - Corrected ProofShinichi Fukushige, Akira Horii10.1016/j.canlet.2012.03.022Cancer Letters (2012)2012-04-25Cancer Letters2012-04-25MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512002157/abstract?rss=yesAbstract: The production of a plethora of reactive oxygen and nitrogen species in the cell and tissues as the result of endogenous or exogenous mechanisms and interaction of our cells with the environment define the so called ‘oxidative load’. The final balance between the oxidatively-induced stress and the various cellular defense mechanisms draw the picture on the landscape of oxidative injury and biological consequences.In this Special Issue, I have compiled a synthesis of concise reviews by leading experts in their fields. The articles focus on the current status and advances in the various pathways leading to the production of high oxidative stress, DNA damage and its processing in human cells and tissues. Significant mechanistic insights are offered as well as connections with biological and clinical significance.Oxidative stress, DNA damage and repair in carcinogenesis: Have we established a connection? - Corrected ProofAlexandros G. Georgakilas10.1016/j.canlet.2012.03.032Cancer Letters (2012)2012-04-25Cancer Letters2012-04-25EDITORIALhttp://www.cancerletters.info/article/PIIS0304383512002340/abstract?rss=yesAbstract: Nasopharyngeal carcinoma (NPC) is endemic in southern China. In a genome-wide screen for genes inactivated by promoter hypermethylation, we identified Ras-related associated with diabetes (RRAD). Expression of RRAD was down-regulated in 83.3% (30/36) of the biopsies from NPC patients. RRAD was aberrantly methylated in 74.3% (26/35) of primary tumors, but not in normal nasopharyngeal epithelium. Ectopic RRAD expression in NPC cell lines inhibited the cell growth, colony formation, and cell migration. These results indicate that RRAD might act as a functional tumor suppressor and its epigenetic inactivation may play an important role in NPC development.Promoter hypermethylation of Ras-related GTPase gene RRAD inactivates a tumor suppressor function in nasopharyngeal carcinoma - Corrected ProofYingxi Mo, Kaoru Midorikawa, Zhe Zhang, Xiaoying Zhou, Ning Ma, Guangwu Huang, Yusuke Hiraku, Shinji Oikawa, Mariko Murata10.1016/j.canlet.2012.03.042Cancer Letters (2012)2012-04-25Cancer Letters2012-04-25http://www.cancerletters.info/article/PIIS0304383512001218/abstract?rss=yesAbstract: Ultrasound (US) has been shown to induce cell death in cancer cells; however, the underlying mechanism remains elusive. Here, we report a set of novel findings on the molecular mechanism. We found that Akt (also known as protein kinase B), a substrate of DNA-dependent protein kinase (DNA-PK), was phosphorylated in U937 cells nullified with p53 or Molt-4 cells artificially abrogated with p53 after US exposure. On the contrary, Akt phosphorylation was transiently down-regulated then recovered in Molt-4 cells harboring wild-type p53 in US-exposed cells, possibly due to a mutual regulation between p53 and Akt. Inhibition of ataxia-telangiectasia mutated (ATM) or DNA-PK revealed that DNA-PK, rather than ATM, was preferentially involved in Akt phosphorylation and cell survival after US-exposure in all cell lines. These results indicate that DNA-PK plays a protective role against US-induced cell death regardless of p53 phenotype. In conclusion, our findings provide the first delineation of the role of DNA-PK in US-induced cell death and suggest that targeting DNA-PK might be a promising strategy to augment cancer eradication by US.Inhibition of DNA-dependent protein kinase promotes ultrasound-induced cell death including apoptosis in human leukemia cells - Corrected ProofYukihiro Furusawa, Yoshisada Fujiwara, Mariame Ali Hassan, Yoshiaki Tabuchi, Akinori Morita, Atsushi Enomoto, Takashi Kondo10.1016/j.canlet.2012.02.020Cancer Letters (2012)2012-04-23Cancer Letters2012-04-23http://www.cancerletters.info/article/PIIS0304383512001437/abstract?rss=yesAbstract: Ser/Thr protein kinase CK2 regulates multiple processes that play important roles in the sensitivity of cancer to epidermal growth factor receptor targeting therapeutics, including PI3K-Akt-mTOR signaling, Hsp90 activity, and inhibition of apoptosis. We hypothesized that top-down inhibition of EGFR, combined with lateral suppression of multiple oncogenic pathways by targeting CK2, would create a pharmacologic synthetic lethal event and result in an improved cancer therapy compared to EGFR inhibition alone. This hypothesis was tested by combining CX-4945, a first-in-class clinical stage inhibitor of CK2, with the EGFR tyrosine kinase inhibitor, erlotinib, in vitro and in vivo in models of non-small cell lung carcinoma, NCI-H2170, and squamous cell carcinoma, A431. Our results demonstrate that combination of CX-4945 with erlotinib results in enhanced attenuation of the PI3K-Akt-mTOR pathway. We also observed an increase in apoptosis, synergistic killing of cancer cells in vitro, as well as improved antitumor efficacy in vivo. Taken together, these data position CK2 as a valid pharmacologic target for drug combinations and support further evaluation of CX-4945 in combination with EGFR targeting agents.Combined inhibition of EGFR and CK2 augments the attenuation of PI3K-Akt-mTOR signaling and the killing of cancer cells - Corrected ProofJoshua Bliesath, Nanni Huser, Mayuko Omori, Daniel Bunag, Chris Proffitt, Nicole Streiner, Caroline Ho, Adam Siddiqui-Jain, Sean E. O’Brien, John K.C. Lim, David M. Ryckman, Kenna Anderes, William G. Rice, Denis Drygin10.1016/j.canlet.2012.02.032Cancer Letters (2012)2012-04-23Cancer Letters2012-04-23http://www.cancerletters.info/article/PIIS0304383512001450/abstract?rss=yesAbstract: Malignant mesothelioma (MM) is a cancer with a high mortality rate and limited therapeutic options, typically presenting as a tumor in the serous membranes, most frequently in the pleura and the peritoneum rather than in the pericardium. There is much evidence that the immune system contributes to the biogenesis, growth and metastasis of MM through the unbalanced production of oxidants and cytokines, mesothelial cell DNA damage and the active support of MM neoangiogenesis and immunosuppression. Because classical therapeutic approaches are generally ineffective, novel immunological tools are being developed to target the immune cells infiltrating the MM foci and exploit the immune system to elicit an effective anti-tumor response. These therapies work by stimulating local inflammatory cells or transferring exogenously activated immunocompetent cells and by depleting MM-associated immunosuppressive clones to target the spontaneous specific immune responses against MM and to subvert MM-driven immunoediting. This review summarizes the recent evidence on the immune system mechanisms that support MM development and the novel therapeutic approaches for strengthening the immune system by MM immunotherapy that are currently being developed in both experimental models and clinical trials.Immunity and malignant mesothelioma: From mesothelial cell damage to tumor development and immune response-based therapies - Corrected ProofValerio Izzi, Laura Masuelli, Ilaria Tresoldi, Calogero Foti, Andrea Modesti, Roberto Bei10.1016/j.canlet.2012.02.034Cancer Letters (2012)2012-04-23Cancer Letters2012-04-23MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512001462/abstract?rss=yesAbstract: In our previous study, we found that blockade of SDF-1/CXCR4 signaling inhibits pancreatic cancer cell migration and invasion in vitro. However, the mechanism governing the downstream regulation of SDF-1/CXCR4-mediated invasion remains unclear. Here we report the role of SDF-1/CXCR4 in pancreatic cancer and the possible mechanism of SDF-1/CXCR4-mediated pancreatic cancer invasion. We show that there is a cross-talk between SDF-1/CXCR4 axis and non-canonical Hedgehog (Hh) pathway in pancreatic cancer. Furthermore, our data demonstrate that the ligand of CXCR4, SDF-1 induces CXCR4-positive pancreatic cancer invasion, epithelial–mesenchymal transition (EMT) process and activates the non-canonical Hh pathway. Moreover, we also demonstrate that the invasion of a pancreatic cancer and EMT resulting from the activation of SDF-1/CXCR4 axis is effectively inhibited by Smoothened (SMO) inhibitor cyclopamine and siRNA specific to Gli-1. Collectively, these data demonstrate that SDF-1/CXCR4 modulates the non-canonical Hh pathway by increasing the transcription of SMO in a ligand-independent manner. Taken together, SDF-1/CXCR4 axis may represent a promising therapeutic target to prevent pancreatic cancer progression.SDF-1/CXCR4 signaling induces pancreatic cancer cell invasion and epithelial–mesenchymal transition in vitro through non-canonical activation of Hedgehog pathway - Corrected ProofXuqi Li, Qingyong Ma, Qinhong Xu, Han Liu, Jianjun Lei, Wanxing Duan, Kruttika Bhat, Fengfei Wang, Erxi Wu, Zheng Wang10.1016/j.canlet.2012.02.035Cancer Letters (2012)2012-04-23Cancer Letters2012-04-23http://www.cancerletters.info/article/PIIS0304383512002121/abstract?rss=yesAbstract: The phosphatase of regenerating liver-3 (PRL-3) gene is associated with metastasis in gastric cancer, and is believed to play a causative role by promoting tumor cell motility, invasion, and metastasis, but little is known of the mechanisms involved. We previously reported that PRL-3 expression is significantly higher in the tissues of primary gastric carcinomas with peritoneal metastasis. In the present study, we found that two microRNAs (miRNAs), miR-495 and miR-551a, predicted to target PRL-3, are downregulated in gastric carcinoma samples. The validation of this interaction between those two miRNAs and PRL-3 was confirmed by western blotting and quantitative real-time PCR (qPCR) in GC cell lines transfected with miR-495 and miR-551a mimics. Furthermore, the migration and invasion of GC cells were significantly inhibited by transfection with miR-495 or -551a mimics, and the mRNA and protein levels of PRL-3 were reduced in cells overexpressing miR-495 or -551a. Collectively, our findings suggest that miR-495 and miR-551a both act as tumor suppressors by targeting the PRL-3 oncogene and inhibiting gastric cancer cell migration and invasion. The findings of this study contribute to current understanding of the functions of miRNA mimics in GC gene therapy.miR-495 and miR-551a inhibit the migration and invasion of human gastric cancer cells by directly interacting with PRL-3 - Corrected ProofZhengrong Li, Yi Cao, Zhigang Jie, Yi Liu, Yingliang Li, Junhe Li, Guoming Zhu, Zhengren Liu, Yi Tu, Gen Peng, Dong-woo Lee, Sung-soo Park10.1016/j.canlet.2012.03.029Cancer Letters (2012)2012-04-23Cancer Letters2012-04-23http://www.cancerletters.info/article/PIIS0304383512002170/abstract?rss=yesAbstract: Development of resistance to endocrine therapy is a clinical issue in estrogen receptor (ER)-positive breast cancer. Here we show that persistent activation of AKT/mTOR signaling is crucial to the acquisition of letrozole resistance in cell clones generated from MCF-7/AROM-1 aromatase-expressing breast cancer cells after prolonged letrozole exposure. ERα plays a marginal role in this context. As a proof of concept, the association between PI3K/AKT/mTOR signaling and insensitivity to endocrine therapies was confirmed in breast cancer patients who developed early letrozole resistance in neoadjuvant setting. In addition our results suggest that, regardless of the mechanism mediating the activation of AKT/mTOR pathway, either RAD001 or NVP-BEZ235 treatment may represent a promising strategy to overcome acquired resistance to letrozole in breast cancers dependent on AKT/mTOR signaling.Overcoming acquired resistance to letrozole by targeting the PI3K/AKT/mTOR pathway in breast cancer cell clones - Corrected ProofAndrea Cavazzoni, Mara A. Bonelli, Claudia Fumarola, Silvia La Monica, Kinda Airoud, Ramona Bertoni, Roberta R. Alfieri, Maricla Galetti, Stefano Tramonti, Elena Galvani, Adrian L. Harris, Lesley-Ann Martin, Daniele Andreis, Alberto Bottini, Daniele Generali, Pier Giorgio Petronini10.1016/j.canlet.2012.03.034Cancer Letters (2012)2012-04-23Cancer Letters2012-04-23http://www.cancerletters.info/article/PIIS0304383512002200/abstract?rss=yesAbstract: Cancer stem cells (CSCs) are involved in tumorigenesis and progression of prostate cancer (PCa). Conventional anticancer therapeutics failed to eradicate CSCs, which may eventually lead to the disease relapse and metastasis. Therefore, targeting prostate CSCs may be an ideal strategy to cure PCa. Genistein is a major isoflavone constituent of soybeans and soy products, which has been shown to exhibit potent anticancer effect on many cancers. We have previously reported that genistein can inhibit PCa cell invasion by reversing epithelial to mesenchymal transition, suggesting that genistein may be effective against metastatic PCa. In addition, we have recently demonstrated that PCa tumorsphere cells (TCs) possess CSC properties. Here, we found that tumorsphere formation and colony formation of Pca cells were noticeably suppressed in the presence of genistein. Pretreatment of PCa TCs with genistein also suppressed tumorigenicity in vivo. Additionally, genistein treatment inhibited tumor growth of PCa TCs. Further studies showed that genistein treatment not only led to the down-regulation of PCa CSC markers CD44 in vitro and in vivo, but also inhibited Hedgehog–Gli1 pathway, which may contribute to the anti-CSC effect of genistein in PCa TCs. Therefore, our findings demonstrated that genistein may be a dietary phytochemical with potential to target prostate CSCs.Genistein inhibits the stemness properties of prostate cancer cells through targeting Hedgehog–Gli1 pathway - Corrected ProofLinlin Zhang, Lei Li, Min Jiao, Dapeng Wu, Kaijie Wu, Xiang Li, Guodong Zhu, Lin Yang, Xinyang Wang, Jer-Tsong Hsieh, Dalin He10.1016/j.canlet.2012.03.037Cancer Letters (2012)2012-04-23Cancer Letters2012-04-23http://www.cancerletters.info/article/PIIS0304383512002303/abstract?rss=yesAbstract: Mitochondrial fusion and fission are dynamically regulated during apoptotic cell death, and mitofusin (Mfn) and related proteins have been shown to be involved in apoptosis-associated changes in mitochondrial morphology and function. Here, we investigated the involvement of Mfn proteins in the conformational activation and mitochondrial translocation of Bax, a key molecule responsible for apoptosis-associated mitochondrial changes. When ectopically expressed, Mfn1 inhibited the amino-terminal activation, but not the mitochondrial translocation, of Bax during staurosporine-induced apoptosis; overexpression of Mfn2 had no effect. Overexpression of Mfn1 mutants carrying point mutations in the GTPase domain (Mfn1-K88T and Mfn1-T109A) did not inhibit the amino-terminal activation of Bax. Furthermore, staurosporine-induced amino-terminal activation of Bax was significantly delayed in Mfn1-shRNA transfected (Mfn1-depleted) HeLa cells compared to cells transfected with control shRNA. These results collectively suggest a role for Mfn1 in regulating the activation of Bax on the outer mitochondrial membrane in a GTPase-dependent manner.Mitofusin 1 inhibits an apoptosis-associated amino-terminal conformational change in Bax, but not its mitochondrial translocation, in a GTPase-dependent manner - Corrected ProofSeung-Wook Ryu, Kyungsun Choi, Jong-Hwan Park, Yeong-Min Park, Sunchang Kim, Chulhee Choi10.1016/j.canlet.2012.03.038Cancer Letters (2012)2012-04-23Cancer Letters2012-04-23http://www.cancerletters.info/article/PIIS0304383512001747/abstract?rss=yesAbstract: Studies on non-small cell lung cancer (NSCLC) patients with KRAS or BRAF mutations are urgently needed to improve clinical outcomes. We evaluated the cytotoxicities of paclitaxel and sorafenib alone and in combination in NSCLC cell lines with KRAS or BRAF mutations and investigated the mechanism of the interaction between the drugs. We found synergistic antitumor efficacy with paclitaxel followed by sorafenib in in vitro and in vivo models of NSCLC. And, we determined that downregulation of the phosphorylated ERK and Rb, and Mcl-1 plays a critical role in the synergistic activity of the drugs. Further clinical trials are needed to verify the antitumor efficacy of this combination.Synergistic antitumor efficacy of sequentially combined paclitaxel with sorafenib in vitro and in vivo NSCLC models harboring KRAS or BRAF mutations - Corrected ProofXiang-Hua Zhang, Jung-Young Shin, Jeong-Oh Kim, Ji-Eun Oh, Seong-Ae Yoon, Chan-Kwon Jung, Jin-Hyoung Kang10.1016/j.canlet.2012.03.015Cancer Letters (2012)2012-04-20Cancer Letters2012-04-20http://www.cancerletters.info/article/PIIS0304383512002315/abstract?rss=yesAbstract: Multidrug resistance (MDR) represents a major obstacle in the successful treatment of breast cancer. The MDR1 gene is a direct target of the Wnt/β-catenin signaling pathway, which controls tumor development. Overexpression of P-glycoprotein, encoded by the MDR1 gene, is one of the most common causes of MDR. We found that the Frizzled 1 (FZD1) protein, which is an essential component of the Wnt/β-catenin pathway, is overexpressed in the multidrug resistant breast cancer cell subline MCF-7/ADM, coincident with MDR1/P-gp. FZD1 silencing induced down-regulation of MDR1/P-gp, restored sensitivity to four chemotherapy drugs, and significantly decreased cytoplasmic and nuclear β-catenin levels. FZD1 appears to mediate multidrug resistance by regulating the Wnt/β-catenin pathway.Interference of Frizzled 1 (FZD1) reverses multidrug resistance in breast cancer cells through the Wnt/β-catenin pathway - Corrected ProofHui Zhang, Xiaofang Zhang, Xiaojuan Wu, Weiwei Li, Peng Su, Hongxia Cheng, Lei Xiang, Peng Gao, Gengyin Zhou10.1016/j.canlet.2012.03.039Cancer Letters (2012)2012-04-20Cancer Letters2012-04-20http://www.cancerletters.info/article/PIIS0304383512002108/abstract?rss=yesAbstract: TNF-α-inducing protein (Tipα) is a unique carcinogenic factor of Helicobacter pylori, which is secreted into culture broth. The biological activities of Tipα and deletion mutant were studied. Tipα protein specifically binds to cell-surface nucleolin and then enters the gastric cancer cells, where TNF-α and chemokine gene expressions are induced by NF-κB activation. Nucleolin localizes on the surface of gastric cancer cells, and interaction between Tipα and cell-surface nucleolin causes a cancer-oriented microenvironment that increases the risk of gastric cancer. This paper discusses a new mechanism of gastric cancer development with H. pylori and provides a new preventive strategy.Human gastric cancer development with TNF-α-inducing protein secreted from Helicobacter pylori - Corrected ProofMasami Suganuma, Tatsuro Watanabe, Kensei Yamaguchi, Atsushi Takahashi, Hirota Fujiki10.1016/j.canlet.2012.03.027Cancer Letters (2012)2012-04-19Cancer Letters2012-04-19MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512002078/abstract?rss=yesAbstract: In radiation oncology, cancer stem cells (CSCs) have become an important research field. In fact, it appears that most cancer types contain populations of cells that exhibit stem-cell properties. CSCs have the ability to renew indefinitely, which can drive tumor development and metastatic invasion. As those cells are classically resistant to conventional chemotherapy and to radiation therapy, they may contribute to treatment failure and relapse. Over past decades, preclinical research has highlighted that variations in the CSCs content within tumor could affect their radiocurability by interfering with mechanisms of DNA repair, redistribution in the cell cycle, tumor cells repopulation, and hypoxia. It is now possible to isolate particular cells expressing specific surface markers and thus better investigating CSCs pathways. Numerous inhibitory agents targeting these specific signaling pathways, such as Notch and Wnt/B-catenin, are currently evaluated in early clinical trials. By targeting CSCs, tumor radioresistance could be potentially overcome to improve outcome for patients with solid malignancies. Radiation therapy using ion particles (proton and carbon) may be also more effective than classic photon on CSCs. This review presents the major pathophysiological mechanisms involved in CSCs radioresistance and recent developments for targeted strategies.Targeting a cornerstone of radiation resistance: Cancer stem cell - Corrected ProofCoralie Moncharmont, Antonin Levy, Marion Gilormini, Gérald Bertrand, Cyrus Chargari, Gersende Alphonse, Dominique Ardail, Claire Rodriguez-Lafrasse, Nicolas Magné10.1016/j.canlet.2012.03.024Cancer Letters (2012)2012-04-16Cancer Letters2012-04-16MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512001644/abstract?rss=yesAbstract: With almost 4000 citations in Medline in a little over 10years, survivin has certainly kept scores of investigators busy worldwide. Tangible progress has been made in revealing the multiple functions of survivin, uncovering their wirings as integrated cellular networks, and mapping their exploitation in virtually every human tumor, in vivo. Considering the normally long and excruciating timeline of oncology drug discovery, it is clearly a resounding success that a better understanding of survivin biology has led to several clinical trials of survivin-based therapeutics in cancer patients. However, the portfolio of survivin antagonists available in the clinic remains small, pressing the need for a less rigid drug development approach to fully unlock the potential of this unique, albeit unconventional oncology drug target.Targeting survivin in cancer - Corrected ProofDario C. Altieri10.1016/j.canlet.2012.03.005Cancer Letters (2012)2012-04-09Cancer Letters2012-04-09MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512001711/abstract?rss=yesAbstract: In this ‘Featuring the editor’ article, we introduce Assoc. Professor Alexandros G. Georgakilas as the guest editor for this Special Issue of Cancer Letters. His main research, educational and editorial achievements in his academic career are presented with emphasis on the various milestones of his involvement in science for more than twenty years. His primary interests in research focus on various radiation and cancer biology aspects especially the involvement of clustered DNA lesions in carcinogenesis.Featuring the Special Issue Editor: Associate Professor Alexandros G. Georgakilas - Corrected ProofAlexandros G. Georgakilas10.1016/j.canlet.2012.03.012Cancer Letters (2012)2012-04-09Cancer Letters2012-04-09MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512001735/abstract?rss=yesAbstract: Cancer stem cell are considered to represent a population within the bulk tumor that share many similarities to normal stem cells as far as their capacities to self-renew, differentiate, proliferate and to reconstitute the entire tumor upon serial transplantation are concerned. Since cancer stem cells have been shown to be critical for maintaining tumor growth and have been implicated in treatment resistance and tumor progression, they constitute relevant targets for therapeutic intervention. Indeed, it has been postulated that eradication of cancer stem cells will be pivotal in order to achieve long-term relapse-free survival. However, one of the hallmarks of cancer stem cells is their high resistance to undergo cell death including apoptosis in response to environmental cues or cytotoxic stimuli. Since activation of apoptosis programs in tumor cells underlies the antitumor activity of most currently used cancer therapeutics, it will be critical to develop strategies to overcome the intrinsic resistance to apoptosis of cancer stem cells. Thus, a better understanding of the molecular mechanisms that are responsible for the ability of cancer stem cells to evade apoptosis will likely open new avenues to target this critical pool of cells within the tumor in order to develop more efficient treatment options for patients suffering from cancer.Regulation of apoptosis pathways in cancer stem cells - Corrected ProofSimone Fulda10.1016/j.canlet.2012.03.014Cancer Letters (2012)2012-04-09Cancer Letters2012-04-09MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512001760/abstract?rss=yesAbstract: Cancer progression in humans is difficult to infer because we do not routinely sample patients at multiple stages of their disease. The identification cancer stem cell (CSC) subpopulations inside tumor opens a new view of cancer development, since it implies that tumors can only be eradicated by targeting CSCs. Several markers have been proposed in the literature to identify CSCs both in breast and melanoma but no consensus has been reached, leading to the hypothesis that the CSC phenotype might be dynamically switched. Herein we provide a critical discussion of the biological markers described in the literature for breast cancer and melanoma. Due to its complexity the field would benefit from an interdisciplinary approach to investigate tumor heterogeneity and its progression. Similar considerations could also be relevant for normal tissue stem cells.Human breast and melanoma cancer stem cells biomarkers - Corrected ProofCaterina A.M. La Porta, Stefano Zapperi10.1016/j.canlet.2012.03.017Cancer Letters (2012)2012-04-09Cancer Letters2012-04-09MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512001772/abstract?rss=yesAbstract: In the past few years, there have been significant advances in the research on cancer stem cells (CSCs). The emerging evidences have demonstrated that CSCs and epithelial–mesenchymal transition (EMT)-type cells, which share molecular characteristics with CSCs, play critical roles in drug resistance, invasion, and metastasis. Pancreatic cancer (PC) has a high mortality due to both intrinsic (de novo) and extrinsic (acquired) drug resistance, leading to increased invasive and metastatic potential of PC cells. Therefore, targeting pancreatic CSCs and EMT-type cells could be a novel therapeutic strategy for the treatment of PC. In this article, we will review the current state of our knowledge on the role of pancreatic CSCs and EMT-type cells, and summarize the novel therapeutic strategies that could target pancreatic CSCs and EMT-type cells, leading to the reversal of EMT phenotype, the induction of drug sensitivity, and the inhibition of invasion and metastasis of PC, which is expected to yield better treatment outcome.Pancreatic cancer stem cells: Emerging target for designing novel therapy - Corrected ProofYiwei Li, Dejuan Kong, Aamir Ahmad, Bin Bao, Fazlul H. Sarkar10.1016/j.canlet.2012.03.018Cancer Letters (2012)2012-04-09Cancer Letters2012-04-09MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512001152/abstract?rss=yesAbstract: Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. High mobility group box chromosomal protein 1 (HMGB)-1 is a widely studied, ubiquitous nuclear protein that is present in eukaryotic cells, and plays a crucial role in inflammatory response. However, the effects of HMGB-1 on human chondrosarcoma cells are largely unknown. In this study, we found that HMGB-1 increased the migration and the expression of α5β1 integrin in human chondrosarcoma cells. Transfection of cells with receptor for advanced glycation end products (RAGE) receptor siRNA reduced HMGB-1-induced cell migration and integrin expression. Activations of phosphatidylinositol 3-kinase (PI3K), Akt, and AP-1 pathways after HMGB-1 treatment were demonstrated, and HMGB-1-induced expression of integrin and migration activity was inhibited by the specific inhibitor and mutant of PI3K, Akt, and AP-1 cascades. Taken together, our results indicated that HMGB-1 enhances the migration of chondrosarcoma cells by increasing α5β1 integrin expression through the RAGE receptor/PI3K/Akt/c-Jun/AP-1 signal transduction pathway.HMGB-1 induces cell motility and α5β1 integrin expression in human chondrosarcoma cells - Corrected ProofChih-Hsin Tang, Yun-Ting Keng, Ju-Fang Liu10.1016/j.canlet.2012.02.014Cancer Letters (2012)2012-03-30Cancer Letters2012-03-30http://www.cancerletters.info/article/PIIS0304383512001267/abstract?rss=yesAbstract: Cancer is a multistage process where each stage involves different molecular, biochemical and cellular events all of which, however, contribute to malignant transformation. Over the last years, substantial scientific evidence has promoted the hypothesis that ROS-induced cellular damage underlies key steps during development of the malignant phenotype including evasion of apoptosis, limitless proliferation, angiogenesis, tissue invasion and metastasis, etc. On the other hand, natural products hold great promise as anti-cancer compounds in preventing against carcinogenesis both in vitro and in vivo. Throughout this article, we aim to review the evidence as to how some of these natural products exert their chemopreventive effects in human carcinogenesis. For this reason, we have placed particular emphasis on oral cancer where significant efforts have been made in alternative therapeutic strategies such as the use of plant-derived natural products. This is of paramount importance given the disease’s high morbidity and mortality rates across the world and specifically in the geographic regions of India and South-East Asia where its incidence is increasing.Pleiotrophic effects of natural products in ROS-induced carcinogenesis: The role of plant-derived natural products in oral cancer chemoprevention - Corrected ProofDominique Ziech, Ioannis Anestopoulos, Rania Hanafi, Georgia Persephoni Voulgaridou, Rodrigo Franco, Alexandros G. Georgakilas, Aglaia Pappa, Mihalis I. Panayiotidis10.1016/j.canlet.2012.02.025Cancer Letters (2012)2012-03-29Cancer Letters2012-03-29MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512001589/abstract?rss=yesAbstract: The aberrant DNA methylation of tumor suppressor genes is well documented in esophageal cancer, including adenocarcinoma (EAC) and squamous cell carcinoma (ESCC) as well as in Barrett’s esophagus (BE), a pre-malignant condition that is associated with chronic acid reflux. BE is a well-recognized risk factor for the development of EAC, and consequently the standard of care is for individuals with BE to be placed in endoscopic surveillance programs aimed at detecting early histologic changes that associate with an increased risk of developing EAC. Yet because the absolute risk of EAC in individuals with BE is minimal, a clinical need in the management of BE is the identification of additional risk markers that will indicate individuals who are at a significant absolute risk of EAC so that they may be subjected to more intensive surveillance. The best currently available risk marker is the degree of dysplasia in endoscopic biopsies from the esophagus; however, this marker is suboptimal for a variety of reasons. To date, there are no molecular biomarkers that have been translated to widespread clinical practice. The search for biomarkers, including hypermethylated genes, for either the diagnosis of BE, EAC, or ESCC or for risk stratification for the development of EAC in those with BE is currently an area of active research. In this review, we summarize the status of identified candidate epigenetic biomarkers for BE, EAC, and ESCC. Most of these aberrantly methylated genes have been described in the context of early detection or diagnostic markers; others might prove useful for estimating prognosis or predicting response to treatment. Finally, special attention will be paid to some of the challenges that must be overcome in order to develop clinically useful esophageal cancer biomarkers.Epigenetic biomarkers in esophageal cancer - Corrected ProofAndrew M. Kaz, William M. Grady10.1016/j.canlet.2012.02.036Cancer Letters (2012)2012-03-29Cancer Letters2012-03-29MINI-REVIEWhttp://www.cancerletters.info/article/PIIS0304383512001115/abstract?rss=yesAbstract: Epigenome alterations are characteristic of nearly all human malignancies and include changes in DNA methylation, histone modifications and microRNAs (miRNAs). However, what induces these epigenetic alterations in cancer is largely unknown and their mechanistic role in prostate tumorigenesis is just beginning to be evaluated. Identification of the epigenetic modifications involved in the development and progression of prostate cancer will not only identify novel therapeutic targets but also prognostic and diagnostic markers. This review will focus on the use of epigenetic modifications as biomarkers for prostate cancer.Epigenetic biomarkers in prostate cancer: Current and future uses - Corrected ProofKaren Chiam, Carmela Ricciardelli, Tina Bianco-Miotto10.1016/j.canlet.2012.02.011Cancer Letters (2012)2012-03-26Cancer Letters2012-03-26MINI-REVIEWhttp://www.cancerletters.info/article/PIIS030438351200119X/abstract?rss=yesAbstract: A tissue field of somatic genetic alterations precedes the histopathological phenotypic changes of carcinoma. Genomic changes could be of potential use in the diagnosis and prognosis of pre-invasive squamous head and neck carcinoma (HNSCC) lesions and as markers for cancer risk assessment. Studies of sequential molecular alterations and genetic progression of pre-invasive HNSCC have not been clearly defined. Studies have shown recurring alterations at chromosome 9p21 (location of the CDKN2A) and TP53 mutations in the early stages of HNSCC. However, gene silencing via hypermethylation is still a relatively new idea in the development of HNSCC and little is known about the contribution of epigenetics to the development of neoplasia, its transformation, progression, and recurrence in HNSCC. This review examines the role of promoter hypermethylation of tumor suppressor genes in the progression continuum from benign papillomas to malignancy in HNSCC.Delineating an epigenetic continuum in head and neck cancer - Corrected ProofMaria J. Worsham, Josena K. Stephen, Kang Mei Chen, Shaleta Havard, Veena Shah, Glendon Gardner, Vanessa G. Schweitzer10.1016/j.canlet.2012.02.018Cancer Letters (2012)2012-03-21Cancer Letters2012-03-21MINI-REVIEW