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• Human Renal Cancer Stem Cells.

  Authors: Benedetta Bussolati, Benjamin Dekel, Bruno Azzarone, Giovanni Camussi

  Cancer letters.

  Cancer stem cells (CSCs), isolated in renal carcinomas, exhibit tumor-initiating capabilities and pluripotency. No specific CSC markers have been identified so far; therefore, their characterizationCancer stem cells (CSCs), isolated in renal carcinomas, exhibit tumor-initiating capabilities and pluripotency. No specific CSC markers have been identified so far; therefore, their characterization is mainly based on functional studies. As they are resistant to chemo and radio therapy, renal CSCs may have a relevant role in tumor establishment, progression, and recurrence. CSCs were also shown to contribute to intra-tumor vasculogenesis through an endothelial differentiation and to favour the generation of the pre-metastatic niche through the release of exosomes/microvesicles.

• Synergistic growth inhibition of human hepatocellular carcinoma cells by acyclic retinoid and GW4064, a farnesoid X receptor ligand.

  Authors: Tomohiko Ohno, Yohei Shirakami, Masahito Shimizu, Masaya Kubota, Hiroyasu Sakai, Yoichi Yasuda, Takahiro Kochi, Hisashi Tsurumi, Hisataka Moriwaki

  Cancer letters.

  Abnormalities in the expression and function of retinoid X receptor (RXR), a master regulator of the nuclear receptor superfamily, are associated with the development of hepatocellular carcinomaAbnormalities in the expression and function of retinoid X receptor (RXR), a master regulator of the nuclear receptor superfamily, are associated with the development of hepatocellular carcinoma (HCC). Dysfunction of farnesoid X receptor (FXR), one of the nuclear receptors that forms a heterodimer with RXR, also plays a role in liver carcinogenesis. In the present study, we examined the effects of acyclic retinoid (ACR), a synthetic retinoid targeting RXRα, plus GW4064, a ligand for FXR, on the growth of human HCC cells. We found that ACR and GW4064 preferentially inhibited the growth of HLE, HLF, and Huh7 human HCC cells in comparison with Hc normal hepatocytes. The combination of 1 μM ACR plus 1 μM GW4064 synergistically inhibited the growth of HLE cells by inducing apoptosis. The combined treatment with these agents acted cooperatively to induce cell cycle arrest in the G(0)/G(1) phase and inhibit the phosphorylation of RXRα, which is regarded as a critical factor for liver carcinogenesis, through inhibition of ERK and Stat3 phosphorylation. This combination also increased the expression levels of p21(CIP1) and SHP mRNA, while decreasing the levels of c-myc and cyclin D1 mRNA in HLE cells. In addition, a reporter assay indicated that the FXRE promoter activity was significantly increased by treatment with ACR plus GW4064. Our results suggest that ACR and GW4064 cooperatively inhibit RXRα phosphorylation, modulate the expression of FXR-regulated genes, thus resulting in the induction of apoptosis and the inhibition of growth in HCC cells. This combination might therefore be effective for the chemoprevention and chemotherapy of HCC.

• Blocking p38/ERK crosstalk affects colorectal cancer growth by inducing apoptosis in vitro and in preclinical mouse models.

  Authors: Fulvio Chiacchiera, Valentina Grossi, Marianna Cappellari, Alessia Peserico, Marta Simonatto, Aldo Germani, Silvana Russo, Mary P Moyer, Nicoletta Resta, Stefania Murzilli, Cristiano Simone

  Cancer letters.

  We recently demonstrated that p38α is required to maintain colorectal cancer (CRC) metabolism, as its inhibition leads to FoxO3A activation, autophagy, cell death, and tumor growth reduction both inWe recently demonstrated that p38α is required to maintain colorectal cancer (CRC) metabolism, as its inhibition leads to FoxO3A activation, autophagy, cell death, and tumor growth reduction both in vitro and in vivo. Here we show that inhibition of p38α is followed by TRAIL-mediated activation of caspase-8 and FoxO3A-dependent HER3 upregulation with consequent overactivation of the MEK-ERK1/2 survival pathway. p38α and MEK combined inhibition specifically induces apoptosis by enabling TRAIL signaling propagation through t-Bid and caspase-3, and fosters cell death in CRC cells and preclinical mouse models. Current MEK1-directed pharmacological strategies could thus be exploited, in combination with p38α inhibition, to develop new approaches for CRC treatment.

• Cells of origin and tumor-initiating cells for nonmelanoma skin cancers.

  Authors: Khanh Thieu, Marlon Ruiz, David M Owens

  Cancer letters.

  The epidermis of the skin is a multilayered stratified epithelium whose primary function is to provide a barrier against our external environment. As a result, cells in the epidermis are subject toThe epidermis of the skin is a multilayered stratified epithelium whose primary function is to provide a barrier against our external environment. As a result, cells in the epidermis are subject to constant assault from environmental pathogens, many of which can cause deleterious mutations. However, most of these mutations do not lead to skin cancer. One explanation is that most genetic hits are sustained by mature or transit cells with limited proliferative capacity and only stem cells that acquire genetic alterations have the potential to propagate a frank tumor. In this mini-review we will discuss recent studies that provide some of the first genetic evidence to support a stem cell origin for a number of skin cancer types.

• (5R)-5-hydroxytriptolide (LLDT-8), a novel immunosuppressant in clinical trials, exhibits potent antitumor activity via transcription inhibition.

  Authors: Lei Wang, Yongping Xu, Li Fu, Yuanchao Li, Liguang Lou

  Cancer letters.

  (5R)-5-hydroxytriptolide (LLDT-8), a triptolide derivative, is a low-toxicity immunosuppressant in Phase I clinical trials. Here, we demonstrate that LLDT-8 displays broad-spectrum, potent (nanomolar(5R)-5-hydroxytriptolide (LLDT-8), a triptolide derivative, is a low-toxicity immunosuppressant in Phase I clinical trials. Here, we demonstrate that LLDT-8 displays broad-spectrum, potent (nanomolar level IC(50)s) antitumor activity, and induces S-phase cell-cycle arrest and apoptosis in vitro. Notably, LLDT-8 effectively overcomes multidrug resistance mediated by P-glycoprotein. In vivo, LLDT-8 demonstrates potent antitumor activity, particularly against human ovarian cancer 3AO and prostate cancer PC-3 xenografts in nude mice. The antitumor activity of LLDT-8 is achieved by virtue of its general inhibition of gene transcription. Our results indicate that LLDT-8 is a novel transcription inhibitor with potential for cancer therapy, particularly for cancers with drug resistance mediated by P-glycoprotein.

• The MAP30 protein from bitter gourd (Momordica charantia) seeds promotes apoptosis in liver cancer cells in vitro and in vivo.

  Authors: Evandro Fei Fang, Chris Zhi Yi Zhang, Jack Ho Wong, Jia Yun Shen, Chuan Hao Li, Tzi Bun Ng

  Cancer letters.

  Human hepatocellular carcinoma Hep G2 cells and Hep G2-bearing mice were used as in vitro and in vivo models to assess the efficacy and safety of MAP30, a natural component from Momordica charantia,Human hepatocellular carcinoma Hep G2 cells and Hep G2-bearing mice were used as in vitro and in vivo models to assess the efficacy and safety of MAP30, a natural component from Momordica charantia, as an anticancer agent against liver cancer. Molecular studies disclosed the contribution of both caspase-8 regulated extrinsic and caspase-9 regulated intrinsic caspase cascades in MAP30-induced cell apoptosis. The antitumor potential was also effective in Hep G2-bearing nude mice. Since bitter gourd is a staple in many Asian countries, MAP30 would serve as a novel and relatively safe agent for prophylaxis and treatment of liver cancer.

• Acetylation of histone H3 prevents resistance development caused by chronic mTOR inhibition in renal cell carcinoma cells.

  Authors: Eva Juengel, Anna Vogt, Jasmina Makarević, Christoph Wiesner, Igor Tsaur, Georg Bartsch, Axel Haferkamp, Roman A Blaheta

  Cancer letters.

  Chronic mTOR inhibition may induce resistance development in renal cell carcinoma (RCC). We analyzed whether long-term exposure of RCC cells to the mTOR-inhibitor RAD001 evokes resistance and whetherChronic mTOR inhibition may induce resistance development in renal cell carcinoma (RCC). We analyzed whether long-term exposure of RCC cells to the mTOR-inhibitor RAD001 evokes resistance and whether additional targeting histone deacetylases (HDAC) by valproic acid (VPA) overcomes RAD001 resistance. It is demonstrated that responsiveness to either drug alone is lost over time, evidenced by increased cell growth, proliferation and de-differentiation. However, drug sensitivity was conserved when RAD001 and VPA were applied in concert. Molecular analysis particularly revealed strong re-activation of Akt under chronic RAD001 or diminished histone H3 acetylation under chronic VPA single drug exposure. Combined drug application did not inactivate Akt but rather resulted in H3 acetylation remaining high while RCC cell growth was still reduced. siRNA experiments revealed that histone H3 acetylation is responsible for preserving drug sensitivity in RCCs.

• Liver tumor-initiating cells as a therapeutic target for hepatocellular carcinoma.

  Authors: Terence Kin Wah Lee, Vincent Chi Ho Cheung, Irene Oi Lin Ng

  Cancer letters.

  Hepatocellular carcinoma (HCC) is a common malignancy worldwide and has poor prognosis. Existing treatment modalities, including surgery, chemotherapy, and radiofrequency ablation, which target tumorHepatocellular carcinoma (HCC) is a common malignancy worldwide and has poor prognosis. Existing treatment modalities, including surgery, chemotherapy, and radiofrequency ablation, which target tumor bulk, have demonstrated limited therapeutic efficacy. In the past ten years, accumulating evidence has supported the existence of cancer stem cells (CSCs) or tumor initiating cells (T-ICs) within tumors including HCC. Identification of liver T-ICs and the signaling pathways that they are involved in may shed light on novel therapeutic strategies against this deadly disease. In this review, we will discuss recent progresses made in the research of liver T-ICs with regard to identification, functional characterization, regulation and therapeutic implications.

• Tumor macrophages as a target for Capsaicin mediated immunotherapy.

  Authors: Amiya K Ghosh, Sreyashi Basu

  Cancer letters.

  Tumor microenvironment contributes to a large extent for failure of immunological destruction of antigenic tumors. Most solid tumors adapt to the microenvironment and escape the host immune system.Tumor microenvironment contributes to a large extent for failure of immunological destruction of antigenic tumors. Most solid tumors adapt to the microenvironment and escape the host immune system. The dramatic and systemic effectiveness of neuro-immune ligand Capsaicin (CP) in regression of established solid tumors led us to investigate its immunomodulatory role in tumor microenvironment. In this report we demonstrate that CP induced tumor cell apoptosis leads to increased sensitization of the surrounding stroma manifested by enhanced antigen presentation by stromal macrophages and its destruction by tumor specific T-cells. Further, CP injection alters the tumor microenvironment with regards to tumor-infiltrating Treg cells as well as the cytokine milieu at the tumor site. Our data collectively demonstrates that injection of CP sets in motion, a cascade of several independent innate and adaptive immunological events initiated at the tumor environment.

• The BH3 mimetic S1 induces autophagy through ER stress and disruption of Bcl-2/Beclin 1 interaction in human glioma U251 cells.

  Authors: Jia-Teng Zhong, Ye Xu, Hao-Wei Yi, Jing Su, Hui-Mei Yu, Xi-Yan Xiang, Xiao-Ning Li, Zhi-Chao Zhang, Lian-Kun Sun

  Cancer letters.

  Previous results showed that a novel BH3 mimetic S1 could induce cell death in a wide range of cancer types in vitro through Bax/Bak-dependent apoptosis. We demonstrated that in addition toPrevious results showed that a novel BH3 mimetic S1 could induce cell death in a wide range of cancer types in vitro through Bax/Bak-dependent apoptosis. We demonstrated that in addition to mitochondrial pathway apoptosis, endoplasmic reticulum (ER) stress-associated apoptosis was also induced by S1. Moreover, S1 can induce autophagy in U251 cells, which may occur through ER stress and disruption of the association of Bcl-2 and Beclin 1. Inhibition of autophagy by the autophagic inhibitors 3-methyladenine (3-MA) or chloroquine (CQ) increased S1-induced apoptosis. In conclusion, autophagy plays an important role in S1-induced U251 cell death.

• MicroRNA-19a and -19b regulate cervical carcinoma cell proliferation and invasion by targeting CUL5.

  Authors: Xue-Mei Xu, Xiao-Bo Wang, Miao-Miao Chen, Tao Liu, Yi-Xuan Li, Wei-Hua Jia, Min Liu, Xin Li, Hua Tang

  Cancer letters.

  MicroRNAs (miRNAs) play a key role in the regulation of gene expression. In this study, we demonstrate that microRNA-19a and -19b (miR-19a/b) are highly expressed in human cervical cancer cells andMicroRNAs (miRNAs) play a key role in the regulation of gene expression. In this study, we demonstrate that microRNA-19a and -19b (miR-19a/b) are highly expressed in human cervical cancer cells and are involved in maintaining the malignant phenotypes of HeLa and C33A cells. Up-regulation of miR-19a and miR-19b promoted cell growth and invasion, whereas knockdown of miR-19a and miR-19b yielded the reverse phenotype. CUL5 was identified as a novel target gene of both miR-19a and miR-19b. CUL5 ectopic over-expression without its 3' untranslated region (UTR) abolished the effect of miR-19a/b on HeLa and C33A cell proliferation and invasion. These results indicated that miR-19a/b directly and negatively regulate CUL5 expression in cervical cancer cells, highlighting the importance of miR-19a and miR-19b and their target genes in tumorigenesis.

• CYP1B1 and hormone-induced cancer.

  Authors: Ketan Gajjar, Pierre L Martin-Hirsch, Francis L Martin

  Cancer letters.

  Cancers in hormone-responsive tissues (e.g., breast, ovary, endometrial, prostate) occur at high incidence rates worldwide. However, their genetic basis remains poorly understood. Studies to dateCancers in hormone-responsive tissues (e.g., breast, ovary, endometrial, prostate) occur at high incidence rates worldwide. However, their genetic basis remains poorly understood. Studies to date suggest that endogenous/exogenous oestrogen and environmental carcinogens may play a role in development and/or progression of hormone-induced cancers via oxidative oestrogen metabolism. Cytochrome P450 1B1 is a key enzyme in the oestrogen metabolism pathway, giving rise to hydroxylation and conjugation. Although CYP1B1 is expressed in many cancers, particularly high levels of expression are observed in oestrogen-mediated disease. CYP1B1 is more readily found in tumour tissue compared to normal. Given the role of CYP1B1 in pro-carcinogen and oestrogen metabolism, polymorphisms in CYP1B1 could result in modifications in the enzyme activity and subsequently lead to hormone-mediated carcinogenesis. CYP1B1 may also be involved in progression of the disease by altering the tissue response to hormones and clinical response to chemotherapy. The exact mechanism behind these events is complex and unclear. Only a few functional single nucleotide polymorphisms of CYP1B1 are known to result in amino acid substitutions and have been extensively investigated. Studies examining the contribution of different CYP1B1 alleles to hormone-mediated cancer risks are inconsistent. The main focus of this review is to appraise the available studies linking the pathogenesis of the hormone-induced cancers to various CYP1B1 polymorphisms. Additionally, we explore the role of a neuronal protein, γ-synuclein, in CYP1B1-mediated pathogenesis.

• Smac: Its role in apoptosis induction and use in lung cancer diagnosis and treatment.

  Authors: Sida Qin, Chengcheng Yang, Shuo Li, Chongwen Xu, Yang Zhao, Hong Ren

  Cancer letters. 318(1):9-13.

  Apoptosis is a conserved and regulated cell suicide process, the malfunction of which is closely linked with carcinogenesis. Caspases control the induction of apoptosis through an enzymatic cascadeApoptosis is a conserved and regulated cell suicide process, the malfunction of which is closely linked with carcinogenesis. Caspases control the induction of apoptosis through an enzymatic cascade that can be activated by both the mitochondrial and death receptor pathways. Smac is a mitochondrial protein that interacts with Inhibitor of Apoptosis Proteins (IAPs) and, upon apoptotic stimuli, is released into the cytoplasm to inhibit the capase-binding activity of IAPs. Smac plays key roles in both the diagnosis and treatment of cancer, especially lung cancer. Our review will focus on the roles of Smac in lung carcinogenesis and cancer progression and its relevance in lung cancer treatment.

• Live-attenuated measles virus vaccine confers cell contact loss and apoptosis of ovarian cancer cells via ROS-induced silencing of E-cadherin by methylation.

  Authors: Shengtao Zhou, Yuhua Li, Fuqiang Huang, Boya Zhang, Tao Yi, Zhengyu Li, Hong Luo, Xiang He, Qian Zhong, Ce Bian, Xiaojuan Lin, Xiaorong Qi, Ping Liu, Canhua Huang, Xia Zhao, Yuquan Wei

  Cancer letters. 318(1):14-25.

  Herein we present a novel molecular mechanism of the antitumor effects of live-attenuated measles virus (MV) vaccine in ovarian cancer. Using a 2-DE/MS-based comparative proteomics strategy, weHerein we present a novel molecular mechanism of the antitumor effects of live-attenuated measles virus (MV) vaccine in ovarian cancer. Using a 2-DE/MS-based comparative proteomics strategy, we identified 17 proteins differentially expressed in live-attenuated MV vaccine-treated SKOV-3 ovarian cancer cells, including oxidative stress-associated enzymes and cell contact-related proteins, which indicated that live-attenuated MV vaccine could induce aberrant ROS activation. It further mediated epigenetic silencing of E-cadherin via upregulating DNMT3a that conferred both cell-cell and cell-matrix contact loss and apoptosis of ovarian cancer cells. This process could be reversed through ROS inhibition. Our study lays the theoretical foundation for the clinical application of live-attenuated MV vaccine as a potential oncotherapeutic agent for ovarian cancer treatment.

• MicroRNAs and cancer stem cells: Therapeutic approaches and future perspectives.

  Authors: J A Leal, M E Lleonart

  Cancer letters.

  Cancer stem cells (CSCs) are a sub-population of cancer cells that possess characteristics associated with normal stem cells but with the peculiarity that they are tumorigenic. This property allowsCancer stem cells (CSCs) are a sub-population of cancer cells that possess characteristics associated with normal stem cells but with the peculiarity that they are tumorigenic. This property allows them to persist in the tumour population, causing relapse and metastasis by giving rise to new tumours. Accordingly, if the CSCs were eliminated, then the tumour would simply regress due to differentiation and cell death. By selectively targeting CSCs, it may be possible to treat patients with aggressive, non-resectable tumours and prevent the tumour from metastasising. MicroRNAs are involved in all biological processes, and several studies have demonstrated their function in human tumourigenesis. Importantly, microRNAs have been implicated in the regulation of stem cells and CSCs. The most important concept to emerge with regard to CSC therapy is still controversial because a number of signalling pathways unique to normal stem cells may also be operating in CSCs, and these offer new targets for therapy. This article reviews how the modulation of microRNAs may revert tumour proliferation in vivo and in vitro and how this approach could be transferred to the clinic. Although the delivery of therapeutic microRNAs to target cells is a challenge that still needs to be overcome, microRNAs offer the advantage that they are small molecules that can be easily transported by body fluids, which makes them good candidates for cancer therapy.

• Breast cancer stem cells: obstacles to therapy.

  Authors: Matthew Smalley, Luke Piggott, Richard Clarkson

  Cancer letters.

  Only a fraction of the cells in a breast tumour are able to seed new tumour growth. These so-called breast cancer stem cells (bCSCs) are characterized by a number of discrete functional properties,Only a fraction of the cells in a breast tumour are able to seed new tumour growth. These so-called breast cancer stem cells (bCSCs) are characterized by a number of discrete functional properties, some of which impact on therapeutic strategies aimed at eliminating these cells from tumours. Here we discuss how recent experimental evidence indicates that phenotypic plasticity is a central feature of tumour cell heterogeneity and drug resistance, traits that must be overcome in order to efficiently target bCSCs as a therapy for breast cancer. We propose that a better understanding of this fundamental property of breast cancer stem cells, over and above their identification in tumours, is a priority for improvement of patient survival.

• Photodynamic therapy-mediated DC immunotherapy is highly effective for the inhibition of established solid tumors.

  Authors: Nam-Chul Jung, Hee Jung Kim, Mi-Sun Kang, Jun-Ho Lee, Jie-Young Song, Han Geuk Seo, Yong-Soo Bae, Dae-Seog Lim

  Cancer letters.

  Dendritic cell (DC)-mediated immunotherapy has not been as effective as expected for most solid tumors. This study demonstrates immune responses against solid tumors mediated by DCs charged withDendritic cell (DC)-mediated immunotherapy has not been as effective as expected for most solid tumors. This study demonstrates immune responses against solid tumors mediated by DCs charged with photodynamic therapy (PDT)-induced tumor lysates, which contain the heat shock protein (HSP) 70. PDT tumor lysate-pulsed DC (PDT-DC) inhibited the growth of mammary EMT6 tumors to a greater extent than freeze/thawed tumor lysate-pulsed DC (FT-DC) or PDT tumor lysates. PDT-DC also showed significant anti-tumor effects against fully-established (i.e., late-stage) solid tumors. Taken together, these results suggest that PDT-DC vaccination is more effective than conventional DC therapy for the treatment of cancers.

• Second-Generation Tyrosine Kinase Inhibitors Reduce Telomerase Activity in K562 Cells.

  Authors: Saar Shapira, Galit Granot, Rahav Mor-Tzuntz, Pia Raanani, Orit Uziel, Meir Lahav, Ofer Shpilberg

  Cancer letters.

  In this study we present the effects of nilotinib and dasatinib on telomerase activity and regulation. Nilotinib and dasatinib strongly reduced telomerase activity in BCR-ABL-positive (K562) andIn this study we present the effects of nilotinib and dasatinib on telomerase activity and regulation. Nilotinib and dasatinib strongly reduced telomerase activity in BCR-ABL-positive (K562) and BCR-ABL-negative (HL60) cells, demonstrating that their effect on telomerase activity is uncoupled from their effect on BCR-ABL. Nilotinib and dasatinib caused a substantial decrease in hTERT mRNA expression. Phospho-Sp1 regulates hTERT transcription. We detected a considerable decrease in Sp1 nuclear expression and binding to the hTERT promoter following exposure to the drugs. We also detected a reduction in Map kinase, known to phosphorylate Sp1. Telomerase is also activated and translocated to the nucleus when phosphorylated by AKT. We detected a decrease in phospho-AKT and a reduction in the nuclear expression of hTERT following exposure to nilotinib and dasatinib. In conclusion, we provide evidence for transcriptional and post-translational inhibition of telomerase by nilotinib and dasatinib which is not necessarily mediated via known targets of these tyrosine kinase inhibitors.

• Functional characteristics of mesenchymal stem cells derived from bone marrow of patients with myelodysplastic syndromes.

  Authors: Zhi-Gang Zhao, Wen Xu, Hai-Peng Yu, Bing-Ling Fang, Shu-Hong Wu, Fang Li, Wei-Min Li, Qiu-Bai Li, Zhi-Chao Chen, Ping Zou

  Cancer letters. 317(2):136-43.

  Mesenchymal stem cells (MSCs) have emerged as excellent candidates for clinical application because of their capabilities of immunomodulatory and supporting hematopoiesis. Nevertheless, it is unclearMesenchymal stem cells (MSCs) have emerged as excellent candidates for clinical application because of their capabilities of immunomodulatory and supporting hematopoiesis. Nevertheless, it is unclear whether the characteristics of MSCs are altered in diseased states. In this study, we obtained and expanded MSCs from bone marrow of patients with myelodysplastic syndromes (MDS). Our results showed that MSCs derived from MDS (MDS-MSCs) were similar to normal adult bone marrow derived MSCs in morphology, growth property, surface epitopes, and differentiation ability in vitro. In addition, MDS-MSCs had normal karyotype and ultrastructure. However, MDS-MSCs appeared to be impaired in immunomodulatory and supporting hematopoiesis function. Although, MDS-MSCs could express hematopoietic cytokines and support hematopoiesis in long term culture, Real time quantitative polymerase chain reaction showed that the expression of hematopoietic cytokines in MDS-MSCs was much lower than that of normal adult derived MSCs. Moreover, MDS-MSCs showed reduced hematopoiesis support function, as compared to their normal counterparts. Lastly, the capacity of MDS-MSCs to inhibit T lymphocyte activation and proliferation was impaired in vitro. These results indicate that MDS-MSCs have impaired immunomodulatory and hematopoiesis support functions, suggesting their critical role in the pathogenesis of MDS.

• Epigenetic Biomarkers in Lung Cancer.

  Authors: Triantafillos Liloglou, Naiara G Bediaga, Benjamin Brown, John K Field, Michael Pa Davies

  Cancer letters.

  Lung cancer mortality is strongly associated with the predominant diagnosis of late stage lesions that hampers effective therapy. Molecular biomarkers for early lung cancer detection is an unmetLung cancer mortality is strongly associated with the predominant diagnosis of late stage lesions that hampers effective therapy. Molecular biomarkers for early lung cancer detection is an unmet public health need and the lung cancer research community worldwide is putting a lot of effort to utilise major lung cancer population programmes in order to develop such molecular tools. The study of cancer epigenetics in the last decade has radically altered our views in cancer pathogenesis, providing new insights in biomarker development for risk assessment, early detection and therapeutic stratification. DNA methylation and miRNAs have rapidly emerged as potential biomarkers in body fluids showing promise to assist the clinical management of lung cancer. These new developments are exemplified in this review, demonstrating the huge potential of clinical cancer epigenetics, but also critically discussing the necessary validation steps to bring epigenetic biomarkers towards clinical implementation and the weaknesses of current biomarker studies.

• SV40 T/t-common polypeptide enhances the sensitivity of HER2-overexpressing human cancer cells to anticancer drugs cisplatin and doxorubicin.

  Authors: Shu-Ping Hsueh, Jia-Ling Du, Wen-Bin Hsu, Chung-An Fang, Hsuan Liu, Won-Bo Wang

  Cancer letters.

  HER2-overexpressing cancer cells are resistant to cisplatin (CDDP) and doxorubicin (DXR). Here we report that SV40 T/t-common polypeptide could specifically sensitize HER2-overexpressing cancer cellsHER2-overexpressing cancer cells are resistant to cisplatin (CDDP) and doxorubicin (DXR). Here we report that SV40 T/t-common polypeptide could specifically sensitize HER2-overexpressing cancer cells to CDDP and DXR and specifically enhance CDDP- or DXR-induced apoptosis in these cells. This activity of T/t-common may be attributed to its ability to inhibit Bcl-2 and Bcl-XL and to suppress ERK activity in CDDP- or DXR-treated HER2-overexpressing cancer cells. T/t-common could enhance the antitumor activity of DXR on HER2-overexpressing ovarian tumor in NOD/SCID mice, suggesting that combination therapy using T/t-common and chemotherapeutic agents may provide a new approach for treating HER2-overexpressing cancers.

• Regulation of Intestinal Cancer Stem Cells.

  Authors: Neil Ashley

  Cancer letters.

  Colorectal tumours harbour a sub-population of cells with stem like properties termed 'cancer stem cells', which are believed to ultimately drive cancer growth. This review discusses recent advancesColorectal tumours harbour a sub-population of cells with stem like properties termed 'cancer stem cells', which are believed to ultimately drive cancer growth. This review discusses recent advances in our understanding of both normal and cancer intestinal stem cells, with emphasis on similarities and differences. Specifically we discuss the role of the Wnt, Notch and BMP pathways and their roles in both stem cell proliferation and differentiation. Furthermore we discuss the emerging role of microRNA and the influence of environmental factors such as myofibroblasts and hypoxia on cancer stem cell regulation.

• Estrogen Receptor Positive Breast Cancer Identified by 95-Gene Classifier as at High Risk for Relapse Shows Better Response to Neoadjuvant Chemotherapy.

  Authors: Ryo Tsunashima, Yasuto Naoi, Kazuki Kishi, Yosuke Baba, Atsushi Shimomura, Naomi Maruyama, Takahiro Nakayama, Kenzo Shimazu, Seung Jin Kim, Yasuhiro Tamaki, Shinzaburo Noguchi

  Cancer letters.

  A 95-gene classifier (95-GC) recently developed by us can predict the risk of relapse for ER-positive and node-negative breast cancer patients with high accuracy. This study investigated associationA 95-gene classifier (95-GC) recently developed by us can predict the risk of relapse for ER-positive and node-negative breast cancer patients with high accuracy. This study investigated association of risk classification by 95-GC with response to neoadjuvant chemotherapy (NAC). Tumor biopsy samples obtained preoperatively from 72 patients with ER-positive breast cancer were classified by 95-GC into high-risk and low-risk for relapse. Pathological complete response (pCR) rate was numerically higher for high-risk (15.8%) than low-risk patients (8.8%) although the difference was not statistically significant. Pathological response evaluated in terms of the pathological partial response (pPR) rate (loss of tumor cells in more than two-thirds of the primary tumor) showed a significant association (P = 0.005) between the high-risk patients and a high pPR rate. Besides, external validation study using the public data base (GSE25066) showed that the pCR rate (16.4%) for high-risk patients (n=128) was significantly (P = 0.003) higher than for low-risk patients (5.7%) (n=159). These results demonstrate that the high-risk patients for relapse show a higher sensitivity to chemotherapy and thus are likely to benefit more from adjuvant chemotherapy.

• Oxidatively generated complex DNA damage: tandem and clustered lesions.

  Authors: Jean Cadet, Jean-Luc Ravanat, Marisa Taverna-Porro, Hervé Menoni, Dimitar Angelov

  Cancer letters.

  There is an increasing interest for oxidatively generated complex lesions that are potentially more detrimental than single oxidized nucleobases. In this survey, the recently available information onThere is an increasing interest for oxidatively generated complex lesions that are potentially more detrimental than single oxidized nucleobases. In this survey, the recently available information on the formation and processing of several classes of complex DNA damage formed upon one radical hit including mostly hydroxyl radical and one-electron oxidants is critically reviewed. The modifications include tandem base lesions, DNA-protein cross-links and intrastrand (purine 5',8-cyclonucleosides, adjacent base cross-links) and interstrand cross-links. Information is also provided on clustered lesions produced essentially by exposure of cells to ionizing radiation and high energetic heavy ions through the involvement of multiple radical events that induce several lesions DNA in a close spatial vicinity. These consist mainly of double strand breaks (DSBs) and non-DSB clustered lesions that are referred as to oxidatively generated clustered DNA lesions (OCDLs).

• Blockade of Sox4 mediated DNA Repair by SPARC Enhances Radioresponse in Medulloblastoma.

  Authors: Chandramu Chetty, Ranadheer Dontula, Meena Gujrati, Dzung H Dinh, Sajani S Lakka

  Cancer letters.

  SPARC is a matricellular glycoprotein and a putative radioresistance-reversal-gene. We therefore explored the possibility of SPARC expression on medulloblastoma radiosensitivity in vitro and in vivo.SPARC is a matricellular glycoprotein and a putative radioresistance-reversal-gene. We therefore explored the possibility of SPARC expression on medulloblastoma radiosensitivity in vitro and in vivo. The combined treatment of the SPARC and irradiation resulted in increased cell death when compared to cells treated with irradiation alone in vitro and in vivo. SPARC expression prior to irradiation suppressed checkpoints-1,-2 and p53 phosphorylation and DNA repair gene XRCC1. We also demonstrate that SPARC expression suppressed irradiation induced SOX-4 mediated DNA repair. These results provide evidence of the anti-tumor effect of combining SPARC with irradiation as a new therapeutic strategy for the treatment of medulloblastoma.

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