http://www.biomedcentral.com/bmccancer/ The latest research articles published by BMC Cancer 2009-12-04T00:00:00Z This is an RSS newsfeed from BioMed Central It is intended to be used with an RSS reader. For more information about RSS newsfeeds from BioMed Central, visit http://www.biomedcentral.com/info/about/rss/ Background: Retinoid Receptors are involved in development and cell homeostasis. Alterations of their expressions have been observed in lung cancer. However, retinoid chemoprevention trials in populations at risk to develop such tumors have failed. Therefore, the pertinence of new clinical trials using second generation retinoid requires prior better understanding of retinoid signalling. This is our aim when validating extensively research tools, focused on Retinoic Acid Receptor beta, whose major role in lung cancer is documented. Methods: Biocomputing was used to assess the genomic organization of RAR beta. Its putative RAR-beta1' promoter features were investigated experimentally. Specific measures realized, with qRT-PCR Syber Green assays and a triplex of Taqman probes, were extensively validated to establish Retinoid Receptors mRNAs reference values for in vivo normal human bronchial cells, lung tumors and cell lines. Finally, a pan-RAR-beta antibody was generated and extensively validated by western-blot and immunoprecipitation. Results: No promoter-like activity was found for RAR-beta1'. RAR-beta2 mRNAs increase signs the normal differentiation of the human bronchial epithelium while a decrease is observed in most lung cancer cell lines. Accordingly, it is also, along with RXR beta, down-regulated in lung tumors. When using nuclear extracts of BEAS-2B and normal lung cells, only the RAR-beta2 long protein isoform was recognized by our antibody. Conclusions: Rigorous samples processing and extensive biocomputing, were the key factors for this study. mRNA reference values and validated tools can now be used to advance researches on retinoid signalling in the lung. http://www.biomedcentral.com/1471-2407/9/423 Stephane Poulain Stephanie Lacomme Shyue-Fang Battaglia-Hsu Stanislas du Manoir Lydia Brochin Jean-Michel Vignaud Nadine Martinet BMC Cancer 2009, 9:423 2009-12-04T00:00:00Z doi:10.1186/1471-2407-9-423 BMC Cancer 1471-2407 9 423 2009-12-04T00:00:00Z PDF Background: Neuroblastoma is a pediatric tumor of neural crest cells that is clinically characterized by its variable evolution, from spontaneous regression to malignancy. Despite many advances in neuroblastoma research, 60% of neuroblastoma, which are essentially metastatic cases, are associated with poor clinical outcome due to the lack of effectiveness of current therapeutic strategies. Membrane-type 1 matrix metalloproteinase (MT1-MMP, MMP-14), an enzyme involved in several steps in tumor progression, has previously been shown to be associated with poor clinical outcome for neuroblastoma. Based on our recent demonstration that MT1-MMP phosphorylation is involved in the growth of fibrosarcoma tumors, we examined the potential role of phosphorylated MT1-MMP in neuroblastoma progression. Methods: Tyrosine phosphorylated MT1-MMP was immunostained on tissue microarray samples from 55 patients with neuroblastoma detected by mass screening (known to be predominantly associated with favourable outcome), and from 234 patients with standard diagnosed neuroblastoma. In addition, the effects of a non phosphorylable version of MT1-MMP on neuroblastoma cell migration and proliferation were investigated within three-dimensional collagen matrices. Results: Although there is no correlation between the extent of tyrosine phosphorylation of MT1-MMP (pMT1-MMP) and MYCN amplification or clinical stage, we observed greater phosphorylation of pMT1-MMP in standard neuroblastoma, while it is less evident in neuroblastoma from mass screening samples (P = 0.0006) or in neuroblastoma samples from patients younger than one year (P = 0.0002). In vitro experiments showed that overexpression of a non-phosphorylable version of MT1-MMP reduced MT1-MMP-mediated neuroblastoma cell migration and proliferation within a three-dimensional type I collagen matrix, suggesting a role for the phosphorylated enzyme in the invasive properties of neuroblastoma cells. Conclusions: Overall, these results suggest that tyrosine phosphorylated MT1-MMP plays an important role in neuroblastoma progression and that its expression is preferentially observed in tumor specimens from neuroblastoma patients showing poor clinical outcome. http://www.biomedcentral.com/1471-2407/9/422 Carine Nyalendo Herve Sartelet Stephane Barrette Shigeru Ohta Denis Gingras Richard Beliveau BMC Cancer 2009, 9:422 2009-12-04T00:00:00Z doi:10.1186/1471-2407-9-422 BMC Cancer 1471-2407 9 422 2009-12-04T00:00:00Z PDF Background: Along with the development of new cancer therapeutics, more effective tools for the estimation of response to therapy and prediction of disease progression are required for the better management of inoperable cancer patients. Methods: We studied 134 newly diagnosed and primarily untreated advanced non-small cell lung cancer patients and 100 controls. Forty two patients received platinum-based chemotherapy. Plasma VEGF levels were quantified in all samples at baseline and also before second and third chemotherapy cycle in 42 patients and correlated with response to therapy as assessed by computed tomography after the third chemotherapy cycle. Results: We observed that, patients who went into remission had significantly lower baseline VEGF levels before second and third cycles of chemotherapy when compared with patients with no change and progression. Plasma VEGF levels showed a greater decrease from cycle 1 to 2 and from cycle 1 to 3 in patients who showed remission in comparison to those with no change or progression. Plasma VEGF levels before the second cycle detected poor response to therapy with a sensitivity and specificity of 76.9% and 75.0%, respectively (area under the ROC curve = 0.724). Early prediction of disease progression was achieved with a sensitivity and specificity of 71.4% for plasma VEGF before cycle 2 (area under the ROC curve = 0.805). The kinetics of VEGF form cycle 1 to 2 and cycle 1 to 3 also gave significant information for predicting disease progression as well as insufficient therapy response. Conclusions: Monitoring of plasma VEGF levels during the course of first-line chemotherapy could identify patients who are likely to have insufficient response to therapy and disease progression at an early stage. This may help in individualizing treatment and could lead to better management of the advanced stage lung cancer. http://www.biomedcentral.com/1471-2407/9/421 Sachin Kumar Randeep Guleria Vikas Singh Alok Bharti Anant Mohan Bhudev Das BMC Cancer 2009, 9:421 2009-12-03T00:00:00Z doi:10.1186/1471-2407-9-421 BMC Cancer 1471-2407 9 421 2009-12-03T00:00:00Z PDF Background: Although postoperative chemotherapy is widely accepted as the standard modality for Dukes' stage C or earlier stage colorectal cancer (CRC) patients, biomarkers to predict those who may benefit from the therapy have not been identified. Previous in vitro and clinical investigations reported that CRC patients with wild-type p53 gene (TP53)-tumors benefit from 5-fluorouracil (5-FU) based chemotherapy, while those with mutated TP53-tumors do not. However, these studies evaluated the mutation-status of TP53 by immunohistochemistry with or without single-strand conformation polymorphism, and the mutation frequency was different from study to study. In addition, the polymorphic status at p53 codon 72, which results in arginine or proline residues (R72P) and is thought to influence the function of the protein significantly, was not examined. Methods: To evaluate the significance of the TP53 mutation as a molecular marker to predict the prognosis of CRC patients, especially those who received postoperative chemotherapy, we examined the mutation by direct sequencing from fresh CRC tumors and evaluated the R72P polymorphism of the mutated TP53 by a combined mutant allele- and polymorphic allele-specific polymerase chain reaction (PCR). Results: The TP53 mutation occurred in 147 (70%) of 211 Japanese CRC tumors. The mutation was observed in 93 (63%) tumors on the R72 allele and in 54 (37%) tumors on the P72 allele. Although the alterations to TP53 have no prognostic significance for CRC patients overall, we found that Dukes' stage C CRC patients who did not receive postoperative chemotherapy and carried the mutated TP53-R72 showed significantly longer survival times than those with the mutated TP53-P72 when evaluated by overall survival (p=0.012). Conclusions: Using a combined mutant allele- and polymorphic allele-specific PCR, we defined the codon 72 polymorphic status of the TP53 mutated allele in Japanese CRC patients. We raised a possibility that Dukes' stage C colorectal cancer patients with tumors carrying TP53 mutation, especially the P72 allele, benefited from 5-FU based postoperative chemotherapy. http://www.biomedcentral.com/1471-2407/9/420 Ten-i Godai Tetsuji Suda Nobuhiro Sugano Kazuhito Tsuchida Manabu Shiozawa Hironobu Sekiguchi Akiko Sekiyama Mitsuyo Yoshihara Shoichi Matsukuma Yuji Sakuma Eiju Tsuchiya Yoichi Kameda Makoto Akaike Yohei Miyagi BMC Cancer 2009, 9:420 2009-12-02T00:00:00Z doi:10.1186/1471-2407-9-420 BMC Cancer 1471-2407 9 420 2009-12-02T00:00:00Z PDF Background: Androgen deprivation therapy leads to a number of adverse effects including deterioration of the musculoskeletal system and increased risk factors for cardiovascular and metabolic complications. The purpose of this study is to determine the effects, efficacy, retention and compliance of a physical exercise intervention in a large established cohort of prostate cancer patients from the Randomised Androgen Deprivation and Radiotherapy (RADAR) study. Specifically, we aim to compare short- and long-term effects of a prostate cancer-specific supervised exercise program to a standard public health physical activity strategy utilizing printed resources on cardiovascular and metabolic risk factors. Our primary outcomes are cardiorespiratory capacity, abdominal obesity, and lipid and glycemic control, while secondary outcomes include self-reported physical activity, quality of life and psychological distress. Methods: Multi-site randomized controlled trial of 370 men from the RADAR study cohort undergoing treatment or previously treated for prostate cancer involving androgen deprivation therapy in the cities of Perth and Newcastle (Australia), and Wellington (New Zealand). Participants will be randomized to (1) supervised resistance/aerobic exercise or (2) printed material comprising general physical activity recommendations. Participants will then undergo progressive training for 6 months. Measurements for primary and secondary endpoints will take place at baseline, 6 months (end of intervention), and at 6 months follow-up.DiscussionThis study uses a large existent cohort of patients and will generate valuable information as to the continuing effects of exercise specifically targeting cardiovascular function and disease risk, insulin metabolism, abdominal obesity, physical function, quality of life and psychological distress. We expect dissemination of the knowledge gained from this project to reduce risk factors for the development of co-morbid diseases commonly associated with androgen deprivation therapy such as cardiovascular disease, obesity, metabolic disease and diabetes, as well as improvements in physical and functional ability, and quality of life.Trial Registration: ACTRN12609000729224 http://www.biomedcentral.com/1471-2407/9/419 Daniel Galvao Nigel Spry Dennis Taaffe James Denham David Joseph David Lamb Greg Levin Gillian Duchesne Robert Newton BMC Cancer 2009, 9:419 2009-12-02T00:00:00Z doi:10.1186/1471-2407-9-419 BMC Cancer 1471-2407 9 419 2009-12-02T00:00:00Z PDF Background: : Despite well-studied tumor hypoxia in laboratory, little is known about the association with other pathophysiological events in the clinical view. We investigated the prognostic value of hypoxia-inducible factor-1 alpha (HIF-1alpha) in hepatocellular carcinoma (HCC), and its correlations with inflammation, angiogenesis and MYC oncogene.MethodS: In a random series of 110 HCC patients, the mRNA of HIF-1alpha, inflammation related factors (COX-2, MMP7, MMP9), angiogenesis related factors (VEGF, PDGFRA) and MYC in tumor tissue were detected by real-time RT-PCR and HIF-1alpha protein was assessed by immunohistochemistry. The correlations between HIF-1alpha mRNA and the factors mentioned previously, the relationship between HIF-1alpha and clinicopathologic features, and the prognostic value were analyzed. Results: : The expression of both HIF-1alpha mRNA and protein in HCC were independent prognostic factors for overall survival (OS) (P=0.012 and P=0.021, respectively) and disease-free survival (DFS) (P=0.004 and P=0.007, respectively) as well. Besides, the high expression of HIF-1alpha mRNA and protein proposed an advanced BCLC stage and more incidence of vascular invasion. The mRNA of HIF-1alpha had significantly positive correlations to that of COX-2, PDGFRA, MMP7, MMP9, MYC, except VEGF. In addition to HIF-1alpha, COX-2 and PDGFRA were also independent prognosticators for OS (P=0.004 and P= 0.010, respectively) and DFS (P=0.010 and P= 0.038, respectively). Conclusions: : HIF-1alpha in HCC plays an important role in predicting patient outcome. It may influence HCC biological behaviors and affect the tumor inflammation, angiogenesis and act in concert with the oncogene MYC. Attaching importance to HIF-1alpha in HCC may improve the prognostic and therapeutic technique. http://www.biomedcentral.com/1471-2407/9/418 Chen-Xin Dai Qiang Gao Shuang-Jian Qiu Min-Jie Ju Ming-Yan Cai Yong-Feng Xu Jian Zhou Bo-Heng Zhang Jia Fan BMC Cancer 2009, 9:418 2009-12-01T00:00:00Z doi:10.1186/1471-2407-9-418 BMC Cancer 1471-2407 9 418 2009-12-01T00:00:00Z PDF Background: TEM1/endosialin is an emerging microvascular marker of tumor angiogenesis. We characterized the expression pattern of TEM1/endosialin in astrocytic and metastatic brain tumors and investigated its role as a therapeutic target in human endothelial cells and mouse xenograft models. Methods: In situ hybridization (ISH), immunohistochemistry (IH) and immunofluorescence (IF) were used to localize TEM1/endosialin expression in grade II-IV astrocytomas and metastatic brain tumors on tissue microarrays. Changes in TEM1/endosialin expression in response to pro-angiogenic conditions were assessed in human endothelial cells grown in vitro. Intracranial U87MG glioblastoma (GBM) xenografts were analyzed in nude TEM1/endosialin knockout (KO) and wildtype (WT) mice. Results: TEM1/endosialin was upregulated in primary and metastatic human brain tumors, where it localized primarily to the tumor vasculature and a subset of tumor stromal cells. Analysis of 275 arrayed grade II-IV astrocytomas demonstrated TEM1/endosialin expression in 79% of tumors. Robust TEM1/endosialin expression occurred in 31% of glioblastomas (grade IV astroctyomas). TEM1/endosialin expression was inversely correlated with patient age. TEM1/endosialin showed limited co-localization with CD31, alphaSMA and fibronectin in clinical specimens. In vitro, TEM1/endosialin was upregulated in human endothelial cells cultured in matrigel. Vascular Tem1/endosialin was induced in intracranial U87MG GBM xenografts grown in mice. Tem1/endosialin KO vs WT mice demonstrated equivalent survival and tumor growth when implanted with intracranial GBM xenografts, although Tem1/endosialin KO tumors were significantly more vascular than the WT counterparts. Conclusions: TEM1/endosialin was induced in the vasculature of high-grade brain tumors where its expression was inversely correlated with patient age. Although lack of TEM1/endosialin did not suppress growth of intracranial GBM xenografts, it did increase tumor vascularity. The cellular localization of TEM1/endosialin and its expression profile in primary and metastatic brain tumors support efforts to therapeutically target this protein, potentially via antibody mediated drug delivery strategies. http://www.biomedcentral.com/1471-2407/9/417 Eleanor Carson-Walter Bethany Winans Melissa Whiteman Yang Liu Sally Jarvela Hannu Haapasalo Betty Tyler David Huso Mahlon Johnson Kevin Walter BMC Cancer 2009, 9:417 2009-11-30T00:00:00Z doi:10.1186/1471-2407-9-417 BMC Cancer 1471-2407 9 417 2009-11-30T00:00:00Z PDF Background: Tumor-specific cytotoxic T cells and infiltrating lymphocytes are frequently found in tumor tissues in patients with nasopharyngeal carcinoma (NPC). Most patients with NPC, however, especially those with advanced stages, have a poor clinical prognosis despite conventional immunotherapy. The aim of this work was to examine the effect of indoleamine 2,3-dioxygenase (IDO), an immunosuppressive enzyme, on the lymphocyte function in NPC. Methods: The NPC cell line CNE2 was treated by interferon-gamma (IFNgamma) and the levels of IDO expression was analyzed by Western blotting and reverse phase high-performance liquid chromatography (HPLC). Lymphocytes from health human exposed to the milieu created by IDO-positive CNE2 cells and the lymphocyte cytotoxicity to target tumor cells was analyzed by standard lactate dehydrogenase (LDH) release assay. Additionally, expression of IDO was determined by Immunohistochemical assay in the tumor tissues form clinically evaluated NPC. Results: IDO expression was acutely induced in the NPC cell line CNE2 by low dose interferon-gamma (IFNgamma) or by co-incubation with activated lymphocytes. Exposure to the milieu created by IDO-positive CNE2 cells did not promote lymphocyte death, but lymphocyte cytotoxicity against target tumor cells was impaired. The suppression of lymphocyte cytotoxic function was fully restored when the conditioned medium was replaced by fresh medium for 24 h. In additionally, the IDO-positive cells were found scattered in the tumor tissues from patients with NPC. Conclusion: Altogether, these findings suggest that IDO-mediated immunosuppression may be involved in the tumor immune evasion, and that blocking IDO activity in tumor cells may help to re-establish an effective anti-tumor T cell response in NPC. http://www.biomedcentral.com/1471-2407/9/416 Peng Liu Bai-Lu Xie Shao-Hui Cai Yun-Wen He Ge Zhang Yan-Mei Yi Jun Du BMC Cancer 2009, 9:416 2009-11-30T00:00:00Z doi:10.1186/1471-2407-9-416 BMC Cancer 1471-2407 9 416 2009-11-30T00:00:00Z PDF Background: The induction of tumor cell invasion is an important step in tumor progression. Due to the cost and slowness of in-vivo invasion assays, there is need for quantitative in-vitro invasion assays that mimic as closely as possible the tumor environment and in which conditions can be rigorously controlled. Methods: We have established a novel asymmetric 3D in-vitro invasion assay by embedding a monolayer of tumor cells between two layers of collagen. The cells were then allowed to invade the upper and lower layers of collagen. To visualize invading cells the gels were sectioned perpendicular to the monolayer so that after seeding the monolayer appears as a thin line precisely defining the origin of invasion. The number of invading tumor cells, their proliferation rate, the distance they traverse and the direction of invasion could then be determined quantitatively. Results: The assay was used to compare the invasive properties of several tumor cell types and the results compare well with those obtained by previously described assays. Lysyl-oxidase like protein-2 (Loxl2) is a potent inducer of invasiveness. Using our assay we show for the first time that inhibition of endogenous Loxl2 expression in several types of tumor cells strongly inhibits their invasiveness. We also took advantage of the asymmetric nature of the assay in order to show that fibronectin enhances the invasiveness of breast cancer cells more potently than laminin. The asymmetric properties of the assay were also used to demonstrate that soluble factors derived from fibroblasts can preferentially attract invading breast cancer cells. Conclusions: Our assay displays several advantages over previous invasion assays as it is allows the quantitative analysis of directional invasive behavior of tumor cells in a 3D environment mimicking the tumor microenvironment. It should be particularly useful for the study of the effects of components of the tumor microenvironment on tumor cell invasiveness. http://www.biomedcentral.com/1471-2407/9/415 Vera Brekhman Gera Neufeld BMC Cancer 2009, 9:415 2009-11-30T00:00:00Z doi:10.1186/1471-2407-9-415 BMC Cancer 1471-2407 9 415 2009-11-30T00:00:00Z PDF Background: Broccoli is a Brassica vegetable that is believed to possess chemopreventive properties. Selenium also shows promise as an anticancer agent. Thus, selenium enrichment of broccoli has the potential to enhance the anticancer properties of broccoli sprouts.MethodSelenium-enriched broccoli sprouts were prepared using a sodium selenite solution. Their anticancer properties were evaluated in human prostate cancer cell lines and compared with those of a control broccoli sprout extract. Results: Selenium-enriched broccoli sprouts were superior to normal broccoli sprouts in inhibiting cell proliferation, decreasing prostate-specific antigen secretion, and inducing apoptosis of prostate cancer cells. Furthermore, selenium-enriched broccoli sprouts but, not normal broccoli sprouts, induced a downregulation of the survival Akt/mTOR pathway. Conclusion: Our results suggest that selenium-enriched broccoli sprouts could potentially be used as an alternative selenium source for prostate cancer prevention and therapy. http://www.biomedcentral.com/1471-2407/9/414 Rizky Abdulah Ahmad Faried Kenji Kobayashi Chiho Yamazaki Eka Suradji Kazuto Ito Kazuhiro Suzuki Masami Murakami Hiroyuki Kuwano Hiroshi Koyama BMC Cancer 2009, 9:414 2009-11-30T00:00:00Z doi:10.1186/1471-2407-9-414 BMC Cancer 1471-2407 9 414 2009-11-30T00:00:00Z PDF