Cancer Research (CANCER RES)

Publications in this journal

• Article: Enhanced effector responses in activated CD8+ T cells deficient in diacylglycerol kinases

  Riese MJ, Wang L-CS, Moon EK, Joshi RP, Ranganathan A, June CH, Koretzky GA, Albelda SM
  Cancer Research 04/2013;
• Article: Elevated ALCAM shedding in colorectal cancer correlates with poor patient outcome.

  Amanda G. Hansen, Tanner J. Freeman, Shanna A. Arnold, Alina Starchenko, Celestial R. Jones-Paris, Michael A. Gilger, Mary K. Washington, Kang-Hsien Fan, Yu Shyr, Robert D. Beauchamp, Andries Zijlstra
  Cancer Research 04/2013;
• Article: Comprehensive genetic characterization of apocrine lesions of the breast

  Costa LJ, Justino A, Gomes M, Alvarenga CA, Gerhard R, Vranic S, Gatalica Z, Machado JC, Schmitt F
  Cancer Research 04/2013;
• Article: Intestinal bacteria modify lymphoma penetrance in genetically susceptible mice via inflammation-mediated systemic host oxidative stress and leucocyte genotoxicity

  Lynn Yamamoto, Irene Maier, Angeline Dang, David Berry, Jared Liu, Paul Ruegger, Jiue-in Yang, Philip Soto, Laura Presley, Ramune Reliene, Aya Westbrook, Bo Wei, Alexander Loy, Christopher Chang, Jonathan Braun, James Borneman, and Robert Schiestl
  Cancer Research 02/2013;
• Article: Oncolytic Vaccinia Virus Disrupts Tumor-Associated Vasculature in Humans.

  Breitbach JC, Arulanandam R, De Silva N, Thorne SH, Patt R, Daneshmand M, Moon A, Ilkow C, Burke J, Hwang TH, Heo J, Cho M, Chen H, Angarita FA, Addison C, McCart JA, Bell JC, Kirn DH
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  ABSTRACT: Efforts to selectively target and disrupt established tumor vasculature have largely failed to date. We hypothesized that a vaccinia virus engineered to target cells with activation of the ras/MAPK signaling pathway (JX-594) could specifically infect and express transgenes (hGM-CSF, β-galactosidase) in tumor-associated vascular endothelial cells in humans. Efficient replication and transgene expression in normal human endothelial cells in vitro required either VEGF or FGF-2 stimulation. Intravenous infusion in mice resulted in virus replication in tumor-associated endothelial cells, disruption of tumor blood flow, and hypoxia within 48 hours; massive tumor necrosis ensued within 5 days. Normal vessels were not affected. In patients treated with intravenous JX-594 in a phase I clinical trial, we showed dose-dependent endothelial cell infection and transgene expression in tumor biopsies of diverse histologies. Finally, patients with advanced hepatocellular carcinoma, a hypervascular and VEGF-rich tumor type, were treated with JX-594 on phase II clinical trials. JX-594 treatment caused disruption of tumor perfusion as early as 5 days in both VEGF receptor inhibitor-naïve and -refractory patients. Toxicities to normal blood vessels or to wound healing were not evident clinically or on MRI scans. This platform technology opens up the possibility of multifunctional engineered vaccinia products that selectively target and infect tumor-associated endothelial cells, as well as cancer cells, resulting in transgene expression, vasculature disruption, and tumor destruction in humans systemically.
  Cancer Research 02/2013; 73(4):1-75.
• Article: Anti-CD20 antibody promotes cancer escape via enrichment of tumor-evoked regulatory B cells expressing low levels of CD20 and CD137L

  Bodogai M, Lee-Chang C, Wejksza K, Lai JP, Merino M, Wersto R, Gress RE, Hessdorffer C, Biragyn A
  Cancer Research 01/2013;
• Article: ING1 Expression Measured by AQUA can be an Independent Prognostic Marker in Breast Cancer

  S Thakur, A Klimowicz, B Pohorelic, M Dean, M Konno, P Bose, A Magliocco, K Riabowol
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  ABSTRACT: Background: Breast cancer accounts for around 45,000 cancer related deaths in North America per year. The high incidence of breast cancer observed in this region is most likely due to the availability of various screening programs used to detect breast cancer, which otherwise may never get diagnosed. There is an inverse relation between the cost of treatment and patient survival as the breast cancer progresses to higher grades. Therefore, screening and diagnosing breast cancers at earlier stages is needed which can improve patient survival. The INhibitor of Growth (ING) family of tumour suppressor proteins are implicated in diverse cellular processes including chromatin remodelling and apoptosis. ING proteins are stoichiometric members of histone acetyl transferase (HAT) and histone deacetylase (HDAC) complexes. Their expression is downregulated in several cancers, including breast carcinoma. Alternatively, ING function may be compromised by mislocalization to the cytoplasm. However, the association of expression of ING proteins and cancer specific survival has not been studied yet. In this study, we aimed to evaluate the prognostic significance of ING1 in breast cancer.
  Cancer Research 12/2012; 72(24):3.
• Article: ING1 Expression Measured by AQUA can be an Independent Prognostic Marker in Breast Cancer

  S Thakur, A Klimowicz, B Pohorelic, M Dean, M Konno, P Bose, A Magliocco, K Riabowol
  [show abstract] [hide abstract]
  ABSTRACT: Background: Breast cancer accounts for around 45,000 cancer related deaths in North America per year. The high incidence of breast cancer observed in this region is most likely due to the availability of various screening programs used to detect breast cancer, which otherwise may never get diagnosed. There is an inverse relation between the cost of treatment and patient survival as the breast cancer progresses to higher grades. Therefore, screening and diagnosing breast cancers at earlier stages is needed which can improve patient survival. The INhibitor of Growth (ING) family of tumour suppressor proteins are implicated in diverse cellular processes including chromatin remodelling and apoptosis. ING proteins are stoichiometric members of histone acetyl transferase (HAT) and histone deacetylase (HDAC) complexes. Their expression is downregulated in several cancers, including breast carcinoma. Alternatively, ING function may be compromised by mislocalization to the cytoplasm. However, the association of expression of ING proteins and cancer specific survival has not been studied yet. In this study, we aimed to evaluate the prognostic significance of ING1 in breast cancer. Patients and Methods: This study included 443 Breast Cancer patients diagnosed in Calgary, Canada from 1985–2000. Clinical data were obtained from the Alberta Cancer Registry and chart review. Tissue microarrays (TMAs) were assembled from triplicate cores of formalin-fixed paraffin-embedded tumour tissue. ING1 protein expression was quantified using fluorescent immunohistochemistry and automated quantitative analysis (AQUA) in normal breast epithelial cells and breast cancer samples. 5 year progression free survival (PFS) was analyzed using Kaplan-Meier plots and Cox proportional hazard modelling. Results: In our study, we found that ING1 expression is significantly downregulated in the breast cancer patient samples relative to normal breast epithelia. High or low ING1 cytoplasmic/nuclear (C/N) ratio results in poor 5 year PFS. Also, the low tumor/stromal (t/s) ratio of ING1 results in poor prognosis. In univariate analysis, t/s ING1 expression showed a negative correlation with tumor stage [p = 0.008]; tumor grade [p = 0.000]; nodal status [p = 0.000] and 5 year PFS [p = 0.004]. However, no correlation was observed with ER, PR or HER2 status. In multivariate analysis, t/s ING1 proved to be an independent and better prognostic marker [HR 0.582, p = 0.037] than HER2 [HR 2.230, p = 0.057]; Age at diagnosis [HR 2.010, p = 0.205] and tumor size [HR 1.471, p = 0.189]. Discussion and Conclusions: This is the first study to evaluate ING1 expression in breast cancer using the AQUA technique. ING1 expression high or low in the C/N ratio might disrupt the stoichiometry of chromatin-modifying complexes and hamper ING1s extra nuclear functions, leading to poor survival. The significantly improved survival observed in patients with high t/s ING1 expression further strengthens the role of ING1 as a tumor suppressor.
  Cancer Research 12/2012; 72(24):3.
• Article: CD40-mediated activation of chronic lymphocytic leukemia cells promotes their CD44-dependent adhesion to hyaluronan and restricts CCL21 induced motility. Girbl T, Hinterseer E, Grössinger EM, Asslaber D, Oberascher K, Weiss L, Hauser-Kronberger C, Neureiter D, Kerschbaum H, Naor D, Alon R, Greil R, Hartmann TN.

  Girbl T, Hinterseer E, Grössinger EM, Asslaber D, Oberascher K, Weiss L, Hauser-Kronberger C, Neureiter D, Kerschbaum H, Naor D, Alon R, Greil R, Hartmann TN
  Cancer Research 11/2012;
• Article: Concomitant targeting of tumor cells and induction of T cell response synergizes to effectively inhibit trastuzumab-resistant breast cancer

  Wang Q, Li SH, Wang H, Xiao Y, Sahin O, Brady SW, Li P, Ge H, Jaffee EM, Muller WJ, Hortobagyi GN, Yu D
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  ABSTRACT: Trastuzumab is an iconic rationally designed targeted therapy for HER2-positive breast cancers. However, the low response rate and development of resistance call for novel approaches for the treatment of patients. Here, we report that concurrent targeting of tumor cells and activation of T cells in the tumor microenvironment results in a synergistic inhibitory effect on tumor growth and overcomes resistance in two distinct PTEN-loss- mediated trastuzumab-resistant mammary tumor mouse models. In vivo combination treatment with HER2/Neu antibody and Akt inhibitor triciribine (TCN) effectively inhibited tumor growth in both models via inhibiting PI3K/AKT and MAPK signaling accompanied by increased T cell infiltration in the tumor microenvironment. We demonstrated that both CD8+ and CD4+ T cells were essential to the optimal anti-tumor effect of this combination treatment in an IFN-γ-dependent manner. Importantly, the anti-tumor activities of HER2/Neu antibody and TCN combination treatment were further improved when co-inhibitory receptor cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) was blocked to enhance the T cell response. Our data indicate that multi-targeted combinatorial therapies targeting tumor cells and concomitantly enhancing T-cell response in the tumor microenvironment could cooperate to exert maximal therapeutic activity suggesting a promising clinical strategy for treating trastuzumab-resistant breast cancers and other advanced malignancies.
  Cancer Research 07/2012;
• Article: Rhythmic regulation of ARF-MDM2 by ATF4 underlies circadian accumulation of p53 protein in malignant tumor cells.

  Michiko Hiroguchi, Satoru Koyanagi, Ahmed Mohsen Hamdan, Naoya Matsunaga, Shigehiro Ohdo
  Cancer Research 07/2012;
• Article: A new method for identifying a data-consistent self-reconfigurable predictive bio-network model of the cell cycle based on time series data and its application in cancer systems biology

  Michael A. Idowu, James Bown, Nikolai Zhelev
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  ABSTRACT: A new method for (re)constructing interaction networks using a limited number of time series data has been developed. This method may provide better opportunities for immediate identification of data-consistent models of biological systems. It may serve as an alternative or complementary approach to other existing data-driven strategies for modeling or mining time-evolutionary properties of complex biological processes based on the analysis of their time series data. We present some practically useful data-mining techniques for constructing self-reconfigurable predictive models of complex biological systems, which approximate their underlying processes. These parametric models, if well reverse-engineered, may help capture key features of data relevant for the purpose of interest. To demonstrate our network inference method, we focus on analyzing time series data of cdk2, cyclinA1, cyclinD1, cycinD2, cyclinD3, E2F1, p16 and p27 obtained from real experiments. The constructed predictive model of the cell-cycle is found to be data-consistent. This model approximates the underlying biological processes hidden in the data, and may help reveal or identify key processes that may govern G1-S phase progression. Given multiple sets of time series data from a cell line, where some sets represent control conditions and other intervention conditions, the method introduced here can help construct interaction networks for each of these data sets. To investigate areas of the signaling network most affected by the intervention, critical areas that have been identified in those networks could be compared to the effects of real perturbations. This may help inform future experimental design by targeting sensitive areas in the signaling network or avoiding resistant pathways.
  Cancer Research 04/2012; 72(8):4921.
• Article: Differences in the DDR enzymes activation kinetics between normal and cancer cells could be utilized to achieve targeted cellular sensitivity towards genotoxic agents

  Hilal S. Khalil, Hemanth Tummala, Tedd Hupp, Nikolai Zhelev
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  ABSTRACT: The DNA damage response (DDR) pathway is a complex signalling network that is activated when eukaryotic cells undergo DNA damage caused by exposure to genotoxic agents. Depending upon the type and scale of DNA damage, the DDR can either cause cell cycle arrest if the DNA lesions are repairable, or trigger apoptosis if the DNA lesions are beyond the repair capacity of the cell. A variety of enzymes take part in this complex signalling network that decides cellular fate after DNA damage, and is comprised of kinases, phosphatases and glycosylases. Here we explored the kinetics of activation of these key enzymes, the rates of their product formation and the interplay between them that impact the decision making process of the cell. We exposed normal (MCF10A, HaCat) and breast cancer cell lines (MCF7, MDA MB231, MDA MB468) to different combinations of radiomimetic drugs, UV radiation and enzyme inhibitors in a time and dose dependent manner and looked at the resulting enzyme activation rates of DDR kinases such as ATM, ATR, Chk1, Chk2, and DDR phosphatases PP2A and WIP1. We studied the effects of such enzymatic activation on their substrates P53, E2F1, BRCA1 and -H2AX and examined its outcome on cell survival. Firstly, we have identified key differences in enzyme activation kinetics that impacted the cell fate decision between normal and cancer cell lines. In addition we established treatment regimes based on those differences that bias the cell fate decision towards apoptosis in cancer cells and cell cycle arrest and repair of DNA in their normal counterparts. Thus, we have demonstrated a link between the rate of induction of different enzyme activities in the DDR pathway, the resulting product formation and cellular sensitivity to genotoxic agents. We have successfully used such information to devise a combinatorial drug treatment regime that is selective for cancer cells. Elucidation of the enzyme activation kinetics in a time and dose dependent manner of the proteins governing cell fate decision can be used to achieve targeted cellular selectivity and sensitivity with lesser side effects on normal cells.
  Cancer Research 04/2012; 72(8).
• Article: A quantitative integrated systems biology approach for modeling cell cycle pathways in normal and tumor cells

  Hemanth Tummala, Hilal S. Khalil, Katarzyna Goszcz, Maria Grazia Tupone, Vili Stoyanova, Ekaterina Nikolova, Vanio Mitev, Nikolai Zhelev
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  ABSTRACT: We have developed a novel biological system for quantitative analysis of biochemical pathways in normal and tumour human cells. The system is based on cells growing in tissue culture media where the concentrations of growth factors, hormones and other components of the media are precisely defined and continuously monitored. Quantitative immunoblotting and luminescence-based reporter assays are then used to measure the cellular concentration of key cell cycle regulatory proteins and their activity in real time in live cells. This technology resulted in accurate measurement of cellular concentration of a number of key cell cycle regulatory proteins such as Cyclins, CDKs and CDK inhibitors during the cell cycle. The data are being utilized in the development of a quantitative integrated systems biology approach to the cell cycle. The approach consists of a comprehensive network of the molecular interaction pathways regulating cell cycle in normal and tumor cells and a model which incorporates the activity of key molecular species in a single dynamical system which can be solved using genetic algorithms designed to match experimental data, both qualitative and quantitative, to the model kinetics. The model could be utilized for the development of new drug targets and would be capable of consistently measuring the effects of existing drugs (either single or in combination) and opens up a methodology for establishing the effectiveness of these drugs with clear implications for cost/benefit assessment. Major impact is expected on clinical research where the model can be a tool in determining intervention strategies in the molecular pathways concerned. Apart from the development of new drug targets the model will be capable of consistently measuring the effects of existing drugs (either single or in combination) and opens up a methodology for establishing the effectiveness of anti-cancer drugs.
  Cancer Research 03/2012; 72(8).