bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2865: The significance of Vitamin D deficiency and low grade pathogens in etiology of prostate cancer.
Authors: Oliver Tim R T D
Published: August 2014

Introduction. Estimations of sun exposure (but less so spot serum Vitamin D levels) correlate with risk of prostate cancer occurrence. This suggests that it is due to long term Vitamin D deficiency over 10-40 years as a possible explanation. This, via diminished macrophage function, could allow persistence of low grade pathogens to set up chronic inflammation that could lead to Proliferative Inflammatory Atrophy (PIA) of the prostate, now thought to be an important precursor of cancer. Despite multiple investigations of sexually transmitted infections, there has been no consistently associated organism. However recently infection with two low grade pathogenic organisms, teenage acne associated anaerobic bacterium Propionibacterium.acnes (PA) and protozoan Trichomonas vaginalis (TA), have shown a more consistent association with prostate cancer. This abstract reports the results of a systematic review of publications investigating the association of sun exposure and prostate cancer and of PA and T V with prostate cancer and considers how these observations could lead to improved specificity of PSA screening

Methods. Pubmed searches using terms prostate or prostatic, sunshine or UVB or Vitamin D and acne or PA or TA were performed and the abstracts reviewed and appropriate papers selected for review and data extraction

Results . Amongst 1134 abstracts investigating PC and Vitamin D were two systematic reviews that failed to produce a consistent association. In contrast four of four studies of an index of sun exposure involving 1568 patients (OR 0.75, 0.75, 0.59 & 0.89) and 6 of 7 geographic studies (0.32, 0.38, 0.44, 0.16, 0.52, 1.63 & 0.64) demonstrated an association of high UVB exposure with reduced PC risk. Four of five publications on PA and PC (1.7, 1.67, 2.17 & 0.67) and 2 of 3 publications on TV and PC (1.23, 1.43 & 0.83) from 205 papers reviewed showed consistent increase risk of PC associated with infection.

Conclusion. Lack of association with spot Vitamin D but clear association with index of sun exposure suggest that the association is due to reduced long term Vitamin D mediated non-specific macrophage surveillance that is involved against lowly pathogenic agents of which PA and TV could be lead organisms. Impact on PSA of elimination of these organisms could become an important strategy in future efforts of to improve the specificity of PSA screening and chemoprevention of PC

Citation Format: Tim R T D Oliver. The significance of Vitamin D deficiency and low grade pathogens in etiology of prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2865. doi:10.1158/1538-7445.AM2013-2865
Abstract 2872: Image analysis algorithms for whole-slide counting, regional assignment, and subtype classification of tumor-associated macrophages (TAMs).
Authors: Laffin Brian E. , Krueger Joseph , Salama Mohamed
Published: August 2014

Tumor-associated macrophages (TAMs) regulate cancer progression on multiple levels, including angiogenesis, treatment response, and metastasis. Additionally, multiple studies have demonstrated a significant association between clinical outcome and TAM abundance, M1 vs. M2 subtype, and intratumoral distribution into stromal or epithelial compartments. However, manual counting of TAMs and assignment into tumor stroma or epithelial nests is laborious, inaccurate, subjective, and does not provide a statistically optimal sample size. These pitfalls may be limiting its utility as a diagnostic tool or an endpoint in drug efficacy studies. Using tissue sections from human breast cancers as a model, we have developed image analysis algorithms for the rapid automated counting and compartmental assignment of total TAMs (CD68+) and TAMs of the more strongly tumor-promoting M2 subtype (CD163+). Using whole slide scanning and proprietary image analysis tools called Feature Analysis on Consectutive Tissue Sections (FACTS), we have developed an approach to not only tally but also map the location of CD68+ and CD163+ macrophages in serial tissue sections, align those sections, and provide information about regional distribution of these macrophages. These outcomes can also be aligned with other serial sections containing relevant biomarkers associated with macrophage infiltration such as hypoxia or angiongenesis, using our proprietary multivariate correlation analysis tool Multivariatemap. Additionally, we have begun investigations into the association of these regional macrophage densities with clinical outcome using patient data available for the model set. These approaches represent a powerful toolkit for elucidating significant quantitative associations between TAMs and tumor vasculature, hypoxia, or other relevant features or markers, for the determination of prognostic or drug efficacy endpoints.

Citation Format: Brian E. Laffin, Joseph Krueger, Mohamed Salama. Image analysis algorithms for whole-slide counting, regional assignment, and subtype classification of tumor-associated macrophages (TAMs). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2872. doi:10.1158/1538-7445.AM2013-2872
Abstract 2875: NF-κB signaling in myeloid cells limits urethane-induced lung tumorigenesis.
Authors: McLoed Allyson , Zaynagetdinov Rinat , Sherrill Taylor , Yull Fiona , Blackwell Timothy
Published: August 2014

The transcription factor Nuclear Factor κB (NF-κB) is a master regulator of inflammation, and its activation is associated with tumorigenesis in a variety of cancers. Our group has shown that NF-κB signaling in lung epithelial cells is critical for lung tumor formation. However, the role of NF-κB in other cell types, such as myeloid cells, during lung carcinogenesis is uncertain. We hypothesized that NF-κB signaling in myeloid cells (macrophages, monocytes, and neutrophils) promotes lung tumorigenesis by facilitating lung inflammation. Surprisingly, we found that mice with myeloid cell-targeted IKKβ deletion (IKKβΔmye mice) developed significantly more tumors than wild-type (WT) mice 4 months following a single intraperitoneal (IP) injection of the lung carcinogen urethane (1g/kg). IKKβΔmye mice exhibited a paradoxical increase in the proinflammatory cytokines IL-1β, TNFα, and CXCL1 at 1 and 2 weeks after urethane treatment, and a more than 3-fold higher influx of CD11b+Ly-6G+ cells into IKKβΔmye lungs compared to WT lungs was observed by flow cytometry 1 week post-urethane. By 6 weeks after urethane, IKKβΔmye mice developed more lung inflammation than WT mice, which was accompanied by an increased burden of atypical adenomatous hyperplasia lesions. Flow cytometric analysis of inflammatory cell populations at this time point revealed a sustained increase in granulocytic cells, indicated by significantly higher numbers of CD11b+Gr-1hi cells in the lungs of IKKβΔmye mice compared to WT mice. Depletion of granulocytic cells using Ly-6G antibody treatment (50ug/weekly IP injection) during the first 6 weeks of urethane-induced lung carcinogenesis reduced lung NF-κB activation and lung tumor incidence in IKKβΔmye mice to levels observed in urethane-treated WT mice, indicating that granulocytic cells play an important role in lung tumorigenesis during early tumor development and may do so by limiting NF-κB activation in lung epithelial cells. Together, our data suggest that the impact of NF-κB signaling on lung tumorigenesis is cell type specific and that myeloid NF-κB signaling limits urethane-induced inflammation and lung tumorigenesis. Granulocytes are important players during early lung tumor promotion, and we propose that they promote lung carcinogenesis through interactions that increase survival and/or proliferation of mutated lung epithelial cells.

Citation Format: Allyson McLoed, Rinat Zaynagetdinov, Taylor Sherrill, Fiona Yull, Timothy Blackwell. NF-κB signaling in myeloid cells limits urethane-induced lung tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2875. doi:10.1158/1538-7445.AM2013-2875
Abstract 2877: Dual role of mast cells in prostate tumors.
Authors: Colombo Mario P. , Pittoni Paola , Sangaletti Sabina , Tripodo Claudio
Published: August 2014

Prostatic carcinoma is most often a multifocal disease, with areas of localized, well-differentiated adenocarcinomas coexisting with poorly differentiated lesions within the same tumor. Mast cells (MC), classically known as the primary responders in allergic reactions, have been recently indicate of prognostic value in prostate cancer. We have evidence of a dual role of MC in prostate cancer. Within the same human tumor, MC are specifically enriched and degranulated in areas of adenocarcinoma, whereas few around anaplastic foci. This observation has been confirmed in tumors from TRAMP (Transgenic Adenocarcinoma of the Mouse Prostate) mice, and in two novel tumor cells lines, derived from them, phenocopying well and poorly differentiated adenocarcinoma: T1525 and T23, respectively. MC promote the growth of the well-differentiated adenocarcinoma T1525 that does not develop when transplanted into MC-deficient mice, or when MC degranulation is pharmacologically inhibited with sodium cromoglycate. In particular, mast cells are essential for the outgrowth of early-stage tumors due to their matrix metalloproteinase-9 production, become dispensable in advanced-stage, post-epithelial-to-mesenchymal transition, and are protective against neuroendocrine prostate tumor variants. Indeed, pharmacological inhibition or genetic ablation of MC in TRAMP mice results in early development of undifferentiated tumors characterized by marked anaplasia, suggesting that the growth of anaplastic clones may be antagonized by MC.

Our data demonstrate that MC can influence the histotype of tumor arising from the prostate and that their targeting may change tumor outcome. As a possible corollary, MC depletion might favor the growth of more undifferentiated and aggressive variants. The common expression of c-Kit by mast cells and neuroendocrine clones suggests a possible competition for the ligand Stem Cell Factor and offers the chance of curing early-stage disease while preventing neuroendocrine tumors using c-Kit-targeted therapy.

Citation Format: Mario P. Colombo, Paola Pittoni, Sabina Sangaletti, Claudio Tripodo. Dual role of mast cells in prostate tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2877. doi:10.1158/1538-7445.AM2013-2877
Abstract 2884: ER stress and autophagy induced in pro-inflammatory mast cells exposed to stimuli associated with a positive energy balance.
Authors: Balajadia Januaria M. , Shimoda Lori , Greineisen William , Turner Helen
Published: August 2014

Over the past two decades there has been an increase in the incidence of obesity and metabolic diseases due to sedentary lifestyles, high caloric intake, genetics and environmental factors. Studies have shown that obesity is linked with multiple co-morbid pathologies, including increases in the incidence of some cancers. We have studied the effect of a nutrient-dense environment upon the mast cell, a pro-inflammatory immunocyte. Our recently published work shows that these immunocytes are sites for ectopic lipid deposition (steatosis) under conditions that mimic high nutrient availability and hyperinsulineamia. Moreover, the steatotic phenotype is associated with phenotypic change in the mast cells, with relative over-production of bioactive eicosanoids and other pro-inflammatory lipid mediators, but suppression of some aspects of the acute Type I hypersensitivity pathway. In the current study we sought to further explore the impact of nutrient abundance upon the cell biology of the mast cell. We observe the induction of ER stress pathways, which is associated with the re-programming of the ER towards lipid synthesis and deposition in lipid bodies. Moreover, we observe the induction of autophagy pathways, which likely reflect cellular attempts to access the dysregulated ER and lipid bodies in an effort to return to homeostasis. These studies deepen our understanding of the degree to which altered nutrient environments can, in turn, cause immunological dysregulation. Of particular interest for future studies will be the links between mast cell dysregulation and the systemic and local inflammatory pathology that is associated with metabolic syndrome.

Citation Format: Januaria M. Balajadia, Lori Shimoda, William Greineisen, Helen Turner. ER stress and autophagy induced in pro-inflammatory mast cells exposed to stimuli associated with a positive energy balance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2884. doi:10.1158/1538-7445.AM2013-2884
Abstract 2885: Features of innate immunity dominate serum and tissue protein and cytokine profiles in both mouse and human inflammatory bowel disease.
Authors: Knutson Charles G. , Mangerich Aswin , Zeng Yu , Raczynski Arkadiusz R. , Liberman Rosa G. , Kang Pilsoo , Ye Wenjie , Gong Guanyu , Prestwich Erin , Lu Kun , Wishnok John S. , Korzenik Joshua R. , Wogan Gerald N. , Gox James G. , Dedon Peter C. , Tannenbaum Steven R.
Published: August 2014

Inflammatory bowel disease (IBD) is a chronic and relapsing intestinal inflammatory disease that arises through unknown genetic, environmental, and bacterial origins. Ulcerative colitis (UC) and Crohn's disease (CD) are the two main forms of IBD, and their incidence is increasing in industrialized countries. Further, IBD is a significant risk factor for the development of colon cancer. Though the specific determinants remain elusive, persistent inflammation is believed to play a significant role in colon cancer carcinogenesis. To better define the molecular mechanisms linking colitis to the identity of disease biomarkers, we performed a translational comparison of protein expression and protein damage products in mouse and human IBD. Helicobacter hepaticus-infected Rag2-/- mice emulate many aspects of human IBD, and our recent work with this model highlights the importance of neutrophils in the pathology of colitis and colon cancer. Analysis of neutrophil- and macrophage-derived damage products revealed accumulation of 3-chlorotyrosine (CTyr) and 3-nitrotyrosine (NTyr) in inflamed mice colons that increased with disease duration. These results were further corroborated in mouse studies by histological evaluation, which demonstrated strong infiltration of neutrophils and macrophages to the site of inflammation. Human studies revealed an increase in CTyr in the colon of UC and CD tissues relative to serum levels. The nucleic acid chlorination damage product, 5-chloro-2′-deoxycytidine (5-Cl-dC), was quantified in human colon and found to be present at similar levels to that of inflamed mice colons. Multivariate analysis of these markers along with serum proteins and cytokines revealed a general signature of activated innate immunity in human IBD. UC sera were strongly suggestive of neutrophil activity while CD and mouse sera were suggestive of macrophage and neutrophil activity. These data point to innate immunity as a major determinant of serum and tissue profiles and provide insight into disease activity in IBD.

Citation Format: Charles G. Knutson, Aswin Mangerich, Yu Zeng, Arkadiusz R. Raczynski, Rosa G. Liberman, Pilsoo Kang, Wenjie Ye, Guanyu Gong, Erin Prestwich, Kun Lu, John S. Wishnok, Joshua R. Korzenik, Gerald N. Wogan, James G. Gox, Peter C. Dedon, Steven R. Tannenbaum. Features of innate immunity dominate serum and tissue protein and cytokine profiles in both mouse and human inflammatory bowel disease. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2885. doi:10.1158/1538-7445.AM2013-2885
Abstract 289: Inhibition of Trk receptor leads to mesenchymal-epithelial transition in human hepatocellular carcinoma cell lines.
Authors: Abe Mitsuhiko , Koga Hironori , Yoshida Takafumi , Masuda Hiroshi , Sakata Masahiro , Ikezono Yu , Nakamura Toru , Taniguchi Eitaro , Kawaguchi Takumi , Yano Hirohisa , Torimura Takuji , Sata Michio
Published: August 2014

Sorafenib, the first molecular targeted agent for HCC, has been shown to be clinically effective in global clinical trials. Although overall survival of HCC patients has been extended by a few months, these results are not satisfactory. Clinical studies involving other molecular targeted therapies and combination therapies are ongoing, but no clearly effective therapy has yet emerged. While we were exploring new targets related to epithelial-mesenchymal transition (EMT), which is involved in metastasis and ivasion of advanced cancers, we found the EMT-inducing potential of the tropo-myosine-related kinase B (TrkB) receptor, whose ligands include brain-derived neurotrophic factor (BDNF).

We observed by phase contrast microscopy that K252a, a Trk inhibitor, induced alterations in cell shape of several HCC cell lines (HAK-1A, HAK-1B, KYN-2, Huh7, and HLF). The morphological change was most obvious in HAK-1B cells, which have been proven to have mesenchymal features: the K252a-treated HAK-1B turned to polygonal epithelial-like cells. In Western blot analysis, the E-cadherin expression level was increased in the K252a-treated HAK-1B cells. Similar findings were demonstrated also in HAK-1A, which is a sister cell line of HAK-1B. The mechanistic basis for the “mesenchymal-epithelial transition (MET)” was down-regulation of E2A, an EMT-regulating transcriptional factor. Although the down-regulation of E2A was universally found in other cell lines, such as KYN-2, Huh7, and HLF, their expression levels of E-cadherin were not apparently increased.

Our findings suggest that inhibition of TrkB signaling may be a new therapeutic approach for advanced HCC, since the inhibition may give rise to “MET” in aggressive tumors. In addition, the present data are impressive insofar as they imply a relationship between the liver and neurosystem.

Citation Format: Mitsuhiko Abe, Hironori Koga, Takafumi Yoshida, Hiroshi Masuda, Masahiro Sakata, Yu Ikezono, Toru Nakamura, Eitaro Taniguchi, Takumi Kawaguchi, Hirohisa Yano, Takuji Torimura, Michio Sata. Inhibition of Trk receptor leads to mesenchymal-epithelial transition in human hepatocellular carcinoma cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 289. doi:10.1158/1538-7445.AM2013-289
Abstract 2893: Integrated genomic meta-analysis of colorectal cancer by elastic-net.
Authors: Lee HoJoon , Flaherty Patrick , Ji Hanlee P.
Published: August 2014

To identify combinatorial sets of known, putative and new cancer drivers responsible for colorectal cancer (CRC) development and other associated specific clinical outcomes, we have developed an integrative analysis method for cancer genome data. This approach is based on the elastic-net algorithm that we have applied to genomic data from the Cancer Genome Atlas (TCGA) Project. Our supervised analysis simultaneously assesses the contribution of i) copy number variation (CNV), ii) gene expression, iii) miRNA, iv) methylation and v) cancer mutations to clinical features. The ongoing TCGA project is generating genomic and clinical data sets from different tumor types including CRC. These detailed catalogues of genetic changes in cancer genomes will continue to provide us with new insights about cancer development. However, extracting biologically/clinically relevant information from TCGA's diverse and large cancer genome data remains a challenge. In attempt to overcome this challenge, we use regularized regression method: elastic-net that improves on “the least absolute shrinkage and selection operator” (Lasso). To demonstrate the performance and validity of this approach, we showed that elastic-net successfully identified i) synthetic genes that have their CNVs perfectly associated with stages from a simulated data ii) TGFBR2 and other driver genes that have mutations associated with CRCs that demonstrate microsatellite instability CRC from TCGA data, and iii) IDH1 that obtained mutations associated with survival according to glioblastoma (GBM) data. In the next phase of the study, we identified the top ranked genes that delineate key clinical features such as TNM stages of CRC. We have identified a series of candidate genes that may indicate clinical stages including novel candidates on chromosome 8. Overall, we have successfully demonstrated that our approach allows for an integrative and highly robust supervised analysis of TCGA data.

Citation Format: HoJoon Lee, Patrick Flaherty, Hanlee P. Ji. Integrated genomic meta-analysis of colorectal cancer by elastic-net. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2893. doi:10.1158/1538-7445.AM2013-2893
Abstract 2899: Significance of microRNA:target interaction in bladder cancer metastasis.
Authors: Ru Yuanbin , Kechris Katerina J. , Smith Steven C. , Calin George A. , Theodorescu Dan
Published: August 2014

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression through base pairing with other mRNA transcripts. MiRNA expression signatures have characterized many phenotypes in bladder cancer, including grade, stage, and metastasis. However, simultaneous mRNA changes accompanying the miRNA profile, along with the miRNA:mRNA interaction, have not been systematically studied in these phenotypes. To gain insights into the miRNA regulatory network in bladder cancer metastasis, we profiled miRNA and mRNA expression in two pairs of metastatic and non-metastatic cell lines. Interactions between differentially expressed miRNAs and mRNAs were predicted using 6 software programs. The candidate miRNA:mRNA pairs were further selected by their clinical relevance, including their expression in grade, stage, and tumor in 2 cohorts totaling 256 human tumors. We identified more miRNA:mRNA pairs with up-regulated miRNAs and down-regulated genes in metastatic cells than the pairs with down-regulated miRNAs and up-regulated target genes. The novel overexpression of one of the miRNAs, hsa-miR-146a, was confirmed by quantitative RT-PCR in metastatic cell lines. It has been shown that decreased level of hsa-miR-146a is associated with progression of prostate cancer and polymorphism in hsa-miR-146a gene is associated with prostate cancer risk. We are carrying out in vitro and in vivo experiments on the top 5 scoring pairs ranked by the number of prediction software and clinical relevance. Our results suggest the significance of miRNA regulatory network in cancer metastasis and provide a list of potential miRNA:mRNA pairs for further investigation.

Citation Format: Yuanbin Ru, Katerina J. Kechris, Steven C. Smith, George A. Calin, Dan Theodorescu. Significance of microRNA:target interaction in bladder cancer metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2899. doi:10.1158/1538-7445.AM2013-2899
Abstract 2900: Phylogenetic classification, structural evolution, and functional divergence of the Ras superfamily of GTPases as tracked by the Conserved Domain Database (CDD)..
Authors: Song James S. , Thanki Narmada , Derbyshire Myra K. , Gwadz Marc , Gonzales Noreen R. , Marchler-Bauer Aron , Bryant Stephen H.
Published: August 2014

The Conserved Domain Database (CDD, http://www.ncbi.nlm.nih.gov/Structure/cdd/cdd.shtml) is part of NCBI's Entrez query and retrieval system and is a collection of annotated multiple sequence alignment (MSA) models representing ancient conserved protein domains, basic units of protein function and protein evolution.These MSA models are available as position specific score matrices (PSSMs) for fast identification of conserved domains in protein sequences via Reverse Position Specific -BLAST (RPS-BLAST), a variation of the commonly used PSI-BLAST. The domain models can be viewed and examined interactively using NCBI's CDTree/Cn3D software applications. Conserved functional annotations such as key catalytic and ligand-binding sites are displayed on protein structures sharing significant homology to the query, thereby inferring the underlying mechanism(s) of the protein domain family. Here, we present the current, functionally annotated, evolutionary classification of the Ras GTPase superfamily, including the circularly permuted Ras-like domain, and its downstream effectors such as RasGAP and RasGEF. Using CDTree/Cn3D tools, subfamilies in diverse organisms were inferred from the MSAs, phylogenetic trees, and domain architectures of the Ras superfamily. Furthermore, several subfamilies comprising of only uncharacterized protein sequences have their functions annotated by inference from the molecular and cellular functions of known related proteins having 3D structure, and based on the available literature. We demonstrate the utility of CDTree/Cn3D in studying molecular evolution of protein domain families, and in accelerating the pace of biological discovery by enabling researchers to obtain valuable clues regarding as-yet-unidentified molecular properties and mechanisms. CDTree/Cn3D software is freely available for download via the CDD website.

Citation Format: James S. Song, Narmada Thanki, Myra K. Derbyshire, Marc Gwadz, Noreen R. Gonzales, Aron Marchler-Bauer, Stephen H. Bryant. Phylogenetic classification, structural evolution, and functional divergence of the Ras superfamily of GTPases as tracked by the Conserved Domain Database (CDD). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2900. doi:10.1158/1538-7445.AM2013-2900
Abstract 2904: An integrative analysis to identify putative drugs for acute myeloid leukemia.
Authors: Chen Yu-Heng , Hsiao Tzu-Hung , Chen Hung-I Harry , Chen Yidong , Chuang Eric Y
Published: August 2014

It is a time-consuming procedure to find an effective drug under current drug development, but the response rates of most anti-cancer drugs were still not high. Furthermore, the survival time of malignant cancer patients were often not prolonged after treatment. Therefore, to facilitate the process of discovering promising drug treatment, we proposed a novel integrative analysis based on gene set enrichment and evaluate the proposed model in acute myeloid leukemia (AML). The analysis was comprised by two methods. First, the enriched biological functions of each drug were identified based on the enrichment analysis of connectivity map, which is an expression profile of more than 950 drug treatments in the HL60 AML cell line. Second, the tumor progression associated functions were identified by using survival analysis. Finally, we integrated the results of two methods to generate a “drug - biological function - cancer” network. Based on the identified network, the putative anti-cancer drugs can be further explored. We applied a AML cohort data set, GSE12417, which contains 163 expression profiles, to our analysis framework. The result showed 429 enriched biological functions were related to 948 drugs. Among them, 21 of the 429 functions were identified as tumor progression associated functions though cox regression analysis. By integrating the two results, finally 174 putative drugs for AML were discovered. Our preliminary results provide valuable information to revisit the putative drugs to “reposition” for cancer therapy through identified biological functions.

Citation Format: Yu-Heng Chen, Tzu-Hung Hsiao, Hung-I Harry Chen, Yidong Chen, Eric Y Chuang. An integrative analysis to identify putative drugs for acute myeloid leukemia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2904. doi:10.1158/1538-7445.AM2013-2904

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 2907: Role of reactive oxygen and nitrogen species in resveratrol-induced lung cancer cell death.
Authors: Monillas Elizabeth S. , Walker Grayson , Brockmiller Aubrey , Iyer Anand , Azad Neelam
Published: August 2014

Lung cancer is the leading cause of cancer related deaths worldwide. In 2008, 158,592 deaths were attributed to this disease and 208,493 new cases were diagnosed in the United States. Resveratrol (trans-3, 5, 4′-trihydroxystilbene), a compound found largely in the skins of red grapes, has been reported to be a promising anticancer agent in various types of cancer. The primary goal of this study is to delineate the key signaling pathways induced in response to resveratrol leading to lung cancer cell death. In this study, we use non-tumorigenic human bronchial epithelial (BEAS-2B) and human lung epithelial cancer (H460) cells to model the response of lung tissue to resveratrol.

We observed an increase in superoxide, hydrogen peroxide and nitric oxide production in response to resveratrol treatment in lung cancer cells (H460) as compared to non-tumorigenic cells (BEAS-2B). Additionally, our data shows an increase in BEAS-2B cell viability as compared to H460 cell viability in response to resveratrol treatment. Overall, we observe an increase in cellular oxidative and nitrosative stress in cancer cells in response to resveratrol treatment which may be responsible for increased apoptosis and decreased viability in these cells. Subsequently, we plan to identify the specific reactive species as well as the major apoptotic pathway induced in response to resveratrol treatment in both normal and cancer cells. We expect resveratrol to have significant effect on lung cancer cells via oxidative/nitrosative stress-mediated modulation of key apoptotic biomarkers. This study will establish the protective role of resveratrol in the pathogenesis of lung cancer and the information can be potentially exploited to improve future lung cancer therapies.

Citation Format: Elizabeth S. Monillas, Grayson Walker, Aubrey Brockmiller, Anand Iyer, Neelam Azad. Role of reactive oxygen and nitrogen species in resveratrol-induced lung cancer cell death. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2907. doi:10.1158/1538-7445.AM2013-2907
Abstract 2908: Function and regulation of peroxiredoxin proteins in doxorubicin-treated MCF-7 breast cancer cells.
Authors: McDonald Caitlin , Perlmutter Gregg , Taparra Kekoa , Muhlbauer Jillian , Passarelli Julie , Phelan Shelley A.
Published: August 2014

The Peroxiredoxin (Prdx) family of genes encodes thiol-specific antioxidant proteins that protect cells from oxidative stress. Mammalian cells express six different Prdx proteins, and these proteins play a role in cell signaling, proliferation and apoptosis. Recent studies have shown that Prdx levels are elevated in many cancers, suggesting that Prdx upregulation may be an advantageous adaptation to the cancerous state. In the present study we investigated the expression and function of different Prdx proteins in untreated and doxorubicin-treated MCF-7 breast cancer cells, as well as noncancerous MCF-10A cells. We used real-time PCR and western blotting to examine Prdx expression in both cell lines, and also measured Prdx protein expression in doxorubicin-treated MCF-7 cells. In addition, we suppressed Prdx expression using transiently transfected siRNA and measured cell proliferation and apoptosis. Our results show that MCF-7 cells are significantly more resistant to cell death induced by the chemotherapy agent doxorubicin. We also found that five of the six Prdxs are overexpressed in MCF-7 cells at the mRNA and protein levels, and that serum deprivation reduced Prdx expression. Treatment of MCF-7 cells with doxorubicin altered expression of specific Prdxs, demonstrating a specific effect on these antioxidants. Transient transfection of MCF-7 cells with Prdx6 siRNA resulted in a marked reduction in Prdx6 suppression, with no change in other Prdx proteins. Suppression of Prdx6 in these cells led to reduced cell proliferation and increased susceptibility to doxorubicin-induced death. Similar studies are currently underway for the other Prdx proteins. Together, these findings suggest that Prdx overexpression in MCF-7 cells may be cytoprotective and that Prdxs may contribute to doxorubicin-resistance in these and other breast cancer cells.

Citation Format: Caitlin McDonald, Gregg Perlmutter, Kekoa Taparra, Jillian Muhlbauer, Julie Passarelli, Shelley A. Phelan. Function and regulation of peroxiredoxin proteins in doxorubicin-treated MCF-7 breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2908. doi:10.1158/1538-7445.AM2013-2908
Abstract 2910: Suppressing excessive reactive oxygen species accumulation by RIP1 potentiates BPDE-induced transformation of human bronchial epithelial cells.
Authors: Wang Qiong , Chen Wenshu , Xu Xiuling , Li Bilan , He Weiyang , Padilla Mabel T.
Published: August 2014

Cell survival signaling is important for the malignant phenotypes of cancer cells. Although the role of receptor-interacting protein 1 (RIP1) in cell survival signaling is well documented, whether RIP1 is directly involved in cancer development has never been studied. In this report, we found that RIP1 expression is substantially increased in human non-small cell lung cancer (NSCLC) tissues and cell lines. RIP1 expression in human bronchial epithelial cells (HBECs) was significantly induced by cigarette smoke extract (CSE) or benzo[a]pyrene diol epoxide (BPDE), the active form of the tobacco-specific carcinogen benzo (a) pyrene (BaP). In RIP1 knockdown HBECs, BPDE-induced cytotoxicity was significantly increased, which was associated with induction of cellular reactive oxygen species (ROS), mainly hydrogen peroxide (H2O2), and activation of mitogen-activated protein kinases (MAPKs) including JNK, ERK and p38. Scavenging ROS suppressed BPDE-induced MAPK activation and inhibiting ROS or MAPKs substantially blocked BPDE-induced cytotoxicity, suggesting ROS-mediated MAPK activation is involved in BPDE-induced cell death. The H2O2-reducing enzyme catalase is destabilized in an ERK- and JNK-dependent manner in RIP1 knockdown HBECs and application of catalase effectively blocked BPDE-induced H2O2 accumulation and cytotoxicity. Importantly, BPDE-induced transformation of HBECs was significantly reduced when RIP1 expression was suppressed. Altogether, these results strongly suggest an oncogenic role for RIP1, which promotes malignant transformation through protecting DNA-damaged cells against carcinogen-induced cytotoxicity associated with excessive ROS production.

Citation Format: Qiong Wang, Wenshu Chen, Xiuling Xu, Bilan Li, Weiyang He, Mabel T. Padilla. Suppressing excessive reactive oxygen species accumulation by RIP1 potentiates BPDE-induced transformation of human bronchial epithelial cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2910. doi:10.1158/1538-7445.AM2013-2910
Abstract 2911: APE1/Ref1, a mammalian DNA repair/redox factor, increases mitochondrial activity.
Authors: Rangaswamy Suganya , Yarana Chontida , Miriyala Sumitra , Izumi Tadahide
Published: August 2014

The mammalian apurinic/apyrimidinic endonuclease 1 (APE1) is an essential DNA repair protein which also functions as a redox sensor (Ref1) to activate many transcription factors. A fraction of APE1/Ref1 protein is localized in the mitochondria for repairing oxidative DNA damage. However, its influence on mitochondrial activity has not been studied. We established genetically modified mouse embryonic fibroblast cells with extremely low APE1, at only 0.2% of the control MEFs. The APE1-knockdown (APE1kd) MEFs grew normally although they were highly sensitive to alkylating reagents. We analyzed the APE1kd MEFs to investigate the effect of APE1 on mitochondrial activity. Compared to the wild-type MEFs, the APE1kd MEFs exhibit a markedly decreased mitochondrial respiration activity and in turn showed glycolysis at a rate higher than the wild-type cells, which presumably compensated low ATP generation from mitochondria. A glycolysis inhibitor, 2-deoxy-D-glucose (2DG) affected ATP generation effectively, suggesting that the cells with low APE1 expression depended on glycolysis much more than the wild-type MEFs. The change in the mitochondrial activity appeared reversible. We propose that the presence of APE1 in the mitochondria/cytoplasm enhances mitochondrial respiration by a mechanism unrelated to its DNA repair activity.

Citation Format: Suganya Rangaswamy, Chontida Yarana, Sumitra Miriyala, Tadahide Izumi. APE1/Ref1, a mammalian DNA repair/redox factor, increases mitochondrial activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2911. doi:10.1158/1538-7445.AM2013-2911
Abstract 2912: Inhibition of redox/Fyn/c-Cbl pathway function by Cdc42 controls tumor initiation capacity and tamoxifen sensitivity in basal-like breast cancer cells.
Authors: Chen Hsing-Yu , Yang Yin , Stevens Brett , Noble Mark
Published: August 2014

Two of the substantial challenges in cancer research are to identify means overcoming resistance of malignant cells to existing therapies and to eliminate the unique small population within bulk tumors, named tumor initiating cells or cancer stem cells which have been proposed to regenerate resistant relapsed tumors. In this study, we offer a novel therapeutic target relevant to both of these goals on basal-like (triple-negative) breast cancer (BLBC) cells, one of the most challenging cancers to treat with current regimens.

Our findings emerged from examining the puzzling differences in regulation of activation of the E3 ubiqutin ligase c-Cbl in normal cells and in cancer cells by low microM concentrations of tamoxifen (TMX). In normal progenitor cells, TMX causes oxidation and sequential activation of Fyn kinase and the c-Cbl ubiquitin ligase. Activation of c-Cbl via this redox/Fyn/c-Cbl (RFC) pathway leads to accelerated degradation of receptor tyrosine kinases that are critical in cell survival and division (such as the epidermal growth factor (EGFR)). In BLBC cells, in contrast, TMX does not activate c-Cbl despite making the cells more oxidized and causing activation of Fyn. Moreover, BLBC cells exposed to TMX show no reduction in levels of EGFR.

We found that TMX-induced activation of c-Cbl in BLBC cells was inhibited due to expression of Cdc42. Cdc42 sequestered c-Cbl, prevented its activation and prevented EGFR from being degraded. Restoration of c-Cbl function, by inhibiting activation of Cdc42, reduced EGFR levels in these cells. More critically, restoring c-Cbl function sensitized these cells to TMX both in vitro and in vivo through estrogen receptor-independent mechanisms. Analysis of tumor growth and formation in vivo showed that reducing the levels of Cdc42 reduced the size of tumors, increased sensitivity to TMX and decreased tumor forming capacity of these cells.

The results provide a novel defense mechanism that BLBC cells utilize to prevent EGFR degradation, which may have high relevance to treatment of these tumors. Of particular importance is the ability of cdc42 to confer TMX sensitivity on these otherwise resistant tumor cells. Moreover, as use of low microM levels of TMX has been attempted for over a dozen different kinds of cancers, at least some of which express increased levels of Cdc42, this strategy may be relevant to the treatment of multiple different cancers.

Citation Format: Hsing-Yu Chen, Yin Yang, Brett Stevens, Mark Noble. Inhibition of redox/Fyn/c-Cbl pathway function by Cdc42 controls tumor initiation capacity and tamoxifen sensitivity in basal-like breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2912. doi:10.1158/1538-7445.AM2013-2912
Abstract 2915: The oxidation state of DJ-1 determines the cell fate during oxidative stress triggered by Fenretinide (4-HPR): autophagy or apoptosis.
Authors: Cao Ji , Ying Meidan , Xie Nan , Zhang Jun , Liu Xiaowen , He Qiaojun , Yang Bo
Published: August 2014

Increasing oxidative stress caused by many anti-cancer drugs is commonly accompanied with a switch from autophagy, a cyto-protective response, to apoptosis in cancer cells. However, the underlying mechanism of this process is still poorly understood. To address this we chose fenretinide (4-HPR) as the candidate drug since the major anti-cancer mechanism of this drug is reactive oxygen species (ROS) induction. We have shown previously and herein that 4-HPR-driven ROS induce the autophagy-apoptosis transition in a threshold manner in vitro and vivo. During this process, ASK1-regulated JNK1 or p38 signaling is response for 4-HPR-induced autophagy or apoptosis, respectively. Given ASK1 play a pivotal role in the selective activation of individual signaling, we further characterize the potential regulating unit of ASK1 by immunoprecipitation following LC/MS/MS analysis. Of note, DJ-1, a crucial antioxidant protein, is identified from a total of 7 fragments. We show that DJ-1 interacts with ASK-1 under moderate oxidative stress, but segregate from ASK-1 under lethal level of oxidative stress, suggesting DJ-1 may be a potent key regulator of autophagy-apoptosis transition. Interestingly, various oxidation statuses and the stability of homo-dimer formation of DJ-1 are highly related to different levels of intracellular oxidative stress. Moreover, we apply two kinds of artificial DJ-1 mutants at position C106 or E18 and further confirm that DJ-1 served as an oxidative sensor to determine the switch between autophagy and apoptosis triggered by 4-HPR. Hence, different oxidation state of DJ-1 modulates ASK-1-JNK1/p38 signaling activation to dictate the cellular response to oxidative stress: to autophagy or apoptosis.

Citation Format: Ji Cao, Meidan Ying, Nan Xie, Jun Zhang, Xiaowen Liu, Qiaojun He, Bo Yang. The oxidation state of DJ-1 determines the cell fate during oxidative stress triggered by Fenretinide (4-HPR): autophagy or apoptosis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2915. doi:10.1158/1538-7445.AM2013-2915

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 292: Breast cancer malignancy is regulated by PAX5 through the disruption of FAK1 signaling.
Authors: Benzina Sami , O'Brien Pierre , Guerrette Roxann , Robichaud Gilles
Published: August 2014

Breast cancer is the most common cancer diagnosed in women worldwide. 30% of these women will succumb to their disease. More specifically, metastasis accounts for 90% of deaths in breast cancers patients. Therefore, the study of genetic factors regulating cancer malignancy is a top priority to mitigate the morbidity and mortality associated to this disease. PAX5 (Paired Box 5) is a transcriptional factor normally implicated in embryogenesis and B cell differentiation. However, the aberrant expression of PAX5 is associated to several types of cancer pathology and more recently in breast cancer.

We have recently reported that PAX5 promotes epithelialisation and its expression inversely correlates with the Focal Adhesion Kinase 1 (FAK1), a key component in cancer motility and invasion leading to metastasis. On one hand, these finding suggest that PAX5 could attenuate FAK-mediated epithelial-mesenchymal transitioning (EMT) of primary tumors. On the other hand, PAX5 could also initiate the mesenchymal-epithelial transitioning (MET) of circulating cancer cells enabling them to colonize and establish secondary tumours.

In this study we set out to validate the role of PAX5 in the metastatic cascade of mammary tumours, particularly to uncover the molecular regulation of FAK1 cascades through PAX5 in breast cancer cell malignancy. Through conditional expression of the PAX5 gene in breast cancer cells, we demonstrate experimentally a negative regulation of FAK1 protein and phosphorylation levels mediated by PAX5 over expression. We also confirm that PAX5 suppresses the transcriptional expression of FAK1. Further investigation shows a PAX5-mediated suppression of FAK1 signaling pathways (e.i. AKT, p38, JNK and Paxillin) leading to attenuated cancer cell proliferation, death and migration processes. These findings bring light to molecular mechanisms driving breast cancer malignancy and benefit our quest in the development of diagnostic and therapeutic strategies.

Citation Format: Sami Benzina, Pierre O'Brien, Roxann Guerrette, Gilles Robichaud. Breast cancer malignancy is regulated by PAX5 through the disruption of FAK1 signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 292. doi:10.1158/1538-7445.AM2013-292