bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5099: Abrogation of cancer cell extravasation in renal cell carcinoma PDX lines via invadopodia dysregulation mediated by PAK1 inhibitors
Authors: Williams Karla , Mazzola Clarisse , Brugarolas James , Power Nicholas , Chambers Ann , Leong Hon 
Published: August 2015

Abstract
Cellular remodeling of the extracellular matrix (ECM), facilitating tumour cell invasion, is a key intrinsic quality in metastatic cells. Invadopodia are actin-driven protease-rich subcellular membrane protrusions formed by tumor cells for localized degradation and remodeling of the ECM. Invadopodia mediate tumor cell extravasation, a key step in the metastatic cascade in which tumor cells undergo transendothelial migration when arrested at distant sites. Using several PDX cell lines, we determine that treatment with PAK1 inhibitors leads to significantly decreased rates of cancer cell extravasation in vivo (IPA-3, 1 uM final concentration) with no impacts on cell viability in vitro. Interestingly, in vitro, there was no significant change in the number of cells forming invadopodia; however, there was more gelatin degradation per cell as determined by in vitro gelatin-Alexa594 invadopodia assays. Time lapse imaging of invadopodia formation in PDX cell lines reveal a decrease in invadopodia disassembly in vitro, resulting in alterations to adhesions to maintain tumor cell anchorage to the CAM vessel wall in vivo. These results reveal the feasibility of targeting extravasation through other mechanisms whilst impairing invadopodia disassembly prior to cancer cell transportation to the underlying tissue.
Citation Format: Karla Williams, Clarisse Mazzola, James Brugarolas, Nicholas Power, Ann Chambers, Hon Leong. Abrogation of cancer cell extravasation in renal cell carcinoma PDX lines via invadopodia dysregulation mediated by PAK1 inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5099. doi:10.1158/1538-7445.AM2015-5099
Abstract 5100: Aerobic glycolysis is the primary metabolic pathway used for prostate cancer cell motility and invasion processes regardless of androgen sensitivity
Authors: Verdone James E. , Zarif Jelani C. , Pienta Kenneth J. 
Published: August 2015

Abstract
The ability of a cancer cell to detach from a primary tumor and intravasate is a fundamental prerequisite for development of metastatic disease. As metastatic tumors are frequently the principal cause of death in cancer patients with advanced disease, targeting the ability of cancer cells to metastasize may improve patient outcomes. Advanced, aggressive prostate cancers are characterized by abnormal metabolic upregulation of aerobic glycolysis, a phenomenon known as the Warburg effect. We have previously demonstrated that prostate cancer and breast cancer cells use aerobic glycolysis as the primary energy pathway for cellular motility and cytoskeletal remodeling. In clinical prostate cancer patients, the progression of cells to an androgen insensitive state renders treatment difficult and often unsuccessful. In the present study, we investigate the role of aerobic glycolysis in motility and invasion in prostate cancer cells with intact androgen signaling.
To test this, we utilized a Seahorse XF24 metabolic to measure aerobic glycolysis and oxygen consumption rate of prostate cancer cells with and without intact androgen receptor signaling. Cellular motility was measured by tracking cell movement over time while subjecting cells to pharmacological inhibition of aerobic glycolysis, mitochondrial oxidative phosphorylation, or fatty acid beta-oxidation. Cellular invasion was measured by a Boyden chamber invasion assay with similar pharmacological inhibition.
As anticipated, prostate cancer cells with intact androgen receptor signaling displayed a modulated usage of aerobic glycolysis, whereas mitochondrial oxidative phosphorylation was unchanged. Consequently, androgen receptor signaling altered cancer cell invasiveness. Notably, regardless of invasiveness and androgen receptor status, cellular motility and invasion capacity can be attenuated upon pharmacological inhibition of aerobic glycolysis. Taken together, these data suggest that targeting aerobic glycolysis in prostate cancer could severely weaken prostate cancer metastatic capability and limit tumor spread from the primary site. In the future, combining glycolytic inhibitors with conventional therapy may prevent dissemination of metastatic clones to distal sites and thus drastically reduce risk of metastatic recurrence.
Citation Format: James E. Verdone, Jelani C. Zarif, Kenneth J. Pienta. Aerobic glycolysis is the primary metabolic pathway used for prostate cancer cell motility and invasion processes regardless of androgen sensitivity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5100. doi:10.1158/1538-7445.AM2015-5100
Abstract 5107: Divergent behaviors and underlying mechanisms of cell migration and invasion in non-metastatic T24 and its metastatic derivative T24T bladder cancer cell lines
Authors: Jin Honglei , Li Jingxia , Huang Chuanshu 
Published: August 2015

Abstract
Previous studies on cancer cell invasion were primarily focused on its migration because these two events were often considered biologically equivalent. Here we found that T24T cells exhibited higher invasion but lower migration abilities than T24 cells. Expression of Rho-GDPases was much lower and expression of SOD2 was much higher in T24T cells than in T24 cells. Indeed, knockdown of SOD2 in T24T cells can reverse the cell migration but without affecting cell invasion. We also found that SOD2 inhibited the JNK/C-Jun cascade, and the inhibition of c-Jun activation by ectopic expression of TAM67 impaired Rho-GDPases expression and cell migration in T24T shSOD2 cells. Further, we found that Sp1 can upregulate SOD2 transcription in T24T cells. Importantly, matrix metalloproteinase-2 (MMP-2) was overexpressed in T24T and participated in increasing its invasion, and MMP-2 overexpression was mediated by increasing nuclear transport of nucleolin, which enhanced mmp-2 mRNA stability. Taken together, our study unravels an inverse relationship between cell migration and invasion in human bladder cancer T24T cells and suggests a novel mechanism underlying the divergent roles of SOD2 and MMP-2 in regulating metastatic behaviors of human bladder T24T in cell migration and invasion.
Citation Format: Honglei Jin, Jingxia Li, Chuanshu Huang. Divergent behaviors and underlying mechanisms of cell migration and invasion in non-metastatic T24 and its metastatic derivative T24T bladder cancer cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5107. doi:10.1158/1538-7445.AM2015-5107
Abstract 5127: The most common mistakes in cancer cell pharmacology
Authors: Lenz Guido , Silva Andrew O. 
Published: August 2015

Abstract
Background: Cancer cell culture has contributed with pivotal discoveries for cancer biology and pharmacology. However, cancer cells in culture have not provided a good test method for patient´s response to chemotherapy to a similar extent as antibiograms have been useful to predict response to antibiotics. Although the reason for this is multifactorial, some very common mistakes in cancer cell pharmacology are made in most studies that, if corrected, could improve the overall results.
Methods: We systematically tested key conditions such as concentration, time of exposure and analysis, methods of analysis and number of cells analyzed in glioma cell lines.
Results: We found that time of exposure to the drug and time of analysis have a large impact on the outcome, with some drugs producing in vitro “relapse” only after 20 days of analysis. Additionally, the initial number of cells plated is also central for the outcome, with resistance being uncovered only after a certain number of cells is treated. Finally, a direct comparison between the MTT viability assay with population doubling assay clearly indicates that the former is not suited for studying effective anticancer drugs and resistance due to its low sensitivity. By systematically analyzing concentration, time of exposure and analysis, number of initial cells and method of analysis we showed that for more meaningful in culture cancer pharmacology, drug exposure should mimic the patient´s exposure time, (5 days for gliomas), analysis should be for at least one treatment cycle (28 days for gliomas), the number of cells tested should be at least more than 15 thousand and the method for analyzing cell number should be repetitive direct counting instead of viability assays such as MTT.
Conclusion: Despite not addressing other very fundamental issues in cancer cell culture such as medium, adhesion, 3D culture and presence of other cell types, these simple improvements should aid to produce more significant in culture cancer pharmacology.
Financial support: FAPERGS, CNPq e CAPES.
Citation Format: Guido Lenz, Andrew O. Silva. The most common mistakes in cancer cell pharmacology. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5127. doi:10.1158/1538-7445.AM2015-5127
Abstract 5128: Changes in mitochondrial background affect nuclear DNA methylation
Authors: Vivian Carolyn J. , Brinker Amanda E. , Gooden Gerald C. , Legendre Christophe , Salhia Bodour , Welch Danny R. 
Published: August 2015

Abstract
There is emerging evidence demonstrating that mitochondrial DNA (mtDNA) contributes to complex genetic diseases such as cancer. To test directly the role of mtDNA in tumorigenicity and metastasis, a new genetically engineered mouse model was created that contains nuclear DNA from one mouse strain and mtDNA contribution from different mouse strain(s). Taking advantage of maternal inheritance, Mitochondrial Nuclear Exchange (MNX) mice can be bred to mice sharing the same nuclear DNA background. As a result, MNX serves as an important tool to determine if and how mitochondrial genetic background contributes to cancer, negating the concern for mixing maternal and paternal nuclear DNA polymorphisms. MNX mice are healthy, breed normally, show no overt differences in cell cycle or apoptosis and are genetically stable for multiple (&gt;10) generations. Nonetheless, they are distinct strains based upon behaviors and gene expression patterns. The mechanisms controlling gene expression in different MNX strains are not yet known; however, retrograde and anterograde cross-talk exists between the nuclear and mitochondrial genomes. Our hypothesis is that important epigenetic changes occur in the nuclear genome depending upon mitochondrial genetics. To test this hypothesis, we performed Meth-Seq using the Agilent Mouse SureSelect platform and Affymetrix gene expression arrays on four mouse brains (8 wk) that were pooled from different litters and cages of wild-type and MNX to minimize age, developmental, inter-individual and generational heterogeneity. Both differential DNA methylation and gene expression patterns were observed but analyses are ongoing to better define the observed differences. Together these observations provide novel insights into how mtDNA could be altering epigenetic regulation and thereby contribute to cancer pathogenesis. Support: Susan G. Komen for the Cure (SAC11037), Natl Fndn Cancer Res., Kansas Bioscience Authority, Steiner Family Fund.
Citation Format: Carolyn J. Vivian, Amanda E. Brinker, Gerald C. Gooden, Christophe Legendre, Bodour Salhia, Danny R. Welch. Changes in mitochondrial background affect nuclear DNA methylation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5128. doi:10.1158/1538-7445.AM2015-5128
Abstract 5142: A naturally occurring model for gastric cancer
Authors: AbdelMageed Manar A. , Betancur-Boissel Monica , Foltopoulou Parthena , Muthupalani Sureshkumar , Fox James G. , McNiel Elizabeth A. 
Published: August 2015

Abstract
Gastric cancer is the fourth most common cancer and the second leading cause of cancer related deaths. While there are increasing data characterizing the molecular features and defining potential targets for gastric carcinoma, preclinical animal models that recapitulate the human disease are limited. We have developed a number of resources to permit the characterization of spontaneously occurring canine gastric cancer which may provide a useful resource to understand gastric cancer carcinogenesis, its prevention and treatment.
While gastric carcinoma is reportedly uncommon in dogs, certain breeds have significantly increased risk. To study this disease, we have established a database and tissue repository. Our goal has been to characterize canine gastric carcinoma clinically, histologically, and molecularly to determine its comparative value as a model for the human disease. Recently, we have performed a histologic review of 50 canine gastric carcinomas and have found that the canine disease is comprises largely of diffuse type gastric carcinoma and is enriched in the signet ring variant.
We report for the first time a technique for culturing primary gastric cancer from affected dogs. Gastric cancer tissue specimens collected from spontaneously occurring tumors in dogs were disaggregated with collagenase and cells were grown in mammary epithelial growth media with or without 5% FBS. Four different cell lines were derived from tumors of a Labrador mix (GC1), a Basset hound (GC2), a Bouvier de Flandres (GC3) and a mixed breed (GC4). Early passages of all cell lines were able to form colonies when grown in soft agar.
Different growth patterns were observed when cells were cultured with versus without serum. Serum treated cells tend to be fast growing, fibroblastic in appearance and senesce within 10 to 18 passages and these may represent cancer associated fibroblasts or mesenchymal differentiation of cancer cells. However, cells grown in mammary epithelial growth media without serum tend to form spheres that grow well when transferred to ultra-low attachment plate and form extensions when grown in matrigel. That semi-attached growth behavior is consistent with that reported for some human gastric cancer cell lines.
Canine gastric cancer cell lines provide a new resource for the characterization of this spontaneous model that recapitulates diffuse, signet ring cell gastric carcinoma.
Citation Format: Manar A. AbdelMageed, Monica Betancur-Boissel, Parthena Foltopoulou, Sureshkumar Muthupalani, James G. Fox, Elizabeth A. McNiel. A naturally occurring model for gastric cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5142. doi:10.1158/1538-7445.AM2015-5142
Abstract 5143: Rats heterozygous for Pten develop fibroadenoma and adenocarcinoma arising from the mammary gland
Authors: McCoy Aaron M. , Manickam Bala , Reid Lara , Weinstein Edward , Cui Xiaoxia 
Published: August 2015

Abstract
To further characterize the function of the tumor suppressor Pten in the role of tumorigenesis we have created a colony of Pten mutant Sprague Dawley (SD) rats. Utilizing zinc finger nuclease technology we introduced a 7bp deletion in Exon 7 of the Pten gene, creating a frameshift mutation and an early stop codon. Pten homozygous null animals are not viable so a colony of heterozygous animals is maintained. Spontaneous tumors of the mammary gland arise in these animals and were removed for staining and pathological analysis. We describe briefly the creation of this model and preliminary genotypic and proteomic characterization. Further we describe pathological observations made on tumor tissues removed from aging Pten heterozygous animals.
We have confirmed a reduction in Pten expression by Western Blot utilizing a monoclonal antibody targeting a central locus in the protein. Heterozygous Pten animals develop spontaneous tumors of the mammary gland which were removed if animals demonstrated deteriorating health or any condition within our Humane Care and Use guidelines. Thirty six tissues from 16 animals were submitted for histopathological analysis. Eight of the animals were male, 8 of the animals were female and had a mean lifespan of 159 days (165 male, 153 female). Remaining consistent with human breast cancer incidence in women below 30 years of age, the most common lesion observed is a benign fibroadenoma (30/36 samples). The malignant adenocarcinoma was observed in 5/36 samples submitted. Fibroadenoma only lesions were observed in 12 of the 16 rats while both fibroadenoma and adenocarcinoma was observed in 4 of the 16 rats.
Taken together we believe that a Pten heterozygous rat provides an additional tool for the elucidation of the role of Pten in human cancers. This model may also be useful in the study of neurological disorders such as Autism, Parkinson's disease, Alzheimer's disease, obesity, cardiovascular disease, and diabetes.
Mutations in Pten strongly correlate with several human disorders including Cowden syndrome, Bannayan-Zonana syndrome, and Lhermitte-Duclos disease. These disorders result in a tumor pathologies including an increased risk for breast cancers.
Citation Format: Aaron M. McCoy, Bala Manickam, Lara Reid, Edward Weinstein, Xiaoxia Cui. Rats heterozygous for Pten develop fibroadenoma and adenocarcinoma arising from the mammary gland. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5143. doi:10.1158/1538-7445.AM2015-5143
Abstract 5147: Canine spontaneous head and neck squamous cell carcinomas represent their human counterparts at the molecular level
Authors: Liu Deli , Xiong Huan , Ellis Angela E. , Northrup Nicole C. , Shin Dong M. , Zhao Shaying 
Published: August 2015

Abstract
Spontaneous canine head and neck squamous cell carcinoma (HNSCC) represents an excellent model of human HNSCC but is greatly understudied. To better utilize this valuable resource, we performed its first genome-wide characterization by investigating 12 canine HNSCC cases, of which 9 are oral, via high density array comparative genomic hybridization and RNA-seq. The analyses reveal that these canine cancers faithfully recapitulate many key molecular features of human HNSCC. These include similar genomic copy number abnormality landscapes, analogous sequence mutation patterns, and recurrent alteration of known HNSCC genes (e.g., MYC, CDKN2A) and pathways (e.g., cell cycle, mitogenic signaling, TGFβ signaling). Amplification or overexpression of protein kinase genes, matrix metalloproteinase genes, and epithelial-mesenchymal transition genes TWIST1 and SNAI are also prominent in these canine tumors.
The strong dog-human molecular homology fundamentally justifies the use of our novel dog-human comparison strategy for driver-passenger discrimination for HNSCC. This cross-species comparison will significantly advance beyond the current findings with the massive genomic data of the cancer genome atlas (TCGA), as exemplified by our pilot study on human 8q, a recurrently amplified site in human HNSCC.
HNSCC represents the sixth leading cancer by incidence in humans; thus developing effective therapeutic interventions is important. While our understanding of the biology of HNSCC has been greatly advanced over past decades, translating these findings into clinical success has been frustratingly slow. A significant obstacle is the lack of translational model that can bridge the gap between preclinical research and human clinical trials. Our study indicates that spontaneous canine HSCC can effectively bridge this gap, significantly accelerating anti-HNSCC drug discovery.
Note: This abstract was not presented at the meeting.
Citation Format: Deli Liu, Huan Xiong, Angela E. Ellis, Nicole C. Northrup, Dong M. Shin, Shaying Zhao. Canine spontaneous head and neck squamous cell carcinomas represent their human counterparts at the molecular level. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5147. doi:10.1158/1538-7445.AM2015-5147
Abstract 5151: Yap reprograms glutamine metabolism and supports growth during liver development and tumorigenesis
Authors: Cox Andrew G. , Hwang Katie L. , Evason Kimberley , Brown Kristin K. , Beltz Sebastian , O'Connor Keelin , Galli Giorgio G. , Yimlamai Dean , Chhangawala Sagar , Lien Evan , Camargo Fernando D. , Asara John , Houvras Yariv , Stainier Didier Y. , Goessling Wolfram 
Published: August 2015

Abstract
Hepatocellular carcinoma is a global health problem with poor prognosis and limited therapeutic options. Recently, the Hippo pathway has emerged as a master regulator of organ size control and tumorigenesis. However, the metabolic impact of the pathway is poorly understood. Using a transgenic zebrafish model with liver-specific activation of the Hippo pathway effector Yap, we have shown that Yap promotes hepatomegaly and liver dysplasia. In addition, we demonstrate that the Yap transgenics are highly susceptible to chemically-induced hepatocarcinogenesis. Transcriptomic and metabolomic profiling reveals that Yap enhances glutamine synthase (GS) expression and elevates steady-state levels of glutamine, respectively. Intervention studies with the GS inhibitor methionine sulfoximine established that elevated GS activity contributes to the rapid liver growth observed during Yap-driven hepatomegaly. Finally, studies in cultured human cancer cells identify GS as a bone-fide Yap target gene, confirming that the GS regulation by Yap is evolutionarily conserved. We conclude that Yap regulates GS expression and reprograms nitrogen metabolism, which contributes to liver growth during development and tumorigenesis. We hypothesize that Yap integrates the anabolic demands of rapid cell proliferation by increasing the flux of glutamine into nucleotide biosynthesis.
Citation Format: Andrew G. Cox, Katie L. Hwang, Kimberley Evason, Kristin K. Brown, Sebastian Beltz, Keelin O'Connor, Giorgio G. Galli, Dean Yimlamai, Sagar Chhangawala, Evan Lien, Fernando D. Camargo, John Asara, Yariv Houvras, Didier Y. Stainier, Wolfram Goessling. Yap reprograms glutamine metabolism and supports growth during liver development and tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5151. doi:10.1158/1538-7445.AM2015-5151