bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3900: Pten deletion in SOX9+ cells leads to tumor initiating cell expansion and tumor development in mouse liver
Authors: Zeng Ni , Kopp Janel , He Lina , Sander Maike , Stiles Bangyan 
Published: May 2015

Abstract
Liver cancer is one of the most aggressive malignancies with a five-year survival rate less than 10%. There is thus an urgent unmet need to understand the process of liver tumorigenesis in order to develop early diagnosis and effective therapeutic treatments. Clinical studies have suggested that tumor initiating cell (TIC) activation is observed in over 70% of liver cancer samples and is closely linked with poor survival outcome after treatment. Consistent with these observations, our previous studies utilizing a Pten (loxp/loxp); Albumin-Cre+ mouse liver cancer model also confirmed the expansion of TICs during liver tumorigenesis. However, how TICs are activated and what mechanisms contribute to liver tumor development remains unclear. Here, we studied the role of tumor suppressor PTEN in TICs using the Pten (loxp/loxp); SOX9-CreER+ mouse model. Lineage tracing results indicated that in the liver SOX9+ cells possess the progenitor cell characteristics and give rise to bile duct cells and peri-portal hepatocytes later on. Pten deletion in SOX9+ cells at 4 weeks of age leads to expansion of both CK+ duct cells and HNF4+ hepatocytes in the peri-portal areas. Interestingly, we also observed tumor development at 12 months old mutant mice and close examinations revealed that the tumors are heterogeneous, indicating the contribution of TICs during this process. Together, our study suggested that the PTEN signaling is critical for TICs regulation and that TICs activation plays a key role in liver tumorigenesis.
Citation Format: Ni Zeng, Janel Kopp, Lina He, Maike Sander, Bangyan Stiles. Pten deletion in SOX9+ cells leads to tumor initiating cell expansion and tumor development in mouse liver. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3900. doi:10.1158/1538-7445.AM2014-3900
Abstract 3902: Liver cancer stem cells initiate extracellular matrix remodeling
Authors: Zhang Zhiqian , Zhao Wei , Yang Xueying , Han Haibo 
Published: May 2015

Abstract
Extracellular matrix is one of the major components of cancer cell's niche. It is well appreciated that extracelluar matrix undergoes remodeling during the process of tumor progression,but the causal factors that initiate extracellular matrix remodeling are poorly understood. Hepatocellular carcinoma, like many other solid tumors, is thought to be hierarchically organized heterogeneous populations of cells with the cancer stem cell compartment sitting on top. We have identified a population of hepatocellular carcinoma cells, which were defined as α2δ1+ cells, exhibiting stem cell-like properties, such as increased invasiveness, expression of stem cell associated genes (OCT4, SOX2, NANOG, and BMI1), increased self-renewal, and the ability of giving rise to both α2δ1+ and α2δ1- cells with a novel monoclonal antibody, 1B50-1, using a whole-cell subtractive immunization approach that recognizes the isoform 5 of the cell surface voltage-gated calcium channel α2δ1 subunit. In order to understand the role of extracellular matrix in the regulation of α2δ1+ hepatocellular carcinoma stem cell properties, we first compared the expression of extracellular matrix components between α2δ1+ and α2δ1- cells. Comparing with α2δ1- cells, the expression of collagen isoforms such as COL6A3, COL1A2, and COL21A1 was up-regulated, while COL1A1, COL2A1, COL6A2 were down-regulated in α2δ1+ hepatocellular carcinoma cells. Interestingly, the collagen cross-linking enzyme-lysyl oxidase (LOX) was also upregulated in α2δ1+ liver cancer stem cells. Furthermore, as a direct target of microRNA-200b which was down-regulated in α2δ1+ liver cancer stem cells, LOX is sufficient to enable α2δ1− liver cancer cells to acquire cancer stem cell-like properties such as self-renewal and tumorigenicity. Knock-down of LOX in α2δ1+ liver cancer stem cells has resulted in decrease of self-renewal and tumorigenic properties. This data suggest that hepatocellular carcinoma stem cells may initiate their niche remodeling to maintain their cancer stem cell properties.
Citation Format: Zhiqian Zhang, Wei Zhao, Xueying Yang, Haibo Han. Liver cancer stem cells initiate extracellular matrix remodeling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3902. doi:10.1158/1538-7445.AM2014-3902
Abstract 3907: Human pancreatic cancer stem cells utilized to generate an in-vivo mouse/rat model system for screening potential drug candidates for treatment of pancreatic cancer patients
Authors: Sharma Cristian , Cleary Patrick , Gomez Esteban , Satish Shruthi , Sharma Michael , Perez Michael , Amecuza Natalee , Jani Jitesh , Punzalan Rubio , Sharma Jay P. 
Published: May 2015

Abstract
Cancer stem cells (CSCs) are critical for engraftment and long-term growth of many tumors, including pancreatic cancer. The Cancer Stem cells are less sensitive to conventional chemotherapies and radiation therapies, and treatments that can target CSCs are critically needed. Human Pancreatic Cancer is a heterogeneous tumor composed of tumor cells and small fraction of cancer stem cells, with high tumorigenic potential. Pancreatic cancer stem cells are phenotypically similar to the normal stem cells, they express CD133 gene and other genes characteristic of neural stem cells (Nestin) and posses self-renewal potential. The CD133+ Pancreatic CSCs have been isolated with Celprogen Media and ECM and characterized as chemo-/radio-resistant tumor-initiating cells which are responsible as one of the major factors involved in post-treatment recurrence. In order to explore the molecular properties of tumorigenic CD133+ Pancreatic CSCs that resist treatment, we isolated CD133+ Pancreatic CSCs from tumors that are recurrent and have previously received chemo-/radio-therapy. We found that the purified CD133+ Pancreatic CSCs sorted from the CD133+ Pancreatic CSC spheres express SOX2 ,CD44, Nestin and are capable of clonal self-renewal. We generated in-vivo model systems in mice and rats with these cells to screen potential drug agents for the treatment of Pancreatic Cancer patients. We were capable of generating Pancreatic tumors in mice and rats within 20 days by subcutaneously injecting 1000 Pancreatic CSCs at the hind limbs of the rodents. Within day 5 the Pancreatic CSCs were already present in the rodent's pancreas. At days 10, 15 & 20 the Pancreatic CSCs labeled with GFP were located in the rodent's pancreas. We tested various compound candidates in this model system and we were able to show decrease in Pancreatic tumor when the treatment was started at day 10. We were able to demonstrate gene signatures associated with Pancreatic CSCs in this model system. We do see a down regulation of certain cancer promoter genes in the treatment group when compared to non-treatment groups.
Citation Format: Cristian Sharma, Patrick Cleary, Esteban Gomez, Shruthi Satish, Michael Sharma, Michael Perez, Natalee Amecuza, Jitesh Jani, Rubio Punzalan, Jay P. Sharma. Human pancreatic cancer stem cells utilized to generate an in-vivo mouse/rat model system for screening potential drug candidates for treatment of pancreatic cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3907. doi:10.1158/1538-7445.AM2014-3907
Abstract 3912: The role of autophagy in prostate tumorigenesis and its therapeutic implications
Authors: Velasco Marco A. De , Kura Yurie , Ando Naomi , Fukushima Emiko , Hatanaka Yuji , Yamamoto Yutaka , Shimizu Nobutaka , Yoshimura Kazuhiro , Nozawa Masahiro , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: May 2015

Abstract
Autophagy is a self-catabolic process that maintains intracellular homeostasis and prolongs cell survival during metabolic stress. Increasing evidence also suggests that autophagy is induced during therapeutic stress and is believed to promote drug resistance limiting the treatment efficacy of anticancer drugs. Our goal was to define the role of autophagy during prostate cancer tumorigenesis and determine the consequences of pharmacological intervention. We used a genetically engineered mouse model of prostate cancer that is based on the PSA-Cre driven inactivation of PTEN to show that autophagy is induced during tumor progression and the transformation to castration resistant prostate cancer. We also report that inhibition of autophagy by the conditional inactivation of ATG7, a gene essential for autophagosome formation, does not contribute to initiate prostate cancer. However, simultaneous inactivation of ATG7 and PTEN leads to suppressed tumor progression in castration-naïve and CRPC models. Additionally PTEN/ATG7 double gene knockout mice were more sensitive to targeted mTOR inhibition than PTEN single gene knockouts. Pharmacological inhibition of autophagy using the lysomotropic agent chloroquine synergized with everolimus to inhibit survival of human and mouse prostate cancer cells in vitro. Despite a strong antitumor activity in vitro, the combinations of everolimus and chloroquine failed to demonstrate any meaningful improvement over everolimus alone when tested in vivo with PTEN-mutant mice. In summary, our findings demonstrate that autophagy is required for prostate cancer progression and contributes to therapeutic resistance; however, pharmacological inhibition of autophagy, using a lysomotropic agent, was ineffective in producing a meaningful antitumor benefit in an autochthonous cancer system. Our preliminary findings suggest a need for further investigation before implementing the concept of autophagy inhibition into clinical trials.
Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Yutaka Yamamoto, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. The role of autophagy in prostate tumorigenesis and its therapeutic implications. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3912. doi:10.1158/1538-7445.AM2014-3912
Abstract 3913: ATP1A1 overexpression correlates with clinical diagnosis and staging of esophageal cancer: from in vivo to human
Authors: Wu Ming-Tsang 
Published: May 2015

Abstract
Purpose: This study aims to identify the novel and potential upregulated genes related to secretionary or membranous proteins for the clinical diagnosis and staging of esophageal squamous cell carcinoma (ESCC).
Methods: By combining microarray-based screening, which contained at least 25,000 DNA oligonucleotide probes, of esophageal tumors from both N-nitrosomethylbenzylamine- and arecoline-induced F344 rats and 17 human ESCC specimens, we further confirmed the potential candidate genes by tissue arrays in 243 cancer tissues and 126 normal tissues of esophagus from Taiwan, Korea, and USA and by ELISA in 78 serum specimens of ESCC patients from Taiwan.
Results: Four candidate genes, including ATP1A1, SPINT2, CMTM8, and AGR2, were chosen due to their up-regulation in more than half of 17 paired tissues from 17 ESCC patients in the microarray-based screening. The four genes were verified by RT-PCR and immunohistochemical (IHC) staining in ESCC tissue specimens and only ATP1A1 (ATPase Na+/K+ transporting alpha 1 polypeptide) expression was consistent and further studied. Among the 243 cancer tissues and 126 normal tissues of esophagus, we found that the positive expressions of ATP1A1 by IHC staining were 207 (85%) of 243 in cancer tissues and 88 (70%) of 126 in normal tissues. After adjusted for age and sex, ATP1A1 overexpression had a 3.2-time (95% CI = 1.8-5.6) to be likely in cancer tissues than in normal tissues. ATP1A1 expression was also correlated to the tumor stage by IHC staining. Using the median level of 1,465.0 pg/mL of serum ATP1A1 protein expression as the cut-off point, we found that patients with stage III-IV had a 2.91-fold (1.12-7.36) likely to have high serum ATP1A1 levels than those with stage I-II after adjusting for age and sex.
Conclusion: ATP1A1 overexpression may serve as a potential noninvasive marker of the clinical diagnosis and staging for ESCC patients.
Note: This abstract was not presented at the meeting.
Citation Format: Ming-Tsang Wu. ATP1A1 overexpression correlates with clinical diagnosis and staging of esophageal cancer: from in vivo to human. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3913. doi:10.1158/1538-7445.AM2014-3913
Abstract 3915: Establishment of novel cell lines recapitulating the genetic landscape of uveal melanoma and preclinical validation of mTOR as a therapeutic target
Authors: Amirouchene-Angelozzi Nabil , Nemati Fariba , Gentien David , Lepage May-Linda , Nicolas André , Madic Jordan , Dumont Amaury , Carita Guillaume , Camonis Jaques , Desjardins Laurence , Cassoux Nathalie , Piperno-Neumann Sophie , Mariani Pascale , Sastre Xavier , Decaudin Didier , Roman-Roman Sergio 
Published: May 2015

Abstract
PURPOSE: Uveal melanoma is the most common primary tumor of the eye in adults. There is no standard adjuvant treatment to prevent metastases and no effective therapy in the metastatic setting. Relevant models of uveal melanoma are necessary to preclinical assessment of drugs activity. The goal of this study was to develop cell lines recapitulating the genetic landscape of uveal melanoma and identify therapeutic approaches for treatment using in vitro and in vivo models.
EXPERIMENTAL DESIGN: Tumors samples from patients or patient-derived xenografts were put into culture.The cell lines obtained were characterized for chromosomal alterations and reported recurrent mutations. They were tested for sensitivity to a selected panel of drugs including the mTOR inhibitor Everolimus. We assessed mTOR signaling activation in the cell lines and evaluated the effect of Everolimus in patient-derived xenografts.
RESULTS: We established seven uveal melanoma cell lines. All display either GNAQ or GNA11 activating mutations, three harbor BAP1 mutations, and one an EIF1AX mutation. No cell line exhibits SF3B1 mutations. mTOR pathway was shown to be activated in these cells. Everolimus reduced viability of the cell lines and significantly delayed in vivo tumor growth of 4 patient-derived xenografts.
CONCLUSIONS: Our established panel of uveal melanoma cell lines represents a relevant preclinical tool for the study of this disease. Our in vitro and in vivo data suggest that mTOR inhibition with Everolimus, most probably in combination with other agents, may be considered as a therapeutic option for the management of uveal melanoma.
Citation Format: Nabil Amirouchene-Angelozzi, Fariba Nemati, David Gentien, May-Linda Lepage, André Nicolas, Jordan Madic, Amaury Dumont, Guillaume Carita, Jaques Camonis, Laurence Desjardins, Nathalie Cassoux, Sophie Piperno-Neumann, Pascale Mariani, Xavier Sastre, Didier Decaudin, Sergio Roman-Roman. Establishment of novel cell lines recapitulating the genetic landscape of uveal melanoma and preclinical validation of mTOR as a therapeutic target. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3915. doi:10.1158/1538-7445.AM2014-3915
Abstract 3916: HSP90 mediates tumor-associated matrix metalloproteinase 2 and Cathepsin L protease activities in ovarian carcinoma
Authors: O'Brien Shane W. , Xiao Fang , Maglaty Marsia A. , Trinadad Joshua S. , Martin Lainie P. , Proia David A. , Connolly Denise C. 
Published: May 2015

Abstract
Ovarian cancer is the fifth leading cause of cancer-related deaths among women in the United States. At diagnosis, disease has commonly spread beyond the ovary. Ovarian cancer cells dislodge from primary tumor and spread locally throughout the abdominal cavity and lymphatics. Cancer cell shedding and colonization at other sites involves the degradation of extra cellular matrix (ECM) by tumor-associated proteases, such as matrix metalloproteinase (MMPs) and cathepsin proteases. Heat shock protein 90 (HSP90) is an ATP-dependent molecular chaperone that interacts with and stabilizes MMPs in some solid tumors. Whether HSP90 regulates cathepsin activity is currently unknown. To determine the role of HSP90 on tumor-associated MMP and cathepsin protease activities in ovarian carcinoma, HSP90 activity was inhibited using pharmacologic and RNA interference (RNAi) approaches. A small molecule inhibitor, ganetespib, and two HSP90 targeting siRNAs were used to determine the effects of HSP90 inhibition on ovarian carcinoma cell line invasion using transwell and spheroid invasion assays. The effects of ganetespib or HSP90 targeting siRNA treatment on MMP and cathepsin protease activities were assayed by gelatin zymography (MMPs), enzyme assay (cathepsins) and by dynamic imaging using protease cleavable imaging probes. The effects of ganetespib treatment on in vivo orthotopic tumor growth, dissemination and tumor associated protease activities were determined using human ovarian carcinoma xenograft models. In vitro, ganetespib treatment or expression of HSP90-targeted siRNAs inhibited transwell and spheroid invasion, and MMP-2 and cathepsin L protease activities. In vivo, ganetespib treatment resulted in decreased growth of primary tumors and disseminated tumor nodules and decreased tumor-associated MMP and cathepsin activities. Importantly, significant inhibition of MMP and cathepsin activities was detected prior to differences in tumor volume, demonstrating rapid functional response to the drug. These results show that HSP90 regulates ovarian carcinoma-associated proteolytic activities that are essential to tumor progression and dissemination. They also point to the potential utility of HSP90 inhibition as a therapeutic strategy for the treatment of ovarian cancer.
Citation Format: Shane W. O'Brien, Fang Xiao, Marsia A. Maglaty, Joshua S. Trinadad, Lainie P. Martin, David A. Proia, Denise C. Connolly. HSP90 mediates tumor-associated matrix metalloproteinase 2 and Cathepsin L protease activities in ovarian carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3916. doi:10.1158/1538-7445.AM2014-3916
Abstract 393: Genome-wide molecular characterization of CIMP positive stage III colon cancer using cDNA microarray analysis
Authors: Jeon Hongjae , Kim Se Hyun , Park Kyu Hyun , Jeung Hei-Cheul , Kim Nam Kyu , Jung Minkyu , Lee Kang Young , Park Chan Hee , Rha Sun Young , Chung Hyun Cheol , Ahn Joong Bae 
Published: May 2015

Abstract
Background: The CpG island methylator phenotype (CIMP) is a distinctive subtype of colon cancers, which leads to the loss of tumor suppressor gene functions by epigenetic regulation. However, molecular characteristics of CIMP+ cancers are not fully understood. Here, we aimed to elucidate the different patterns of gene expression according to the CIMP status.
Method: 158 patients with stage III colon cancer were enrolled for the analysis of CIMP status. Pyrosequencing was used to examine the methylation status of 7 CpG island loci (p14, p16, MINT1, MINT2, MINT31, hMLH1, and WNT5a) in DNA extracted from formalin-fixed paraffin-enbedded specimens. Gene expression analyses of the same samples were also performed using a human cDNA microarray to identify molecular signatures.
Result: Among the 158 patients, 31 (19.3%) were CIMP+. Microarray results revealed distinctive gene expression profiles between CIMP+ and CIMP- cancers. Among 57 genes which showed significant changes between CIMP+ and CIMP- cancers, Axin2, the canonical Wnt suppressor, displayed the strongest correlation with the CIMP status (p=0.007). Axin2 was downregulated in CIMP+ cancers compared to CIMP- cancers (p=0.005). In terms of disease-free survival (DFS), tumors with low Axin2 expression showed poor prognosis compared to tumors with high Axin2 expression in microsatellite stable (MSS) patients (p=0.038), while there were no significant changes in DFS of microsatellite instable (MSI) patients (p=0.32). These findings indicate the clinical importance of epigenetic silencing of Axin2 and the subsequent activation of Wnt signaling pathway in MSS colon cancer patients.
Conclusion: Axin2 is downregulated in CIMP+ stage III colon cancer patients and the consequent decreased expression of Axin2 is a poor prognostic factor for the DFS in MSS patients.
Citation Format: Hongjae Jeon, Se Hyun Kim, Kyu Hyun Park, Hei-Cheul Jeung, Nam Kyu Kim, Minkyu Jung, Kang Young Lee, Chan Hee Park, Sun Young Rha, Hyun Cheol Chung, Joong Bae Ahn. Genome-wide molecular characterization of CIMP positive stage III colon cancer using cDNA microarray analysis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 393. doi:10.1158/1538-7445.AM2014-393
Abstract 3934: Angiogenin and PlexinB2 promote glioblastoma progression by stimulating tumor angiogenesis, cancer cell survival and invasion
Authors: Yang Hailing , Hu Guo-fu 
Published: May 2015

Abstract
Glioblastoma (GBM) tumors secrete high level of angiogenic factors and feature vascular abnormality. Targeted therapy, such as Bevacizumab, which neutralizes VEGF and normalizes tumor vasculature, has been approved to treat recurrent GBM. However, it only marginally increases patients' overall survival with inevitable resistance. It suggests that therapy targeting complementary angiogenic pathway in GBM could suppress Bevacizumab resistance and extend patients' survival.
Angiogenin (ANG) is involved in tumor angiogenesis where it regulates ribosomal RNA transcription and functions downstream of VEGF and other related angiogenic factors. Like VEGF, ANG is also up-regulated in GBM patients. Inhibition of ANG by neutralizing monoclonal antibody delays U87 human GBM xenografts on nude mice. My preliminary data have shown that ANG is essential for GBM cell line s.c. vessel formation and tumor proliferation. In Rcas/tva orthotropic GBM model, Ang1 knockout mice show lower penetration and better survivals. ANG knockdown increases apoptosis during GBM cell line colony formation in agarose. Notably, ANG's role in tumor proliferation might extend beyond GBM, since oncogenic KRas transformed Ang1 knockout MEFs also fail to grow in agarose. Lastly, I have shown that PlexinB2, ANG cellular receptor, can mediate ANG cellular uptake and also modulate GBM apoptosis in agarose. In conclusion, inhibition of ANG inhibits GBM progression both in vitro and in vivo and thus represents a new molecular target for GBM treatment.
Citation Format: Hailing Yang, Guo-fu Hu. Angiogenin and PlexinB2 promote glioblastoma progression by stimulating tumor angiogenesis, cancer cell survival and invasion. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3934. doi:10.1158/1538-7445.AM2014-3934