bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3278: Novel knock-in mice expressing human/mouse chimeric endoglin (ENG; CD105) develop normally and will be valuable for evaluating clinical application of anti-human ENG antibodies
Authors: Toi Hirofumi , Duzen Jill , Fujita Kanako , Tsujie Masanori , Tsai Hilda , Seon Ben K. 
Published: June 2012

Abstract
The major objective of this study is to develop a novel animal model to facilitate optimal clinical application of anti-human ENG (huENG) monoclonal antibodies (mAbs) to treat cancer patients. ENG is a proliferation-associated homodimeric cell membrane antigen of endothelial cells and leukemia cells. It is strongly expressed on angiogenic vascular endothelium in tumors and also expressed in lymphatic vessels in tumors. Furthermore, ENG is a TGF-β coreceptor and essential for angiogenesis/vascular development. Mice lacking ENG die from defective vascular development. Mutations in the huENG gene are associated with hereditary hemorrhagic telangiectasia type 1 (HHT1) which is characterized by vascular malformations and recurrent bleeding. huENG shows a relatively restricted expression pattern in tissues and cells. We hypothesized that huENG is a safe and effective target in vascular-targeting antiangiogenic therapy (VTAT). Clinical trials of a chimeric anti-huENG mAb c-SN6j (also known as TRC105) are in progress (ClinicalTrials.gov Identifier: NCT00582985 and NCT01090765). The major obstacle in animal model studies of anti-huENG mAbs is that most anti-huENG mAbs do not react with mouse ENG or mouse endothelial cells. To overcome this obstacle, we generated knock-in mice expressing human/mouse chimeric ENG. We designed the chimeric vectors to contain huENG gene segments of desired location and length so that the expressed huENG protein contains desired epitopes. Nevertheless, the major concern was that the generated knock-in mice might suffer from defective vascular development or HHT-like symptoms if the chimeric ENG does not function properly in mice. We generated two types of knock-in mice containing different sizes of huENG gene. In both cases, mice develop normally and show no sign of HHT-like symptoms in the homozygous mice. Tumors of 4T1 breast cancer cells and Colon26 colon cancer cells were generated in the knock-in mice to test expression of chimeric ENG protein in the tumor microvessels. Immunohistochemical staining of the tumors using several anti-huENG mAbs showed that the tumor microvessels express desired epitopes of huENG protein which are candidate targets for VTAT. The epitopes defined by these mAbs have been mapped. This novel knock-in mouse model will be useful for evaluating antitumor efficacy of many anti-huENG mAbs. In addition, this model will be useful for evaluating appropriate combination of an anti-huENG mAb with other anticancer agents to achieve optimal antitumor efficacy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3278. doi:10.1158/1538-7445.AM2011-3278
Abstract 3292: The exploration of novel strategy for treatment of pancreactic cancer using genetically engineered mice
Authors: Tada Motohisa , Ijichi Hideaki , Miyabayashi Koji , Mohri Dai , Asaoka Yoshinari , Ikenoue Tsuneo , Tateishi Keisuke , Mikata Rintarou , Ishihara Takeshi , Kanai Fumihiko , Imazeki Fumio , Moses Harold L. , Omata Masao , Yokosuka Osamu 
Published: June 2012

Abstract
(Background and Aim) Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease in human. Previously, we have reported a genetically engineered mouse PDAC progression model which has pancreatic-specific transforming growth factor-beta receptor type II knockout in the context of Kras activation (Ijichi H, et al 2006). This model shows PDAC with 100 % penetrance and recapitulates the signature of human PDAC well. Using this model, we explored novel treatment for PDAC.
(Materials and Methods) For single agent treatment, mice were treated orally 6 times per week with vehicle (0.5 % carboxymethyl cellulose, CMC), sunitinib, axitinib, 5 kinds of anigiotensin II receptor blockers (ARBs), such as candesartan, telmisartan, losartan, valsartan, or olmesartan, respectively from the 3 wk of age. For combined agent experiment, mice were treated orally with vehicle (0.5 % CMC), axitinib or candesartan from the 3 wk of age and also treated with saline or gemcitabine, i.p. twice a week, from the 4 wk of age. Treatment continued until the mice became distressed, and then they were dissected. In vivo anti-tumor effect and survival time were assessed. Immunostaining of tumor tissue for caspase 3, Ki67, CD31, and VEGF was performed.
(Results)Median survival time of single use of axtinib and sunitinib group was statistically longer and that of candesartan and telmisartan group was tended to be longer than that of control group. Axtinib, sunitinib, candesartan, and telmisartan group showed significant anti-tumor effect in vivo. In the combined treatment experiment, using gemcitabine showed statistically significant longer survival and more anti-tumor effect than that of single agent treatment group. Axitinib and sunitinib group showed significantly higher caspase 3 score and lower Ki67 score than that of control, however, candesartan and telimisartan group showed no change of these scores, compared to control. Microvessel density of axtinib, sunitinib, candesartan, and telmisartan group was significantly lower than that of control and other ARBs. VEGF expression of candesartan and telmisartan group was significantly lower than that of control and other ARBs.
(Conclusion)Targeting angiogenesis with multikinase inhibitor or ARB in addition to gemcitabine may be a promising therapeutics for PDAC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3292. doi:10.1158/1538-7445.AM2011-3292
Abstract 3296: KLF9, a differentiation-associated transcription factor, suppresses Notch1 signaling and inhibits glioblastoma-initiating stem cells
Authors: Ying Mingyao , Sang Yingying , Li Yunqing , Guerrero-Cazares Hugo , Quinones-Hinojosa Alfredo , Vescovi Angelo L. , Eberhart Charles G. , Xia Shuli , Laterra John 
Published: June 2012

Abstract
Tumor-initiating stem cells (alternatively called cancer stem cells, CSCs) are a subpopulation of tumor cells that plays unique roles in tumor propagation, therapeutic resistance and tumor recurrence. It is becoming increasingly important to understand the molecular signaling that regulates the self-renewal and differentiation of CSCs. Transcription factors are critical for the regulation of normal and neopolastic stem cells. The Krüppel-like family of transcription factors (KLFs) consists of 17 evolutionarily conserved zinc finger containing proteins with diverse regulatory functions. KLFs bind to GC-GT rich sites in gene promoter and enhancer regions and are known to contextually regulate the growth, proliferation, and differentiation of cells including non-neoplastic stem cells and cancer cells.
Here, we examined the expression and function of KLF transcription factors in human glioblastoma (GBM)-drived neurosphere lines and low passage primary GBM-derived neurospheres that are enriched for tumor-initiating stem cells. We identify KLF9 as a relatively unique differentiation-induced transcription factor in GBM-derived neurospheres. KLF9 knockdown rescues GBM-derived neurospheres from Retinoic -acid-induced growth inhibition and differentiation. KLF9 induction is shown to induce neurosphere cell differentiation, inhibit neurosphere formation and deplete neurospheres of CD133+ stem-like cells. KLF9 induction also inhibits the growth of tumor xenografts established from GBM-derived neurospheres. We also show that KLF9 regulates GBM neurosphere cells by binding to the Notch1 promoter and suppressing Notch1 expression and downstream signaling. We compared the KLF9 expression between human GBM tumors and non-neoplastc human specimens. KLF9 is down regulated in human GBM tumors relative to normal brain.
Our findings expand the role of KLF family members in stem cell and cancer biology, support KLF9 as a regulator of GBM malignancy, and as a potential biomarker and target for cancer therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3296. doi:10.1158/1538-7445.AM2011-3296
Abstract 3302: The effects of the g-quadruplex ligand telomestatin to human brain tumor stem cell survival and growth
Authors: Miyazaki Takeshi , Pan Yang , Hu Bin , Demir Habibe , Joshi Kaushal , Okabe Sachiko , Yamori Takao , Viapiano Mariano , Shin-ya Kazuo , Seimiya Hiroyuki , Nakano Ichiro 
Published: June 2012

Abstract
Glioblastoma multiforme (GBM) is the leading cause of death among primary brain tumors in adults and the current therapies have only palliative effect on prognosis of patients. Recently, stem cell-like cells in GBM (brain tumor stem-like cells; BTSC) have gained substantial attention as a potential therapeutic target. Hallmarks of BTSC include their self-renewal capacity and highly migratory potential. In this study, we demonstrate that treatment of patient-derived BTSC with a G-quadruplex ligand, telomestatin (TMS), inhibits BTSC self-renewal and maintenance of their stem cell state, and induces their apoptosis in vitro and in vivo. In contrast, both normal precursors and non-stem tumor cells from the matched samples are relatively resistant to TMS treatment. Treatment with a lower dose of TMS specifically inhibits BTSC migration into normal brain. Immunofluorescence in situ hybridization with TMS-treated GBM cells displays both telomeric and non-telomeric DNA damage in BTSC but not in non-stem tumor cells. cDNA microarray analysis identifies a proto-oncogene, c-Myb, as a target of TMS in BTSC, and the pharmacodynamic analysis with TMS-treated tumor-bearing mouse brains demonstrates reduction of c-Myb expression in tumors. An elevated c-Myb expression is found in surgical specimens of GBM compared to normal brain tissues. Lastly, TMS treatment of BTSC-derived mouse intracranial tumors reduces tumor sizes in vivo without any noticeable apoptotic cells in the normal brain, and a combined treatment of TMS with radiation or temozolomide results in additive inhibitory effects on GBM sphere growth in vitro. Collectively, these data indicate a potential avenue toward BTSC-directed therapeutic strategy using TMS via telomeric DNA damage and inhibition of c-Myb, which may offer a novel therapeutic approach for GBM.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3302. doi:10.1158/1538-7445.AM2011-3302
Abstract 3303: BRAF activation induces cellular transformation and senescence and down-regulates SOX2 in human neural stem cells: a model of pilocytic astrocytoma
Authors: Raabe Eric H. , Lim Kah Suan , Mao Xing-Gang , Bar Eli , Meeker Alan , Kahlert Ulf , Maciaczyk Jaroslaw , Nikkhah Guido , Eberhart Charles G. 
Published: June 2012

Abstract
In pilocytic astrocytomas, the primary molecular alteration is BRAF activation occurring via gene duplication/fusion or V600E point mutation. To investigate the mechanisms by which BRAF activation leads to transformation, BRAF V600E was introduced into cortical and cerebellar human fetal neural stem and progenitor cells. Overexpression of BRAF V600E did not lead to increases in cellular proliferation compared to controls, but did promote colony forming ability in soft agar. However, after initially growing well, BRAF V600E expressing cells subsequently showed decreased proliferation as compared to control cells, though they remained viable visually. Because constitutive BRAF activation in melanocytes usually leads to cellular senescence, with only rare lesions progressing to melanoma, we examined if senescent markers were induced in our system. Overexpression of BRAF V600E led to an increase in markers of oncogene-induced senescence, such as acidic beta-galactosidase and p16. FISH analysis revealed no differences in telomere length in BRAF over-expressing cells compared to GFP-transduced control cells, indicating that this phenotype was not due to telomere shortening. The pattern of initial transformation followed by senescence is similar to the frequently indolent course of pilocytic astrocytoma, suggesting that overexpressing constitutively active BRAF in human neural stem and progenitor cells phenocopies the behavior of this tumor. To further investigate the mechanism of oncogene-induced senescence, we examined SOX2 expression. This human somatic cell reprogramming factor is an important neurodevelopmental gene and is known to prevent the induction of cellular senescence. However, the functional role of SOX2 in gliomas is poorly understood. We found that although SOX2 was expressed in control GFP transduced neurospheres, high-level expression of BRAFV600E led to downregulation of SOX2 in association with senescence. Our data support the concept that BRAF oncogene-induced senescence plays a role in the pathobiology of pilocytic astrocytoma, and suggest that modulation of SOX2 may play an important role in this process.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3303. doi:10.1158/1538-7445.AM2011-3303
Abstract 3314: Potential role of mitochondrial respiration in serum-induced tumor stem cell differentiation
Authors: Hammoudi Naima , Wang Feng , Huang Peng 
Published: June 2012

Abstract
Glioblastoma remains the deadliest form of brain tumors. The poor prognosis of glioblastoma patients is associated with a high rate of relapse after therapy. It has been suggested that the presence of cancer stem cells, which are relatively resistant to radiation and chemotherapy, may play a significant role in the recurrence of brain tumor. Understanding the biological property of brain tumor stem cells is important to develop effective therapeutic strategies for glioblastoma. In vitro, glioblastoma stem cells cultured in serum-free medium form self-renewing neurospheres, express the neural stem marker CD133, and are highly tumorigenic. On the other hand, in the presence of fetal bovine serum (FBS), the glioblastoma stem cells tend to undergo differentiation. In this study we used glioblastoma stem cells, NSC11 and NSC23, previously isolated from glioblastoma patients and expressed stem cell markers CD133 and SOX 2, to explore their bioenergetics by monitoring the oxygen consumption as an indication of mitochondrial respiration cultured in serum-free medium in comparison with that incubated in medium containing 5% FBS. We found that NSC11 and NSC23 stem cells exhibited low mitochondrial respiration when cultured in stem cell medium without serum. Upon exposure to 5% fetal bovine serum, mitochondrial respiration increased significantly. Moreover we assessed the protein expression of the mitochondrial respiratory complex (MRC) components in the cells cultured in serum-free medium in comparison with that in medium containing 5% FBS for various lengths of time by western blotting analysis. We observed a marked up-regulation of the protein subunits of MRC complexes I and IV in glioblastoma stem cells when they were exposed to FBS. Analysis of the mRNA expression levels for the mitochondrial DNA-encoded MRC components showed an increase in the expression of these genes, indicating an increase in the mitochondria biogenesis upon the FBS exposure. Based on these preliminary findings, we postulate that maintaining low mitochondrial respiration may be important to maintain the stemness of the glioblastoma stem cells, while the activation of the respiration may promote stem cell differentiation and affect their tumorgenecity. Further studies are required to elucidate the detail molecular pathways governing glioblastoma stem cell self-renewal and differentiation and the mechanistic link to mitochondrial function.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3314. doi:10.1158/1538-7445.AM2011-3314
Abstract 3319: Cell cycle regulation of glioblastoma progression by cord blood stem cells is mediated by downregulation of cyclin D1
Authors: Velpula Kiran Kumar , Dasari Venkata Ramesh , Tsung Andrew J. , Gondi Christopher S. , Klopfenstein Jeffrey D. , Mohanam Sanjeeva , Rao Jasti S. 
Published: June 2012

Abstract
Normal progression of the cell cycle requires sequential expression of cyclins. Rapid induction of cyclin D1 and its associated binding with cyclin-dependent kinases, in the presence or absence of mitogenic signals, is considered a rate-limiting step during cell cycle progression through the G1 phase. In the present study, human umbilical cord blood stem cells (hUCBSC) co-cultured with glioblastoma cells (U251 and 5310) not only induced G0-G1 phase arrest, but also reduced the number of cells at the S and G2-M phases of the cell cycle. Western and FACS analyses of cell cycle regulatory proteins showed decreased expression levels upon treatment with hUCBSC. Co-localization experiments under in vivo conditions in nude mice brain xenografts with cyclin D1 and CD81 antibodies demonstrated decreased expression of cyclin D1 in the presence of hUCBSC. Treatment with hUCBSC decreased expression of the cyclin D1 and CDK4 complex as well as cyclin D1 and CDK6 complexes. However, there was no significant change in the CDK4 and CDK6 complex. Our results indicate that hUCBSC can attenuate uncontrolled cell cycle progression of glioma cells by downregulating the expression levels of cyclin D1 and its partner kinases CDK4 and CDK6 at the cell cycle level. Our data elucidate a model to regulate glioma cell cycle progression in which hUCBSC act to control cyclin D1 induction and its partner kinases, CDK4 and CDK6, by mediating cell cycle arrest via G0-G1 arrest.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3319. doi:10.1158/1538-7445.AM2011-3319
Abstract 3331: An increase in cancer stem cell population after primary systemic therapy is a poor prognostic factor in breast cancer
Authors: Lee Hee Eun , Kim Jee Hyun , Kim Yu Jung , Kim Sung-Won , Kim In Ah , Kim Eun Joo , Park So Yeon 
Published: June 2012

Abstract
Introduction: The cancer stem cell (CSC) hypothesis has important clinical implications for cancer therapeutics because of the proposed role of CSCs in chemoresistance. The aim of this study was to investigate changes in the CSC populations before and after primary systemic therapy (PST) and their prognostic role in human breast cancer.
Methods: Paired samples (before and after PST) of breast cancer tissue were obtained from clinical stage II or III patients (n=92) undergoing PST and subsequent breast resection. The proportions of putative CSCs with CD44+/CD24- or ALDH1+ phenotypes were determined by immunohistochemistry.
Results: A higher proportion of CD44+/CD24- tumor cells and ALDH1 positivity in pre-chemotherapy biopsy was correlated with higher histologic grade, estrogen receptor negativity, high Ki-67 proliferation index and basal-like subtype of breast cancer. ALDH1 positivity in pre-chemotherapy biopsy was also associated with a higher rate of pathologic complete response (pCR) following PST. In comparisons of putative CSC populations before and after PST, the proportions of CD44+/CD24- and ALDH1+ tumor cells were significantly increased after PST. The cases with increased CD44+/CD24- tumor cell populations after PST showed high Ki-67 proliferation index in post-chemotherapy specimens and those with increased ALDH1+ tumor cell population after PST were associated with estrogen receptor negativity and p53 overexpression. Furthermore, cases showing such an increase had significantly shorter disease-free survival time than those with no change or a reduced number of CSCs.
Conclusions: The present study provides the clinical evidence that the putative CSCs in breast cancer are chemoresistant and are associated with tumor progression, emphasizing the need for targeting of CSCs in the breast cancer therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3331. doi:10.1158/1538-7445.AM2011-3331
Abstract 3360: Epithelial-mesenchymal transition (EMT) stimulates tumor cells to produce invadopodia-like protrusions in collagen matrix, suppressing cell growth
Authors: Oyanagi Jun , Higashi Shouichi , Miyazaki Kaoru 
Published: June 2012

Abstract
Epithelial tumor cells often change their epithelial phenotype to mesenchymal one when they invade into surrounding stromal tissue. This change, called epithelial-mesenchymal transition (EMT), is thought to be a crucial event in tumor progression. EMT is known to be regulated by environmental factors. However, it is unclear how EMT contributes to invasive growth of tumor cells. To address this question, we characterized EMT-induced tumor cells under various conditions in vitro. EMT was induced in three human carcinoma cell lines of the lung, pancreas and stomach by treating with TGF-beta and/or TNF-alpha. The EMT treatment of these cell lines induced expression of the invasion marker laminin gamma2 chain and MT1-MMP, in addition to other well-known phenotypes such as the morphological change and vimentin expression. EMT induction enhanced cell motility in monolayer culture. Although EMT cells showed comparable cell growth with the control cells in monolayer culture, their growth rates were extremely suppressed in collagen gel and soft agar culture conditions. Most characteristically, EMT-induced tumor cells commonly and markedly extended invadopodia-like protrusions in collagen gel. Such protrusion formation in collagen gel was effectively blocked by the TGF-beta/Smad pathway inhibitor SB431542 but scarcely suppressed by the synthetic and natural MMP inhibitors, TAPI-1 and TIMP-2, respectively. These data suggest that EMT may enhance interstitial tumor infiltration without cell growth by promoting prominent invadopodia formation and cell motility. The TGF-beta-induced cytoskeletal change seems to play a more critical role than MMP expression in the tumor invasion.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3360. doi:10.1158/1538-7445.AM2011-3360