bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3287: Investigating the role of PTX3 in cervical cancer
Authors: Wada Yumi , Akutagawa Osamu , Nishi Hirotaka , Higuma Chinatsu , Terauch Fumitoshi , Isaka Keiichi 
Published: February 2011

Abstract
Tumor progression requires tumor angiogenesis, as newly-formed blood vessels supply necessary oxygen and nutrition to the growing tumor. Many unknowns remain in our understanding of the cancer metastasis process.
Pentraxin3 (PTX3) is categorized as a long pentraxin in the pentraxin family and is produced by macrophages and vascular endothelial cells. PTX3 concentrations reportedly increase with exposure to IL-1 and TNF-α. Recently, PTX3 has gained attention as a potential marker that reflects inflammation in blood vessels, as well as that which may predict the onset of various diseases, including vascular diseases.
The present study examined whether or not an analysis of PTX3 expression may contribute to a mechanistic understanding of carcinogenesis (metastasis) of cervical cancer.
Subjects and Methods:
Cervical Cancer Cell Lines
A comparative study of PTX3 was performed at the protein level and the RNA level by cultivating each of the cervical cancer cell lines CasKi and SiHa under normal conditions and under hypoxic conditions.
Clinical Tissue Samples
Normal cervical tissues (n=7) and cervical cancer tissues (n=20) were collected from subjects after an explanation of the study was given and consent was obtained. PTX3 expression in both groups was compared.
All measurements were taken using ELISA, Western blot, and real time RT-PCR methods.
Results:
Increased PTX3 expression was observed both at the protein level and at the RNA level in cervical cancer cell lines grown under hypoxic conditions. Conversely, in clinical samples, we observed many samples for which PTX3 expression decreased in cervical cancer samples, contrary to our expectations.
Discussion:
These results indicate a potential role of PTX3 in the carcinogenesis mechanism of cervical cancer. Further, PTX3 may exhibit cytoprotective effects, which may have played a role in our present study. Future investigation of these results is necessary.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3287.
Abstract 3292: Discordance between receptor status in primary and metastatic breast cancer: No discordance for HER-2 based on IHC and FISH
Authors: Lee Soohyeon , Koo Ja Seung , Park Jong-Pil , Park Byeong-Woo , Kim Seung-Il , Park Seho , Moon Yongwha , Roh Jae Kyung , Kim Joohang , Jung Hyun Cheol , Sohn Joohyuk 
Published: February 2011

Abstract
Background: The assessment of tumor receptor profile (ER, PR, and HER-2) is necessary to select patients who are candidate for hormonal and anti-HER-2 therapy. The occurrence of changes in tumor receptor profile (ER, PR and HER-2) between primary and metachronous metastatic tissue has been recognized, which might have significant implications in terms of treatment. The primary aim of this analysis was to compare ER, PR and HER-2 status in primary tumor versus metastatic sites in breast cancer patients.
Materials and Methods: Thirty patients with available paired samples from both primary tumors and metastases were included in this study and re-analyzed by an independent and blind pathologist. HER-2 status was evaluated by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH); ER and PR status were assessed by IHC.
Results: The median age was 40.3 years (range: 27.6∼87.4 years) and 25(83%) patients were premenoposal status. For paired metastases, a change in ER status was observed in 3 cases (10%): 2 cases from positive to negative, while 1 case converted from negative to positive and a change in PR status was observed in 4 cases (13.3%). HER-2 status was not changed in all cases based on IHC and FISH technique. In addition, there was a strong correlation of amplification index (AI) between primary and metastatic tissue based on FISH test (p&lt;0.0001).
Conclusions: This study suggests that while there was around 10% of discordance rate for hormone receptor status, HER2 receptor discordance was not found between primary and metastatic breast cancer samples.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3292.
Abstract 33: Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
Authors: Fantin Valeria R. , Dang Lenny , White David W. , Gross Stefan , Bittinger Mark A. , Driggers Edward M. , Jang Hyun Gyung , Jin Shengfang , Keenan Marie C. , Marks Kevin M. , Yen Katharine E. , Ward Patrick S. , Prins Robert M. , Liau Linda M. , Bennett Bryson D. , Rabinowitz Joshua D. , Cantley Lewis C. , Thompson Craig B. , Heiden Matthew Vander , Su Shinsan M. 
Published: February 2011

Abstract
Mutations in the enzyme isocitrate dehydrogenase 1 (IDH1) are a common feature of most gliomas and secondary glioblastomas, as well as approx 10% acute myeloid leukemias. This event results in loss of the enzyme's ability to catalyze conversion of isocitrate to α -ketoglutarate. However, these mutations are all heterozygous and occur at a single amino acid residue of the IDH1 active site consistent with an enzymatic gain of function rather than a simple loss of function. To test this hypothesis we characterized mutant IDH1 (IDH1m) biochemically. We have shown that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2-HG). Patients with an inherited, neurometabolic disorders called 2-hydroxyglutaric aciduria exhibit an accumulation of 2-HG in their CNS, and an increased risk of developing malignant brain tumors. Similarly, in human malignant gliomas harboring IDH1 mutations, we find elevated levels of 2-HG. Altogether our data demonstrate that the IDH1 mutations result in production of 2-HG, and suggest that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 33.
Abstract 3318: Molecular targeting of brain tumor stem cells
Authors: Eyler Christine E. , Forrester Michael T. , MacSwords Jennifer M. , Wu Qiulian , LaFiura Katherine M. , Lathia Justin D. , Sloan Andrew E. , Lee Jeongwu , McLendon Roger E. , Hjelmeland Anita B. , Rich Jeremy N. 
Published: February 2011

Abstract
Although current therapeutic strategies for malignant gliomas are non-specifically directed against the tumor bulk, increasing evidence suggests that a single glioma contains a range of phenotypically disparate cell populations with differential capacity for tumor maintenance and initiation. Recent work in brain tumors suggests the existence of cellular sub-populations (known as cancer stem cells, or CSCs) that possess stem cell-like behaviors and a potent capacity for tumor initiation in transplantation assays relative to non-CSCs. Specifically targeting the highly tumorigenic CSCs has the potential to improve the prognosis of malignant glioma patients, but many molecularly-directed anti-CSC agents may also compromise the survival of normal neural stem cells due to molecular similarities between CSCs and normal stem cells. Here we demonstrate that malignant glioma CSCs express high levels of a particular protein relative to non-CSCs. Glioma CSC growth and tumorigenic capacity were abrogated by multiple strategies interfering with the expression and activity of this protein, including RNA interference, pharmacological inhibition, and heterologous expression of a prokaryotic enzyme that specifically consumes the enzymatic product of this critical protein. Importantly, tumor growth was inhibited by systemic treatment of xenograft-bearing mice with a well-studied small molecule inhibitor of this protein that has already demonstrated low toxicity in clinical trials for other diseases. Though the activity of this protein appears critical for the maintenance of highly tumorigenic glioma CSCs, our examination of both normal human neural progenitor cells and neural stem cells derived from genetically disrupted mice indicate no substantial role for this protein in normal neural stem cells. Our findings identify a novel glioma therapeutic target with a negligible role in normal neural stem cells, suggesting clinical utility for selective inhibitors of this CSC-specific molecular target.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3318.
Abstract 3325: Cancer stem cell like properties of 5-fluorouracil resistant Panc-1 cell
Authors: Izumiya Motoko , Higuchi Hajime , Kabashima Ayano , Igarashi Toru , Nakamura Shoko , Funakoshi Shinsuke , Adachi Masayuki , Takaishi Hiromasa , Hibi Toshifumi 
Published: February 2011

Abstract
Cancer stem cells (CSCs), a small fraction of tumor-initiating cells, are known to be resistant to chemotherapy-induced apoptosis. CSCs are considered to be responsible for self-renewal/differentiation, invasion, and metastasis of malignant tumor. We have previously reported that pancreatic cancer derived side population (SP) cells, a cancer stem cell enriched fraction, were more resistant to chemotherapeutic agents and more likely to cause epithelial-to-mesenchymal transition (EMT) compare to major population (MP) cells. Therefore, we formulated the HYPOTHESIS that 5-fuluorouracil (5-FU) resistant population cells are enriched with CSCs. The AIM of this study is to evaluate whether apoptosis-resistant cancer cells have CSC-like properties, i.e., self-renewal, local invasion and EMT. METHODS: Seventy to eighty percent confluent pancreatic cancer cells, PANC-1, were incubated in the presence of 5-FU (30mg/ml) for 24 hours, and further incubated for one to five weeks without 5-FU. To assess the capacity of self-renewing, cells were planted using a method for anchorage-independent culturing to form spheroids. EMT was induced with TGF-beta (7.5 ng/ml, for 3 days), then evaluated mRNA expression by real time PCR for E-cadherin, Snail, and vimentin. E-cadherin protein level was also examined for immunoblot analysis. Activity of local invasion was analyzed by Matrigel invasion assay. To evaluate tumorigenicity, 5-FU resistant cells were injected into NOD/SCID mice. RESULTS: 5-FU induced significant apoptosis in PANC-1 cells, reducing the number of surviving cells to less than one percent. The survived cells showed a colony-forming activity as they started to re-proliferate at four weeks after 5-FU removal. There was a group of cells among the 5-FU resistant surviving cells, that gradually regains sensitivity to 5-FU by re-plating. The frequency of cells that were capable of initiating spheres was higher in 5-FU resistant cells and they over expressed stem cell marker genes, Oct 4 and Nanog. Incubation with TGF-beta induced EMT-associated gene alterations. These alterations were greater in 5-FU resistant surviving cells as compared to untreated cells. Matrigel invasion activity of apoptosis-resistant PANC-1 cells was greater by seven fold than controlled cells. In addition, in vivo tumor experiments showed 5-FU resistant cells to be more tumorigenic than conventional Panc-1 cells. In CONCLUSION, apoptosis-resistant cancer cells have CSC-like properties, i.e., initiating sphere formation, expressing stem cell genes, and respond to EMT stimulation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3325.
Abstract 3334: Telomerase activity corresponds to the level of aggressiveness of ovarian cancer stem cells and are a potential site of targeted therapy
Authors: Meng Erhong , Taylor Brandon A. , Shevde Lalita A. , Rocconi Rodney P. 
Published: February 2011

Abstract
Objective:
Cancer stem cells possess the important property of self-renewal. Telomerase activity (TA) is often used as a molecular marker for cancer aggressiveness and allows propagation of cancer cells by adding telomere repeats which can result in unlimited cell replication. As such, the potential of telomerase in maintaining self-renewal properties of cancer stem cells have been proposed. Our objectives were to determine the TA of ovarian cancer stem cells (OSC) and the effectiveness of targeting telomerase for cancer therapy.
Methods
Ovarian cancer cell lines (ES2, TOV112D, and SKOV3) were grown in non-adherent growth conditions to form spheroid forming cells for numerous successive spheroid generations. Flow cytometry determined the CD44+/CD24- phenotype consistent with cancer stem-cells. Histologic subtypes were chosen to correspond to decreasing levels of aggressiveness: ES2- clear cell; SKOV3- papillary serous; and TOV112D- endometrioid. TRAPEZE RT Telomerase Detection Kit utilized flourescently labeled primers to detect and quantify telomerase activity by RT-PCR. Results were confirmed with luciferase reporter plasmid containing promoter of human telomerase reverse transcriptase (hTERT). Each cancer cell line was treated with 10, 20, 50, and 100uM of a small molecule telomerase inhibitor BIBR1532 measured by cell proliferation survival assay for a total of 72 hours.
Results
All ovarian cancer cell lines readily formed spheroids in non-adherent growth conditions with flow cytometry demonstrating the enrichment of cancer stem cell phenotype: CD44+/CD24-. TA was significantly increased in spheroid forming cells enriched for OSC in both ES2 (5-fold increase) and SKOV3 (6-fold increase) (p &lt; 0.001), however TOV112D showed a decrease in TA. Similarly, ES2 and SKOV3 showed significant TA by luciferase assay with 400% and 1,700%, respectively (p &lt; 0.001), while TOV112D had a decrease in TA. In all cell lines studied, treatment with BIBR1532 demonstrated significant cell death in a dose-dependent fashion with a 5-fold cell kill and only 20% of cancer cell survival at 72 hours.
Conclusions
Telomerase activity appears to increase with ovarian cancer stem cells and supports the hypothesis that it could be important in the self-renewal properties of cancer stem cells. Inhibition of telomerase with a competitive small molecule demonstrated significant response in-vitro and could represent novel targeted therapy for ovarian cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3334.
Abstract 3343: Targeting thyroid cancer stem cells with PPARγ agonists
Authors: Vu-Phan Dang L. , Koenig Ron , Wicha Max 
Published: February 2011

Abstract
Ligand activation of PPARγ is reported to inhibit proliferation and promote differentiation in many tissue types, including thyroid. Nonetheless, clinical trials treating thyroid cancer with the PPARγ agonist rosiglitazone yielded disappointing results when the measured outcomes were reacquisition of radioiodine uptake and overall survival. We report here evidence that PPARγ agonists preferentially target cancer stem cells and may still be useful for treatment of thyroid cancer in a different context, especially in combination with reagents that can target the remaining bulk of the tumor.
We used for our studies FTC236 and FTC238, two related cell lines derived from follicular thyroid carcinoma metastases to lymph node and lungs. Both cell lines had robust PPARγ expression and harbored no known PPARγ fusion protein.
Stem cell populations within the cell lines were measured using the Aldefluor (Aldf) assay for Aldehyde Dehydrogenase activity. Both cell lines have 5-10% Aldf+ cells. Populations which contained Aldf+ were the only ones capable of forming passageable sphere colonies in serum free suspension cultures and the only ones capable of forming tumors in NOD/SCID mice. Furthermore, FTC populations grown as spheres had six times more Aldf+ cells than those grown on plastic; therefore serum free suspension cultures was an effective way to enrich for FTC stem cells.
FTC cells grown on plastic expressed PPARγ at five times the level seen in FTC spheres. We activated PPARγ signalling in FTC cells by addition of rosiglitazone or CAY10410, a chemical analogue of the natural PPARγ agonist 15-deoxy-Δ12,14-Prostaglandin-J2. At concentrations which exhibited less than 50% growth inhibitory effects, PPARγ agonists reduced the Aldf+ percentage of the treated population by 90%. Addition of PPARγ agonists into suspension cultures at the same concentrations reduced sphere formation by 80%.
We identified the Aldefluor positive fraction as the tumorigenic and sphere-forming cancer stem cell population within our FTC cell lines. This population exhibited reduced PPARγ expression and was depleted upon treatment with PPARγ agonists. We hypothesize that downregulation of PPARγ signalling is required for maintenance of the stem cell phenotype and that induced activation of PPARγ is a possible strategy for targeting thyroid cancer stem cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3343.
Abstract 3344: Two different stem cell populations exist in breast cancer to control tumor initiation
Authors: Grant Denise , Ma Jun , Sell Stewart , Glinsky Gennadi 
Published: February 2011

Abstract
The cancer stem cell theory states that a determinate number of cells within a tumor have unique, stem cell-like features to regenerate the entire tumor mass. However, a cancer stem cell may need the right microenvironment to have its greatest tumor initiation potential. We have documented the presence of two stem cell populations within a tumor to yield consistent and most aggressive recapitulation of tumor initiation in vivo. To isolate cancer stem cells, we used the MMTV-PyMT transgenic model of breast cancer in mice to generate stable cell lines from spontaneous breast tumors. Stable in vitro cultures of FACS analyzed cancer stem cells and tumor-residing mesenchymal stem cells were established and tested for tumor initiating ability using two methods of implantation: subcutaneous (s.c.) injection and cleared mammary fat pad (CMFP) injection. To determine the limit of tumor initiation, a highly malignant cancer stem cell culture (419) was injected s.c. This cell culture produced tumors with 1×104, 1×103, and 1×102 cells with 100%, 93%, and 33% tumorigenicity, respectively. In comparison, 100% tumorigenicity was obtained with 1×102 419 cells implanted in the CMFP, a significant increase compared to s.c. injection (Chi-squared, p&lt;0.001). S.c. injection of a less malignant cancer stem cell culture (145) produced tumors less efficiently, with 100% tumorigenicity with 1×104 cells but 13% tumorigenicity with 1×103 cells. To increase tumorigenicity at low cell numbers, cancer stem cell cultures were combined with tumor-residing mesenchymal stem cells just prior to injection. Cancer stem cell cultures were s.c. injected with 1×105 tumor-residing mesenchymal stem cells (383) at the tumor limiting dose, 1×101 for 419 and 1×103 for 145; tumorigenicity increased 160% in the highly malignant cells (419) and 133% in the less malignant cells (145). The tumor-residing mesenchymal stem cells increased tumorigenicity significantly compared to cancer stem cell injection alone (Chi-squared, p&lt;0.002). Control experiments using non-tumorigenic mesenchymal cells did not produce any increase in tumorigenicity. Genome-wide expression profiling experiments were carried out to demonstrate the clinical relevance of the varying malignancy settings in the cancer stem cell and tumor-residing mesenchymal stem cell cultures. Our results suggest that the cellular composition of the local microenvironment within the breast tumors is the major determinant of efficiency of tumor initiation. The addition of tumor-residing mesenchymal stem cells markedly increases the tumor initiation potential of breast cancer stem cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3344.
Abstract 335: Therapeutic targeting of EphB4 with a novel monoclonal antibody
Authors: Spannuth Whitney A. , Krasnoperov V. , Liu R. , Nick Alpa M. , Lin Yvonne G. , Merritt William , Coleman Robert L. , Gill Parkash S. , Sood Anil K. 
Published: February 2011

Abstract
Objective: EphB4 is a transmembrane receptor tyrosine kinase that plays an important role in neural plasticity and angiogenesis. Its biological and clinical relevance in ovarian cancer is the focus of this study.
Methods: Benign ovarian (ML5 and ML10) and ovarian cancer (Hey, SKOV3ip1, A2780-par, A2780-cp20, and IGROV-af1) cell lines, 7 normal ovarian and 85 invasive ovarian cancer samples were evaluated for EphB4 expression by Western blot or immunohistochemistry. Univariate and multivariate analyses were performed for clinical correlation. EphB4 blockade was accomplished using a novel EphB4-targeted monoclonal antibody (EphB4-131). Systemic delivery of EphB4-131 antibody was utilized in vivo to target EphB4 in orthotopic mouse models of ovarian cancer.
Results: By Western blot analysis, all five malignant cell lines overexpressed EphB4, whereas the two benign cell lines had low EphB4 expression. All of the normal ovarian tissues had low or absent EphB4 expression. Among the invasive ovarian carcinomas (mean age of patients was 59.4 years), 73 (86%) had some level of EphB4 expression and overexpression (moderate or strong) was noted in 58% of all samples. EphB4 overexpression significantly correlated with advanced stage (III or IV; p&lt;0.001) and presence of ascites (p&lt;0.001). In multivariate analysis, EphB4 overexpression (p=0.04) and stage (p=0.03) were independent predictors of poor survival. EphB4-131 antibody led to decreased EphB4 expression in A2780-cp20 and IGROV-af1 cell lines, lasting for over 5 days. Compared to controls, EphB4-131 antibody alone significantly decreased tumor growth in A2780-cp20 (83%, p&lt;0.01) and IGROV-af1 (80%, p&lt;0.001) orthotopic ovarian cancer models. Combination therapy with EphB4-131 antibody and docetaxel resulted in the greatest tumor reduction in both A2780-cp20 and IGROV-af1 cell lines (94-98% reduction versus controls; p&lt;0.01).
Conclusions: EphB4 overexpression is predictive of poor clinical outcome in ovarian cancer patients and is associated with aggressive features. Therapeutic targeting of EphB4 with the novel antibody EphB4-131 is an attractive strategy for further development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 335.