bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5047: Survival signal pathways as potential therapeutic targets in soft tissue sarcoma cell lines
Authors: Han Jung Woo , Kwon Bo Ram , Park Chan Hee , Lee Gui Youn , Jeung Hei-Cheul , Kim Se-Kyu , Roh Jae Kyung , Chung Hyun Cheol , Rha Sun Young 
Published: June 2012

Abstract
Introduction: Soft tissue sarcomas (STS) are rare malignancies but have poor survival rate. Surgery with standard chemotherapy has been the mainstay of treatment but newer strategies are necessary to improve survival. The investigations for targeted therapy are underway but little is known about potential targets until now. We previously presented potential molecular targets in osteosarcoma (OS) cell lines (101st AACR annual meeting 2010, abstract No.2451). We tried to compare the protein and mRNA profilings between the OS and STS cell lines to suggest the feasibility for developing molecular targeted agents in STS.
Methods: We examined the protein expression of c-Met, Akt, mTOR, and their phosphorylated status, and PTEN in seven OS (MG-63, HOS, KHOS/NP, SK-ES-1, U-2OS, Saos-2, and G-292) and five STS cell lines (SK-UT-1, A-673, SW-871, SW-982, HT-1080) using western blotting. The gene expression profilings of the cell lines were performed by 44K microarray (Agilent Inc.).
Results: Microarray data showed that whole genome expression pattern of STS was different from OS cell lines. But, the expressions of 94 mRNAs within the signal transduction pathways, which represent the currently utilized drug targets, revealed similar pattern between two groups of cell lines. To verify the possibility of developing molecular targeted agents in STS, we examined the activation patterns of signal transduction pathway proteins in each STS cell line.
All STS cell lines except A-673 with low c-Met, but high p-Met, expressed moderate level of c-Met and p-Met. PI3K was expressed in all cell lines, with higher p-PI3K in SK-UT-1 and A-673 than in other STS cell lines. All but SW-872 cell line expressed Akt, and SK-UT-1, SW-872 and HT-1080 had higher levels of p-Akt. SW872 showed negligible PTEN and high level of p-Akt. SW982 generally repressed level of p-Met, p-PI3K, p-Akt, p-mTOR comparing with other STS cell lines. Meanwhile, mTOR and p-mTOR were expressed relatively even in all STS cell lines.
Conclusion: We presented that STS cell lines had variously activated signal pathway status as in OS cell lines. Common potential targets such as mTOR was revealed, and the specific targets including PI3K or Akt were also presented. It suggests the possibility of developing specific molecular targeted agents in each type of STSs.
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 5047. doi:10.1158/1538-7445.AM2011-5047
Abstract 5049: Cyclopamine modulates ABCG2 activity in glioblastoma side population cells
Authors: Balbuena Jana , Pachon Gisela , Lopez-Torrents Guillermo , Fan Xing , Castresana Javier S. , Petriz Jordi 
Published: June 2012

Abstract
The Sonic Hedgehog pathway (HH) has been implicated in the maintenance of stem cells in adult tissues. Abnormal HH activation is also associated with initiation of neoplasia by cancer stem cells. Cyclopamine has been used as an inhibitor of the HH, with potential effectiveness in several xenograft models, including gliomas. Side Population (SP) cells are stem cells with expression of ABCG2, a multidrug ABC transporter, able to extrude dyes as Hoechst 33342 (Ho342). SP cells, then, present low fluorescence after staining with Ho342. ABC transporters have been identified as drug-resistance proteins. HH regulates the expression of ABC transporters, and promotes multi-drug resistance by increasing drug efflux by the ABC transporters. Different research groups have shown that SP cells can be depleted following cyclopamine treatment, an observation that would support that SP cells are HH pathway-dependent.
We hypothesized that cyclopamine might interact with ABCG2 and limit the number of SP cells. Therefore, we analyzed the effect of cyclopamine and temozolomide on the MXRA cell line (KB cells transfected with the full-length ABCG2 cDNA), and on five astrocytoma cell lines, both in the parental cell lines and in their SP cells. We first evaluated the modulatory effect of cyclopamine on ABCG2 function by measuring the intracellular accumulation of two substrates of ABCG2, Ho342 and mitoxantrone. Secondly, we analyzed the effect of these drugs in the phenotype of SP cells (the cells were incubated with only Ho342, or a combination of Ho342 and cyclopamine, or a combination of Ho342, cyclopamine and temozolomide; afterwards we analyzed the number of SP cells).
We saw that cyclopamine significantly decreased the fraction of SP cells but not through a depletion of the SP compartment, but as a consequence of the molecular mechanisms involved in the affinity of cyclopamine and Ho342 for ABCG2, as cyclopamine modulated the ABCG2 transporter by increasing Ho342 and mitoxantrone uptake. Temozolomide had no effect on the SP cells.
Therefore, cyclopamine, although decreases the SP fraction of cancer stem cells in glioblastoma cell lines, does not deplete the SP compartment, but modulates ABCG2 activity.
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 5049. doi:10.1158/1538-7445.AM2011-5049
Abstract 505: Multiscale mathematical model of skin reveals the critical role of stromal aging in melanoma initiation
Authors: Kim Eunjung , Basanta David , Rebecca Vito , Messina Jane , Mathew Rahel , Smalley Keiran S. , Anderson Alexander R. A. 
Published: June 2012

Abstract
Melanoma initiation is known to involve specific genetic changes as well as the disruption of both cell-cell and cell-microenvironment interactions. However, the mechanisms by which dysregulated cell-cell interactions lead to melanoma development remain elusive. To better understand melanoma initiation and progression we have developed a hybrid multiscale mathematical model of normal skin (virtual skin). The model focuses on key cellular and microenvironmental variables that regulate normal homeostatic skin function, and is constructed to recapitulate how keratinocytes and fibroblasts regulate melanocyte proliferation, migration and death.
Experimentally, we have shown that as fibroblasts age and become senescent their behavior changes significantly, leading to the expression of multiple growth factors, matrix proteins and proteases. We also showed, using 2D/3D culture, that interactions with senescent fibroblasts can aid melanoma initiation.
Using our virtual skin model, we systematically investigated the effects of disrupting interactions between melanocytes, keratinocytes, fibroblasts and the microenvironment in driving melanoma initiation. The resulting virtual skin pathology readily recapitulates a spectrum of aberrant clinical pathology. Direct comparison between these pathologies allowed us to find the key perturbations leading to melanoma initiation and progression. To better understand the role of aging we also integrated senescent fibroblasts into our virtual skin model.
Our primary finding is that melanoma initiation can be directly facilitated by fibroblast senescence. However, successful initiation requires the existence of preexisting mutations within the melanocyte population allowing them to exploit the stromal activation. These findings provide additional evidence demonstrating the importance of therapeutically targeting the stroma. We believe that any effective therapy will need to not only eradicate the melanoma population but also restore normal homeostatic stromal 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 505. doi:10.1158/1538-7445.AM2011-505
Abstract 5050: Biomarkers for sensitivity to gamma secretase inhibitors in mouse models of pancreatic adenocarcinoma
Authors: Dasari Arvind , Powell Rebecca W. , Puls Lauren , Quackenbush Kevin , Tan Aik Choon , Messersmith Wells , Boylan John , Arcaroli John 
Published: June 2012

Abstract
Background: The Notch pathway is important in carcinogenesis and maintenance of pancreatic adenocarcinoma through its effects on cancer stem cells, cell differentiation and neoangiogenesis. RO4929097 is a novel oral inhibitor of the Notch pathway through its effects on γ-secretase, a key enzyme in this pathway. Several clinical trials are currently in progress with RO4929097 including a CTEP sponsored phase II trial in gemcitabine resistant metastatic pancreas cancer by our group. However, there are no biomarkers of sensitivity available currently for therapy with RO4929097 or other γ-secretase inhibitors (GSIs).
Methods: We intend to treat 12 human pancreas cancer cell line mouse xenografts and 6 human primary pancreas tumor explants with RO4929097 (alone or in combination with gemcitabine) to identify sensitive (defined as tumors with ≥ 50% relative tumor growth inhibition with treatment) and resistant tumors. Subsequently, we propose to identify differences in gene expression by RT-PCR (Notch pathway), gene array or gene copy number by FISH between the resistant and sensitive tumors as potential biomarkers.
Results: Of the eight pancreas cell line xenografts treated so far, four are sensitive to RO4929097. Comparison between sensitive and resistant tumors by gene array suggests that the sensitive cell lines exhibit higher levels of mesenchymal markers. In addition, two of the four human primary pancreatic explants treated thus far show intermediate sensitivity. RO4929097 in combination with gemcitabine in the four explants reveals a significant decrease in tumor growth inhibition for the combination compared to RO4929097 alone but the additive effect appears to be entirely due to gemcitabine. Similar effects were observed on tumor regrowth, upon observation after an initial period of treatment with either agents alone or in combination. In addition, future experiments to identify stem cell and/or angiogenesis specific biomarkers are also planned. Updated results will be presented at the meeting.
Acknowledgements: This work was supported by Roche Pharmaceuticals
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 5050. doi:10.1158/1538-7445.AM2011-5050
Abstract 5053: ß-catenin inhibitor SST-024 selectively kills tumor initiating cells (TICs)
Authors: Xu Wei 
Published: June 2012

Abstract
Recent studies have shown that tumor initiating cells (TICs) are more resistant to therapies than differentiated cancer cells. We have previously shown that aberrant Wnt signaling contributes to the radio-resistance of TICs in breast cancer. Herein, we used SST-024 (StemSynergy), an inhibitor of ß-catenin and WNT signaling, to test whether pharmacologic inhibition of ß-catenin can selectively kills TICs. Sum-149 and MDA-IBC-3, two inflammatory breast cancer cell lines, Sum-159, a non-inflammatory basal-type breast cancer cell line and MCF-12F, a non-tumorigenic breast cell line were used in these studies. We found that SST-024 inhibits proliferation in Sum-159, Sum-149 and MDA-IBC-3 cells with an IC-50 of 140 nM, 200 nM and 15 nM respectively. We also found that SST-024 inhibits mammosphere formation in Sum-159, Sum-149 cells, and MDA-IBC-3 at IC-50 ∼ 5 nm, 0.5nm and 5 nM respectively. On the other hand, the IC-50 for mammosphere formation inhibition in MCF-12F was 100 nM. To test the effect of SST-024 on TICs self-renewal, the secondary mammosphere formation was examined. IC-50 of SST-024 for secondary mammosphere formation inhibition is 3 nM for Sum-159, 5 nM for Sum-149 and 15 nM for MBA-IBC-3. They are all lower than the IC-50 of proliferation inhibition except MAB-IBC-3. Similar efficacy against TICs was seen in assessments of alternative TIC surrogates including aldefluor staining by flow cytometry. In in vivo assay, intra-tumor injection at 0.1µg/per tumor caused tumor growth delay and massive necrosis in tumor. In the meantime, we also tried to find if SST-024 can sensitize the cancer stem cell to radiation therapies. In an in vitro assay, we found that SST-024 can not sensitize the cancer stem cell to radiation therapies, but can sensitize the differentiated cells to radiation therapies. Moreover, we found that SST-024 can significantly reduce the expression of a panel of EMT markers. In summary, SST-024 demonstrates significant efficacy against breast cancer TICs in vivo and in vitro. It can not sensitize TICs to radiation, but sensitize non-TICs to IR. The mechanism is probably through the down-regulation of EMT signaling. All these findings imply targeting Wnt β-catenin signaling may be a feasible strategy to target breast cancer TICs.
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 5053. doi:10.1158/1538-7445.AM2011-5053
Abstract 5068: Proteomics based prognostic signature of head and neck cancer
Authors: Ralhan Ranju , Tripathi Satyendra C. , Matta Ajay , DeSouza Leroi V. , Kaur Jatinder , Grigull Joerg , Chauhan S. S. , Shukla Nootan K. , Siu KW Michael 
Published: June 2012

Abstract
Introduction. Molecular cancer diagnostics is rapidly moving beyond genomics to proteomics. Clinical cancer proteomics has the potential to discover, identify, and quantify novel biomarkers for early detection, diagnosis, prediction of the clinical outcome, and to develop effective therapeutic interventions by using these biomarkers as molecular targets. Despite therapeutic interventions, the five-year survival rate of head and neck cancer patients is less than 50%, and the prognosis of advanced HNSCC cases has not improved much over the past three decades.
Methods. Using high-throughput proteomics, we identified a panel of biomarkers in head and neck cancer. This panel of markers was verified in a large independent cohort of paraffin embedded head and neck cancer tissues (n=100) using immunohistochemistry (IHC). Kaplan Meier analysis and multivariate logistic regression analysis was carried out to predict the prognosis of these head and neck cancer patients. Positive and negative predictive values (PPV and NPV respectively) were calculated as function of follow-up period.
Results. Our immunohistochemical analysis demonstrated overexpression of a panel of proteins including 14-3-3zeta, 14-3-3sigma, heterogeneous nuclear ribonuclear protein K (HNRNPK), S100A7 and prothymosin alpha (PTMA) in head and neck cancer patients. Kaplan Meier analysis revealed shorter disease-free survival (DFS = 4 mths.) in head and neck cancer patients showing overexpression of the panel of proteins in comparison to patient cohort not showing overexpression of this panel (DFS = 41 mths., p &lt; 0.001). Positive predictive value (PPV) and Negative predictive value (NPV) further verified the reduced disease free survival of these patients. Logistic regression analysis clearly demonstrated the relevance of this panel as the best prognostic signature for head and neck cancer patients (p &lt; 0.001, Hazards ratio, H.R.=19.6, 95% C.I. = 2.3 – 8.5) in comparison to combinations of 2 – 4 markers and clincopathological parameters.
Conclusions. In conclusion we identified, verified and developed a proteomics-based prognostic signature for head and neck cancer patients which may find its utility in follow-up clinics to accurately predict the recurrence of the disease after primary treatment.
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 5068. doi:10.1158/1538-7445.AM2011-5068
Abstract 5074: Evaluation of PTEN and TMPRSS2-ERG abnormalities in prostate cancer by FISH and immunohistochemistry to address intra- and inter- tissue heterogeneity and disease progression
Authors: Joshua Anthony M. , Cockburn Norah , Evans Andrew , Squire Jeremy , Yoshimoto Maisa , Ludkovski Olga , Tan Shyh-Han , Dobi Albert , Furusato Bungo , Petrovics Gyory , Srivastava Shiv , Sesterhenn Isabell 
Published: June 2012

Abstract
Background: Gene fusions involving the ERG oncogene and deletions of the PTEN tumor suppressor gene are frequent alterations in prostate cancer. Recent reports highlighted the cooperation of these two pathways in prostate cancer progression using mouse models and human tumors. We recently developed a monoclonal antibody (CPDR ERG-MAb) that specifically recognizes the ERG oncoprotein in human prostate tumors. The objective of this study was to determine the frequency of ERG positive prostate cancer by immunohistochemistry (IHC) compared to ERG gene fusion frequency by fluorescent in situ hybridization (FISH), their association with PTEN deletion, and correlation with clinico-pathological parameters of disease progression.
Design: A tissue microarray (TMA) was constructed from 142 radical prostatectomy (RP) specimens with usual acinar-type prostate carcinoma obtained at University Health Network (UHN) between 2001 and 2002 comprising 742 spots. The TMA was constructed using up to six 0.6 mm donor cores from each RP specimen. In cases of multi focal and bilateral carcinoma, 3 donor cores were obtained from the largest foci in each lobe. Different Gleason patterns were also sampled within each focus. Standard clinical follow-up data, representing 7-9 years of follow-up, were compiled for each case using a UHN RP clinical database.
Results: Of the 742 cores, analysis was performed in 536 evaluable cores. Concordance between the ERG IHC and TMPRSS2 FISH in this multi-sampled TMA was 71%. Heterogeneity of the PTEN locus was widespread both within tumor foci and between foci. The assay methodology influenced overall results. For example, FISH analysis showed wild type (wt) PTEN and wt ERG in 48% of tumor specimens in comparison to 31% by PTEN FISH and ERG IHC. Higher association of PTEN deletion rate was noted in ERG IHC positive tumors. Of note, higher frequency of homozygous PTEN deletions associated with the ERG IHC positive (5%) tumors in comparison to ERG negative (1.5%) tumors.
Conclusions: Comparison of FISH and IHC based assays to analyze ERG alterations in the prostate tumors need continued evaluations in independent studies. PTEN interaction with ERG status may reveal mechanistic insights in disease progression. Further validation studies are needed.
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 5074. doi:10.1158/1538-7445.AM2011-5074
Abstract 5076: Multi-protein tissue and blood plasma protein marker patterns of endometrioid endometrial and squamous cervical cancers
Authors: Lomnytska Marta , Becker Susanne , Hellman Ulf , Engström Ulla , Hellström Ann-Cathrin , Hellman Kristina , Lundgren Caroline , Andersson Sonia , Mints Miriam , Auer Gert 
Published: June 2012

Abstract
Endometrial cancer is the second spread cancer of women in Western Europe and Nothern America. There is no screening developed for early detection of endometrial cancer, its major types and precursor lesions.
We used proteomics-based methods including two-dimensional gel electrophoresis of tissue and blood plasma proteins, analyses of gels by SameSpot (Nonlinear) software and MALDI-TOF MS-assisted identification of proteins. Measurement of DNA ploidy was used for the selection of genomic subtypes of endometrial cancer. Expression of identified proteins was evaluated in endometrial cancers, atypical and simple hyperplasia and normal endometrium using immunohistochemistry. Tumor tissue biopsies of endometrial cancer, normal endometrium, squamous cervical cancer, and squamous cervical epithelium as well as low-abundant blood plasma proteins of the same patients were used for two-dimensional gel electrophoresis. We also analyzed published data on chromosomal changes in early and prognostically unfavorable endometrial cancer and corresponded proteins identified by us to the corresponding coding genes.
One hundred and thirty differentially expressed tissue proteins were identified as being related to malignant transformation towards endometrial and cervical cancers. Among them is a group of proteins that specifically differentiate genomically stable and unstable endometrial cancers. Many similarities between the protein expression were found for genomically unstable endometrial cancer and squamous cervical cancer which in most cases are genomically unstable. Moreover, inclusion of squamous cervical cancer cases made it possible to select proteins that are specific for endometrial cancer and proteins which characterize non-malignant tissues. Using available data on chromosomal changes in endometrial cancer we have selected proteins that are markers of prognostically unfavourable endometrial cancer and that change their expression already in atypical hyperplasia of the endometrium. By analysis of low-abundant blood plasma proteins we have identified 18 marker proteins that differentiate endometrial cancer from cervical cancer.
In conclusion, proteins differentially expressed in tissue of endometrial cancer include patterns that are typical for genomically stable and unstable subtypes and changes in their expression are detectable already in atypical hyperplasia of the endometrium. Endometrial and cervical cancers are characterized by differential blood plasma protein expression patterns.
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 5076. doi:10.1158/1538-7445.AM2011-5076