bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2021: A novel model to study the stroma-induced drug resistance in glioblastoma cells
Authors: Yang Ning , Zhu Huaiyang , Yan Tao , Liang Xiao , Leiss Lina Wik , Enger Per Øyvind , Li Xingang , Wang Jian 
Published: May 2015

Abstract
Glioblastomas (GBMs) are lethal cancers with a limited response to chemotherapies. In order to study whether stromal cells convey drug resistance to glioma cells, we have established a 3 D glioma cell-specific bioluminescence assay which mimics the growth of glioma in vivo and allows for direct measurements of tumor cell viability. With lentiviral transfection experiments we have provided a panel of human glioma cell lines stably expressing the luciferase reporter gene. Luciferase expression was proportional to the number of glioma cells, but not influenced by the presence of stromal cells. This way, Luciferase signal detection could be used to monitor glioma cell viability following treatment. Glioma cells alone or cultured with stromal cells can form 3 D spheroids, then treated with Temozolomide and Doxorubicin. Through comparative analysis, stromal cells influenced the sensitivity of different chemotherapy drugs in several glioma cell lines. Experiment also proved bioluminescence assay was more sensitive than MTS assay in co-culture system. This glioma cell-specific bioluminescence platform possibly provided a tool to screen stroma-induced changes in anti-tumor drug activity. Using the platform, we will be able to screen FDA-approved drugs on different glioma cell lines and biopsies, which will potentially guide the selection of tumor associated stromal specific targets for therapeutic validation.
Citation Format: Ning Yang, Huaiyang Zhu, Tao Yan, Xiao Liang, Lina Wik Leiss, Per Øyvind Enger, Xingang Li, Jian Wang. A novel model to study the stroma-induced drug resistance in glioblastoma cells. [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 2021. doi:10.1158/1538-7445.AM2014-2021
Abstract 2029: Insight of 3D multicellular tumor spheroids for innovative culture models of potential relevance for the screening of anti-CRC compounds
Authors: Däster Silvio , Amatruda Nunzia , Calabrese Diego , Zajac Paul , Spagnoli Giulio C. , Iezzi Giandomenica , Mele Valentina , Muraro Manuele Giuseppe 
Published: May 2015

Abstract
OBJECTIVE - Multicellular tumor spheroid is a well-known method for 3D in-vitro culture that better represent in-vivo condition. We exploited this system to culture human established colorectal cell lines to investigate how the presence or absence of hypoxic and/or necrotic area can influence the gene expression profile and the responsiveness to drugs compared to 2D-culture and in-vivo xenografted cells.
METHODS - HT29 cell line was cultured as MCTS by hanging-drop method. At size-defined time-point spheroids were analyzed for the presence of hypoxic and necrotic areas. The expression of a panel of genes related to tumor progression, metastatic behavior, and drug resistance was evaluated by real time PCR on MCTS at different growth stages in comparison to conventional 2D cultures and xenografts generated upon injection of HT29 cells in immunodeficient mice.
RESULTS - Based on the absence or presence of hypoxic and/or necrotic core, we identified three different MCTS growth stages: stage 1 (MCTS diameter size &lt;200μm) defined by the absence of hypoxia/necrosis, stage 2 (300-350μm) characterized by the presence of hypoxic, but not apoptotic or necrotic areas, and stage 3 (&gt;500μm) identified by the presence of both hypoxic and necrotic areas. The expression of a panel of genes, including putative cancer stem cell markers CD133, CD44, CD24 was found to be upregulated in stage 1 MCTS, as compared to 2D cultures. Most interestingly a further upregulation of these genes was detected in stage 2 and especially in stage 3. Importantly, expression levels in stage 3 were the most similar to those detected in xenografts.
CONCLUSION - Our results showed that culture of CRC cell lines offer the opportunity to investigate in standardized condition different MCTS stages possibly proving an improved model of in-vivo tumor growth. The next generation sequencing and drug-responsiveness of tumor cells cultured in 2D and 3D at different spheroid maturation stages is currently being evaluated.
Citation Format: Silvio Däster, Nunzia Amatruda, Diego Calabrese, Paul Zajac, Giulio C. Spagnoli, Giandomenica Iezzi, Valentina Mele, Manuele Giuseppe Muraro. Insight of 3D multicellular tumor spheroids for innovative culture models of potential relevance for the screening of anti-CRC compounds. [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 2029. doi:10.1158/1538-7445.AM2014-2029
Abstract 2034: Development of 3D bioprinted human breast cancer for in vitro drug screening
Authors: King Shelby M. , Presnell Sharon C. , Nguyen Deborah G. 
Published: May 2015

Abstract
As breast cancer is a disease of multiple cell types in which the growth, invasion, and metastasis of epithelial carcinomas is heavily influenced by the surrounding cell types, screening of anti-cancer compounds using cancer cell lines grown in 2D often overestimates drug potency. Regulatory agencies are currently seeking improved preclinical oncology models to overcome hurdles to efficient drug development, including bridging the gap between the use of 2D cell lines and 3D animal models. One way to more accurately determine the effects of anti-cancer compounds is through the use of cancer tissue models that incorporate stromal cells of the tumor microenvironment. Breast stroma, composed of fibroblasts, endothelial cells, and adipocytes, plays a key role in the process of carcinogenesis and metastasis. These cell types secrete extracellular matrix, growth factors, and hormones that affect how therapeutic agents access and target cancer cells. We have used Organovo's NovoGen BioprintingTM Platform to develop a model of human breast cancer in which a core of breast cancer cells is surrounded by a physiologically-relevant stromal milieu consisting of adipocytes, mammary fibroblasts, and endothelial cells. This system has several advantages over current screening tools, including the ability to simultaneously measure the effects of small molecules on cancer cells as well as different cell types in the breast microenvironment. Histological analyses of bioprinted neotissues demonstrated that they were stable and viable for at least 14 days in culture and characterized by interaction between stroma and carcinoma compartments. Incorporation of endothelial cells into the 3D neotissue led to the formation of robust microvascular networks. Breast cancer neotissues were fabricated directly into multi-well plates and used to establish biological response profiles to the standard chemotherapeutic agents cisplatin, paclitaxel, methotrexate, and tamoxifen. The cytotoxic effects of chemotherapeutic drugs on specific cell types within the neotissues were assessed biochemically and histologically. he response of the 3D breast cancer neotissues to chemotherapeutic gents was compared to the response of 2D breast cancer cell lines to determine he relative efficacy of compounds in 2D versus 3D. This model can be used to screen new anti-cancer therapeutics in the context of the in vivo-like microenvironment, leading to enhanced efficiency and accuracy of the drug development process.
Citation Format: Shelby M. King, Sharon C. Presnell, Deborah G. Nguyen. Development of 3D bioprinted human breast cancer for in vitro drug screening. [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 2034. doi:10.1158/1538-7445.AM2014-2034
Abstract 2038: Establishment and analysis of an in vitro model for hemangioblastomas of the central nervous system
Authors: Metelo Ana Martins , Lockerman Elizabeth , Barker Fred , Engelman Jeffrey , Iliopoulos Othon 
Published: May 2015

Abstract
Von-Hippel Lindau (VHL) disease is a familial genetic syndrome characterized by a germline mutation in the VHL gene. VHL patients develop different tumors, including renal cell carcinomas, pheochromocytomas and hemangioblastomas (HB). HBs are complex tumors located in the central nervous system and are currently the main cause of morbidity and mortality among VHL patients. 60-80% percent of VHL patients will develop multiple, synchronous or metachronous HBs in the Central Nervous System. These tumors can also occur sporadically. HBs are refractory to radiation or current targeted therapies. Surgery is the only treatment modality, but due to their location (brain, cerebellum, spine and retina) surgery may be debilitated or not even feasible at all.
Both alleles of the VHL gene were reported as inactivated (mutations and LOH studies) in both VHL-related and sporadic HB, but the cellular component(s) harboring this bi-allelic inactivation are unknown. HBs have a complex histology and unclear cell lineage. They are known to consist of a network of stromal cells, endothelial cells and pericytes. Hematopoetic cells may also be present in some HB tumors. In addition to this cellular complexity, the origin of the tumor cell -“stromal cell” - remains unknown.
To gain insight into the biology and therapeutic targets of HB, we established an in vitro model of the disease. Using modifications of a previously described technique (Am J Pathol. 2012;180(2):599-607) we generated cell lines from hemangioblastomas of VHL patients. This approach allows the propagation of diverse cell clones, reflecting the complexity of the tumor microenvironment. The different clones and polyclonal populations were characterized using qRTPCR and immunofluorescence. The molecular and phenotypic analysis of the cell lines will be presented. This resource is fundamental for the study of HB biology and it will allow us to dissect the cellular origin of these tumors. In addition, it may facilitate the development of HB xenografts.
Citation Format: Ana Martins Metelo, Elizabeth Lockerman, Fred Barker, Jeffrey Engelman, Othon Iliopoulos. Establishment and analysis of an in vitro model for hemangioblastomas of the central nervous system. [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 2038. doi:10.1158/1538-7445.AM2014-2038
Abstract 2042: Deregulated TS promotes tumor progression in diverse hematopoietic and mesenchymal cell lineages
Authors: Chen Min , Nawab Akbar , Kaye Frederic J. , Zajac-Kaye Maria 
Published: May 2015

Abstract
Our laboratory recently showed that elevated TS plays a direct causal role in tumorigenesis of NIH3T3 cells in vitro and in the development of endocrine pancreatic mouse tumors in vivo. This observation changed the paradigm of TS as a passive biomarker and has significance for cancer treatment as it refocuses attention on the importance of TS as a tumor-promoting signal. To address whether TS plays an early role in tumorigenesis that is restricted to specific tumor types or if TS plays a late role associated with enhanced progression of established tumors of diverse histologic origin, we have now cross-bred human TS (hTS) transgenic mice with Ink4a/Arf null mice, a common somatic mutation frequently found in adult human cancers. Median survival of hTS/Ink4a/Arf+/- (n=15) mice was reduced 24% (313 vs. 411 days, p &lt;0.05). Both hTS/Ink4a/Arf+/- and hTS/Ink4a/Arf-/- mice (n=16) showed an increase in lymphoma, histiocytic sarcoma (HS) and soft tissue sarcoma (SS). For example, the incidence of HS in hTS/Ink4a/Arf-/- male mice was 31% versus 12% in Ink4a/Arf-/- minus (p&lt;0.01), and tumor cells had spread to multiple tissues (as many as 9 different organs) as compared to hTS minus mice where tumors were localized in lymph nodes and spleen. Strikingly, the tumor burden was markedly increased in hTS/Ink4a/Arf-/- mice: average spleen weight 1.11 vs. 0.49 g, p&lt;0.001, lymph nodes, 1.06 g vs. 0.42 g, p&lt;0.001. We also detected an increase in size and extent of tumor mass of SS (average weight 5.8 g). We detected increased aneuploidy in hTS/Ink4a/Arf-/- HS cell lines as compared to Ink4a/Arf-/- HS cell lines: chromosomal loss 32.1% vs. 16.7%, p&lt;0.05, gain 24.5% vs. 0%, p&lt;0.001 and translocations 9.4% vs. 0%, p&lt;0.05 by spectral karyotyping analysis. Treatment of TS positive HS tumor cells with lenti-TS shRNAs downregulated TS expression and resulted in tumor growth inhibition in vitro as well as in mouse orthotopically transplanted xenograft. In addition, combined TS shRNAs with gemcitabine or pemetrexed treatment showed synergistic inhibition of HS tumor cell growth. These data demonstrate that deregulated TS enhanced genome instability and promote tumor progression in diverse hematopoietic and mesenchymal tumor cells.
Citation Format: Min Chen, Akbar Nawab, Frederic J. Kaye, Maria Zajac-Kaye. Deregulated TS promotes tumor progression in diverse hematopoietic and mesenchymal cell lineages. [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 2042. doi:10.1158/1538-7445.AM2014-2042
Abstract 205: Imatinib sensitizes endometrial cancer cells to cisplatin by targeting CD117-positive growth-competent cells
Authors: Nakamura Mitsuhiro , Kyo Satoru , Zhang Xiuzhi , Takakura Masahiro , Mizumoto Yasunari , Bono Yukiko , Sasagawa Toshiyuki , Fujiwara Hiroshi 
Published: May 2015

Abstract
The use of molecular target therapy has not been established for endometrial cancer. The present study investigated the potential therapeutic strategy of targeting CD117-positive cancer cells as a novel molecular target therapy. FACS-sorted CD117+ cells isolated from endometrial cancer cell lines (Ishikawa or MFE280 cells) exhibited higher proliferative capacity in vitro and colony forming activity on soft agar, and decreased sensitivity to cisplatin, compared to CD117- cells. Immunohistochemical analyses with surgical specimens of endometrial cancers showed that high CD117 expression was tightly linked to advanced FIGO stages, myometrial invasion and histological grade, and was significantly associated with poor overall survival and relapse-free survival (Kaplan-Meier analysis; p&lt;0.001, log-rank test). The Cox-regression hazard model identified high CD117 expression to be an independent prognostic factor for survival (p&lt;0.05). In vitro assay confirmed that stem cell factor (SCF), a ligand of CD117, was produced specifically in CD117+ cells of endometrial cancer, and the colony-forming activity were abrogated by adding anti-SCF antibody, indicating an SCF-dependent growth property. Imatinib was confirmed to selectively target CD117+ cells in vitro, and synergistically enhanced the anti-tumor effect of low dose cisplatin in vivo, which showed only modest effects when used as a single use. These findings suggest that CD117 can be a marker of aggressive behavior of cells as well as an independent prognostic marker in endometrial cancer. Targeting of the SCF/CD117 axis by imatinib sensitized endometrial cancer cells to cisplatin, proposing a novel therapeutic strategy for this tumor type.
Citation Format: Mitsuhiro Nakamura, Satoru Kyo, Xiuzhi Zhang, Masahiro Takakura, Yasunari Mizumoto, Yukiko Bono, Toshiyuki Sasagawa, Hiroshi Fujiwara. Imatinib sensitizes endometrial cancer cells to cisplatin by targeting CD117-positive growth-competent cells. [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 205. doi:10.1158/1538-7445.AM2014-205
Abstract 2056: Identification of microscopic ovarian tumor foci utilizing a novel imaging device in a murine ovarian cancer model, an opportunity to improve optimal cytoreduction
Authors: Na Youngjeong , Kwok Tim , Awtrey Christopher , Strasfeld David B. , Ferrer Jorge M. , Lee David , Birrer Michael J. 
Published: May 2015

Abstract
Survival of ovarian cancer patients is directly related to the amount of residual disease present after debulking surgery. In 80% of the cases, extensive microscopic cancer remains even after the patient is deemed optimally debulked. Hence, detection of sub-mm cancer clusters during tumor excision is a critical unmet need. Recent studies have shown that reducing the dimensions of residual cancer to less than 1 mm significantly improves clinical outcomes. In the present study we evaluate the performance of a fluorescent, molecular imaging agent, LUM015 (Lumicell, Wellesley, MA), which is activated by cathepsin enzymes in the tumor, and a wide-field-of-view imaging device (Lumicell) to detect sub-mm residual cancer clusters in an mouse model for ovarian cancer.
In this study, we generated orthotopic ovarian cancer mouse models(n=10) with well characterized serous ovarian cancer cell lines, CP70 and SKOV3. Once the tumor disseminated, the imaging agent LUM015 (3.52 mg/kg) was injected via the tail vein, and after 6 hours, the mice were euthanized. Tumor debulking was performed throughout the abdominal cavity. After debulking, the whole abdominal wall was dissected in 4 quadrants, organs were harvested and all were imaged with the LUM device. Features exhibiting high fluorescence were marked and dissected, prepared into slides, and stained with hematoxylin and eosin for pathologic correlation with LUM015 fluorescence imaging.
In 36 tissues from orthotopic ovarian cancer mouse models, LUM015 imaging system could detect the tumor presence with 100% of sensitivity and 60% of specificity. We demonstrated that the imaging system can detect sub-mm cancer clusters that could not be identified with visual inspection.
With a cathepsin activated fluorescence imaging molecule (LUM015) and a wide-field-of-view imaging device, we detected microscopic residual ovarian cancer tumors in orthotopic xenograft models after debulking grossly with high sensitivity. Translation of this imaging technology into the clinical setting may help to detect microscopic residual tumor features during the debulking operation in ovarian cancer.
Citation Format: Youngjeong Na, Tim Kwok, Christopher Awtrey, David B. Strasfeld, Jorge M. Ferrer, David Lee, Michael J. Birrer. Identification of microscopic ovarian tumor foci utilizing a novel imaging device in a murine ovarian cancer model, an opportunity to improve optimal cytoreduction. [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 2056. doi:10.1158/1538-7445.AM2014-2056
Abstract 2061: Extended adjuvant temozolomide improves survival in a glioblastoma mouse model
Authors: Wang Hanxiao , Al-Holou Wajd , Heist Kevin , Galbán Craig J. , deCarvalho Ana C. , Mikkelsen Tom , Ross Brian D. , Rehemtulla Alnawaz 
Published: May 2015

Abstract
Glioblastoma (GBM) represents the most aggressive malignant primary brain tumor. Temozolomide (TMZ) is a standard of care for newly diagnosed GBM patients in conjunction with ionizing radiation (IR) or as an adjuvant agent. Yet the prognosis of GBM remains devastating with a median survival of 14 months. We investigated whether extended TMZ treatment cycles would provide survival benefit for GBM patients. To recapitulate the genomic and pathological heterogeneity found in GBM patients, we utilized patient derived xenograft (PDX) mouse models.
We demonstrated that the combination of TMZ and IR prevents tumor progression, but tumors ultimately recur and lead to death. Overall survival was prolonged when adjuvant TMZ treatment was administered with minimal toxicity. Additionally, development of resistance to TMZ and IR was often correlated with an increase in levels of MGMT protein, irrespective of the promoter methylation status. Moreover, we demonstrate the utility of a voxel-based MRI biomarker, the functional diffusion map (fDM), as an imaging surrogate to detect spatially varying changes in tumor response, as well as a more sensitive predictor of overall response versus whole-volume tumor measurements. The fDM biomarker was also useful as an early predictor of impeding resistance to TMZ and IR.
In summary, we demonstrate that prolonged TMZ treatment should be considered for the treatment of GBM patients. Furthermore, MRI based imaging allows early prediction of therapy response as well as impeding resistance.
Citation Format: Hanxiao Wang, Wajd Al-Holou, Kevin Heist, Craig J. Galbán, Ana C. deCarvalho, Tom Mikkelsen, Brian D. Ross, Alnawaz Rehemtulla. Extended adjuvant temozolomide improves survival in a glioblastoma mouse model. [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 2061. doi:10.1158/1538-7445.AM2014-2061
Abstract 2070: In vivo imaging of therapy response to novel antibody mixtures targeted at the human epidermal growth factor receptor family using FDG and FLT positron emission tomography
Authors: Nielsen Carsten H. , Jensen Mette M. , Jacobsen Helle J. , Poulsen Thomas T. , Horak Ivan D. , Lantto Johan , Kragh Michael , Kjaer Andreas 
Published: May 2015

Abstract
Dysregulation and overexpression of the human epidermal growth factor receptor (HER) family plays an important role in many cancers. Simultaneously targeting multiple members of the HER family may increase the therapeutic efficacy. Here, we report the ability to image the therapeutic response obtained by targeting the HER family members individually or simultaneously using novel monoclonal antibody (mAb) mixtures.
Mice with subcutaneous BxPC-3 pancreas adenocarcinomas were divided into five groups (n=8) receiving vehicle or mAb mixtures directed against HER1 (EGFR), HER2, HER3, or pan-HER. Small animal positron emission tomography/computed tomography (PET/CT) with 18F-FDG and 18F-FLT was performed at baseline and day 1 or 2 after initiation of therapy. The changes in tumor uptake of tracers were quantified and related to the efficacy of each therapy on tumor size measured by caliper. Imaging results were further validated by immunohistochemistry on tumor samples obtained 2 and 7 days after initiation of therapy.
The pan-HER mAb mixture showed the greatest efficacy with significant smaller tumor volumes (146±39 mm3, Mean ±SEM) compared with the other groups (vehicle: 660±99 mm3, EGFR: 363±67 mm3, HER2: 458±45 mm3, HER3: 274±37 mm3) at the end of therapy (day 23). Mean FDG and FLT uptake in the pan-HER group decreased by 19±4.3% and 24±3.1%, respectively, at day 1 or 2 compared with baseline, which was significantly greater than for the other groups. Importantly, the early change in mean FDG and FLT uptake correlated with tumor growth at day 23 relative to day 0 (r=0.67, p&lt;0.001; r=0.63, p&lt;0.001, respectively).
In conclusion, we demonstrate the ability to image therapeutic responses to a novel pan-HER mAb mixture using PET/CT imaging with FDG and FLT. We suggest the use of FDG and FLT PET/CT as an imaging biomarker in clinical evaluation of the pan-HER mAb mixture.
Citation Format: Carsten H. Nielsen, Mette M. Jensen, Helle J. Jacobsen, Thomas T. Poulsen, Ivan D. Horak, Johan Lantto, Michael Kragh, Andreas Kjaer. In vivo imaging of therapy response to novel antibody mixtures targeted at the human epidermal growth factor receptor family using FDG and FLT positron emission tomography. [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 2070. doi:10.1158/1538-7445.AM2014-2070