bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2996: Sunitinib withdrawal uncovers complementary stromal- and tumor-mediated mechanisms of resistance and rebound growth in metastatic mouse models
Authors: Mastri Michalis , Tracz Amanda , Lee Christina R. , Deveci Derya , Ebos John M. L. 
Published: May 2015

Abstract
Background: Despite the clinical approval of VEGF pathway targeted agents in the treatment of late-stage metastatic disease, sustained benefits are not seen in the majority of patients, and eventual relapse occurs. Understanding mechanisms of intrinsic and acquired drug resistance has taken on increasing importance as both host- and tumor-mediated pathways may contribute to treatment failure. However, few studies have aimed to assess resistance in clinically-relevant spontaneous metastatic disease after surgical resection of the primary tumor.
Methods: Here we describe the derivation of spontaneous metastatic human kidney, breast, and melanoma cell lines following long-term in vivo sunitinib treatment. Re-exposure of selected tumor and stromal cells to drug in vitro for extended periods allowed evaluation of reversible and irreversible gene expression changes. Cells were implanted orthotopically and then surgically removed to assess primary and metastatic growth potential following treatment cessation.
Results: Our results show that metastatic sunitinib-resistant cells retained treatment sensitivity when re-implanted orthotopically regardless of in vitro drug exposure conditions, suggesting a predominant host-mediated role in treatment failure. However, sunitinib treatment withdrawal elicited significant increases in tumor growth and metastatic potential, a finding which was enhanced when non-tumor bearing mice were ‘conditioned’ with drug prior to i.v. tumor cell inoculation. Parallel studies in vitro show increased proliferation and migration following therapy removal. Results from gene and protein expression analysis of cells in different sunitinib treatment conditions will be presented showing that coordinated tumor and host reactions can contribute to changes in metastatic phenotype upon therapy removal.
Conclusions: Taken together, clinically relevant models of drug-resistant spontaneous metastatic disease may have the potential to distinguish tumor- and stromal-responses to treatment that can alter in vivo disease progression both on (and off) therapy.
Citation Format: Michalis Mastri, Amanda Tracz, Christina R. Lee, Derya Deveci, John M. L. Ebos. Sunitinib withdrawal uncovers complementary stromal- and tumor-mediated mechanisms of resistance and rebound growth in metastatic mouse models. [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 2996. doi:10.1158/1538-7445.AM2014-2996
Abstract 2998: Akt-activated endothelium constitute the niche for residual disease and resistance to bevacizumab in ovarian cancer
Authors: Guerrouahen Bella Samia , Pasquier Jennifer , Kaoud Nadine Abou , Beauchamp Marie-Claude , Maleki Mahtab , Ghiabi Pegah , Lis Raphael , Saleh Ahmed , Gotlieb Walter H. , Rafii Shahin , Rafii Arash 
Published: May 2015

Abstract
Ovarian cancer is the second leading cause of cancer-related death in women worldwide. Despite optimal cytoreduction and adequate adjuvant therapies, initial tumor response is often followed by relapse suggesting the existence of a tumor niche. Targeted therapies have been evaluated in ovarian cancer to overcome resistant disease. Among them anti-angiogenic therapies inhibit new blood vessel growth, induce endothelial cell apoptosis, and block the incorporation of haematopoietic and endothelial progenitor cells into new blood vessels. Despite in vitro and in vivo successes antivascular therapy with bevacizumab targeting VEGF has limited efficacy in ovarian cancer. The precise molecular mechanisms underlying clinical resistance to anti-VEGF therapies are not yet well understood. Among them tumor and stromal heterogeneity might determine the treatment outcomes. The present study investigates whether abnormalities in the tumor endothelium may contribute to treatment resistance to bevacizumab and promote a residual microscopic disease. Here we showed that ovarian cancer cells (OCC) activate akt phosphorylation in endothelial cells inducing resistance to bevacizumab leading to an autocrine loop based on FGF2 secretion. Altogether our results point out the role of an activated endothelium in the resistance to bevacizumab and in the constitution of a niche for a residual disease.
Citation Format: Bella Samia Guerrouahen, Jennifer Pasquier, Nadine Abou Kaoud, Marie-Claude Beauchamp, Mahtab Maleki, Pegah Ghiabi, Raphael Lis, Ahmed Saleh, Walter H. Gotlieb, Shahin Rafii, Arash Rafii. Akt-activated endothelium constitute the niche for residual disease and resistance to bevacizumab in ovarian cancer. [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 2998. doi:10.1158/1538-7445.AM2014-2998
Abstract 3009: Membrane pseudokinase PTK7 regulates metastasis
Authors: Golubkov Vladislav , Zhang Yong , Prigozhina Natalie , Hoffman Robert M. , Strongin Alex 
Published: May 2015

Abstract
Studies by others indicate that the membrane pseudokinase 7 (PTK7) regulates canonical and non-canonical Wnt pathways and controls orientation of cells in a tissue plane (planar cell polarity, PCP). There is still no clear understanding of the PTK7 role in cancer: Is it pro-tumorigenic or anti-tumorigenic? Our live cell imaging and cell invasion studies suggest that full-length PTK7 expressed in HT1080 fibrosarcoma cells inhibits directed cell motility, lamellipodia polarization and cell invasion. Using the fluorescence imaging we demonstrated that the expression of full-length PTK7 in HT1080-RFP cells in nude mice significantly reduces lung colonization (metastasis). The pro-invasive membrane type-1 matrix metalloprotease (MT1-MMP/MMP-14) coupled with an ADAM/ADAMTS family member(s) directly cleave PTK7 at the cell surface and reverse the inhibitory anti-invasive signal of full-length PTK7. Ectodomain proteolysis was a prerequisite for the intramembrane cleavage of the residual fragments of PTK7 by γ-secretase. The resulting C-terminal PTK7 fragment translocated to the cell nucleus. To identify the molecular mechanisms downstream of PTK7 proteolysis, we used genome-wide transcriptional profiling and kinome analysis. Full-length PTK7 and the PTK7 mutants representing the cleaved PTK7 forms differentially regulated the expression of multiple genes and induced signaling pathways associated with cell movement, Wnt signaling and cancer. We believe that the regulation of PTK7 proteolysis opens new possibilities to control Wnt signaling, cancer cell invasion and metastasis.
Citation Format: Vladislav Golubkov, Yong Zhang, Natalie Prigozhina, Robert M. Hoffman, Alex Strongin. Membrane pseudokinase PTK7 regulates metastasis. [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 3009. doi:10.1158/1538-7445.AM2014-3009
Abstract 3014: Hyaluronan-mediated motility receptor maintains stemness and tumorigenic potential of glioblastoma stem cells
Authors: Tilghman Jessica , Laterra John , Ying Mingyao 
Published: May 2015

Abstract
Glioblastoma (GBM) stem cells (GSCs) are a subpopulation of tumor cells that display stem-like characteristics (stemness) and play unique roles in tumor propagation, therapeutic resistance and tumor recurrence. It is becoming increasingly important to identify novel therapeutic targets in GSC for anti-GBM therapies. Here, we demonstrate that hyaluronan-mediated motility receptor (HMMR) is hyper-expressed in GBM tumors and supports the self-renewal and tumorigenic potential of GSCs. HMMR silencing impairs GSC self-renewal and inhibits the expression of GSC markers and regulators. HMMR silencing suppresses GSC-derived tumor growth and extends the survival of mice bearing GSC xenografts. HMMR overexpression promotes GSC self-renewal and intracranial tumor propagation. In human GBM tumor specimens, HMMR expression is positively correlated with the expression of cell-stemness-associated markers and regulators. Our findings identify HMMR as a potential therapeutic target for inhibiting GSCs, suggesting therapeutic applications against GBM.
Citation Format: Jessica Tilghman, John Laterra, Mingyao Ying. Hyaluronan-mediated motility receptor maintains stemness and tumorigenic potential of glioblastoma stem 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 3014. doi:10.1158/1538-7445.AM2014-3014
Abstract 3019: Aberrant NF-κB and Notch pathways promote CD133+ cancer stem cells in human primary cutaneous squamous cell carcinoma
Authors: Quan Xinxin , Voong Nga , Chen Weiping , Coupar Jamie , Lee Steven , Petersen David W. , Edelman Daniel C. , Meltzer Paul S. , Montemarano Andrew , Braun Martin , Vogel Jonathan , Waes Carter Van , Chen Zhong 
Published: May 2015

Abstract
The cancer stem cell (CSC) subpopulation has been implicated in inducing tumorigenesis and drug resistance, however, the unique gene program and regulatory signaling that contribute to the CSC phenotypes in human cutaneous squamous cell carcinoma (hcSCC) have not been defined. In this study, a newly improved cell sorting method was developed using a panel of multiple cell surface markers to isolate the small percentage of CD133+ cell population enriched for CSC in primary hcSCC specimens. These cells exhibited CSC features including enhanced spheroid formation in vitro and tumor formation in vivo. Distinct gene expression signatures of the CD133+ subset were profiled by comparing CD133+ CSC with CD133- cancer cells using microarray, which revealed that CD133+ cells expressed enriched stem cell and cancer-related gene programs. In the CD133+ subset, 80 differentially expressed stem cell genes were identified, with an additional set of 69 altered genes enriched in key regulatory pathways, including Notch, NF-κB, Wnt, EMT, and STAT signaling, using Gene Ontology (GO) and Ingenuity Pathway Analysis (IPA). The expression patterns of combined signature genes of CSC and the key regulatory pathways were validated with Nanostring gene expression assay in independent tumor samples. Notch and NF-κB signaling emerged as important pathways. Inhibitors or siRNA knockdown of Notch1/2 and IKKα inhibited NF-κB activity and altered CSC phenotypes, including percentage of CD133+ cells, colony and spheroid formation. Elevated NF-κB signaling was observed in CSCs in the tumor tissues, where immunofluorescent staining showed co-localization of CD133+ and molecules of NF-κB pathway in SCC tumor specimens. Our data support the importance of aberrant NF-κB and Notch signaling in promoting CSC gene program and biologic functions, which could represent predictive diagnostic and prognostic parameters and potential targets for skin cancer prevention and treatment.
Supported by NIDCD intramural projects ZIA-DC-000016, 73 and 74.
Citation Format: Xinxin Quan, Nga Voong, Weiping Chen, Jamie Coupar, Steven Lee, David W. Petersen, Daniel C. Edelman, Paul S. Meltzer, Andrew Montemarano, Martin Braun, Jonathan Vogel, Carter Van Waes, Zhong Chen. Aberrant NF-κB and Notch pathways promote CD133+ cancer stem cells in human primary cutaneous squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3019. doi:10.1158/1538-7445.AM2014-3019
Abstract 3025: HER2/Stat3 signaling mediated radioresistance in U87 glioma cancer cells through suppressed apoptosis and enhanced glycolysis
Authors: Qin Lili , Fan Ming , Li Jian Jian 
Published: May 2015

Abstract
GBM is the most common and aggressive malignant primary brain tumor, and the prognosis for GBM patients remains poor. Radiotherapy continues to play a central role in the management of brain tumors. Even though the advances of radiotherapy strategies and techniques, frequent failure of radiotherapy made GBM a disease difficult to be treated. GBM cancer stem cells (CSCs) are reported to be responsible for resistance to chemo- and radiotherapy, and chemotherapy and radiotherapy resistant GBM CSCs have been isolated from GBM. However, the mechanisms of radioresistance of glioma cells are still elucidative. In this study, we investigated the role of HER2-Stat3 signaling pathway in radioresistance using human glioma cell line U87. We found that long-term therapeutic dose of fragmented irradiation induces repopulation of human glioma U87 cells with increased number of CD133+/HER2+ stem-like cells. FIR-surviving CD133+/HER2+ U87 cells have coactivation of HER2 and Stat3 and increased cell proliferation and invasion abilities. More importantly, we found that U87-FIR cells have lower level of mitochondria metabolism and ROS level, and higher mitochondrial membrane potential, while 5Gy single dose radiation induces increased mitochondria function. Furthermore, U87 cell injection derived xenograph tumor also has increased mitochondrial membrane potential and decreased mitochondria function after radiation. These results suggest that the radioresistance of GBM CSCs possibly due to the suppressed apoptosis and enhanced glycolysis mediated by HER2/STAT3 pathway.
Citation Format: Lili Qin, Ming Fan, Jian Jian Li. HER2/Stat3 signaling mediated radioresistance in U87 glioma cancer cells through suppressed apoptosis and enhanced glycolysis. [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 3025. doi:10.1158/1538-7445.AM2014-3025
Abstract 3031: HMGA2 promotes invasion and stemness in glioblastoma
Authors: Kaur Harpreet , Hütt Marianne , Mao Xing-gang , Orr Brent A. , Eberhart Charles G. , Raabe Eric H. 
Published: May 2015

Abstract
Glioblastoma Multiforme (GBM) causes the majority of brain tumor-related deaths in the United States. The high invasiveness of GBM prevents complete surgical resection, allowing tumor recurrence. The lack of curative treatment highlights a dire need to develop specific targeted therapeutics. Identifying and targeting novel molecular markers in glioma stem-like cells (GSCs), one of the major causes of tumor invasion and recurrence, could lead to development of better therapies. HMGA2, a non-histone transcriptional modulator, is a regulator of normal and cancer stem cells. The significance of HMGA2 as a potential therapeutic target in GBM has not been investigated. To elucidate the role of HMGA2 in GBM, we have used a combination of in vitro and in vivo techniques. We found increased HMGA2 expression in the mesenchymal subgroup of GBM tumors in the The Cancer Genome Atlas (TCGA) database and in a subset of primary human GBM tumors. HMGA2 is expressed in multiple patient-derived GBM neurosphere lines with increased expression in CD133+ neurospheres compared to CD133- neurospheres. Lentiviral short hairpin RNA (shRNA)-mediated reduction of HMGA2 significantly inhibited invasion of GBM neurosphere lines (040821, 62% reduction with HMGA2 shRNA vs. control shRNA, P&lt;0.001) in transwell invasion assays. Conversely, lentiviral-mediated overexpression of HMGA2 in GBM neurosphere lines increased invasion (GBM1 and 040821, 100-130% increase with HMGA2 overexpression vs. control vector, P&lt;0.001) in transwell invasion assays. In addition, overexpression of HMGA2 increased clonogenicity of GBM neurosphere lines in vitro in soft agar and methylcellulose colony formation assays (40-60% increase with HMGA2 overexpression vs. control vector, P&lt;0.001). Importantly, log-rank analysis of Kaplan-Meier plots showed increased survival of mice injected with GBM neurosphere lines transduced with HMGA2 shRNA compared to control shRNA (P&lt;0.05) in an in vivo, orthotopic, intracranial mouse xenograft model. To elucidate the molecular mechanism by which HMGA2 promotes invasion and stemness in GBM, we performed mRNA expression profiling on GBM neurosphere lines lentivirally transduced to express HMGA2 or empty vector control. We found increased CD44 expression in HMGA2-overexpressing GBM neurosphere lines compared to control. Together, our results suggest an oncogenic role of HMGA2 in promoting GBM tumorigenicity by increasing invasiveness and a stem cell-like state, thereby suggesting that HMGA2 is a potential therapeutic target in GBM.
Citation Format: Harpreet Kaur, Marianne Hütt, Xing-gang Mao, Brent A. Orr, Charles G. Eberhart, Eric H. Raabe. HMGA2 promotes invasion and stemness in glioblastoma. [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 3031. doi:10.1158/1538-7445.AM2014-3031
Abstract 3036: Basal stem cells contribute to squamous cell carcinomas in the oral cavity
Authors: Tang Xiao-Han , Scognamiglio Theresa , Gudas Lorraine 
Published: May 2015

Abstract
The cells of origin of oral cavity squamous cell carcinoma (OCSCC) are unknown. We used a cell lineage tracing approach (adult K14-CreERTAM; ROSA 26 mice transiently treated with tamoxifen) to identify and track normal epithelial stem cells (SCs) in mouse tongues by X-gal staining and to determine if these cells become neoplastically transformed by treatment with a carcinogen, 4-nitroquinoline 1-oxide (4-NQO). Here we show that in normal tongue epithelia, X-gal(+) cells formed thin columns throughout the entire epithelium 12 weeks after tamoxifen treatment, indicating that the basal layer contains long lived SCs that produce progeny by asymmetric division to maintain homeostasis. Carcinogen treatment results in a ∼ 10 fold reduction in the total number of X-gal(+) clonal cell populations and horizontal expansion of X-gal(+) clonal cell columns, a pattern consistent with symmetric division of some SCs. Finally, X-gal(+) SCs are present in papillomas and invasive OCSCCs, and these long-lived X-gal(+) SCs are the cells of origin of these tumors. Moreover, the resulting 4-NQO induced tumors are multi-clonal. These findings provide insights into the identity of the initiating cells of oral cancer.
Citation Format: Xiao-Han Tang, Theresa Scognamiglio, Lorraine Gudas. Basal stem cells contribute to squamous cell carcinomas in the oral cavity. [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 3036. doi:10.1158/1538-7445.AM2014-3036
Abstract 3037: Adipokines modulate human mammary stem cell self-renewal through mTOR
Authors: Esper Ray , Michael Dame , Djuric Zora , Smith William , Wicha Max , Brenner Dean 
Published: May 2015

Abstract
Rationale: Excess visceral adiposity is associated with an increased incidence of a variety of human ailments, including cancer. We tested the hypothesis that adipose-derived factors drive normal mammary stem cell self-renewal.
Methods: Visceral adipose tissue explants from obese F344 rats and cultured mouse 3T3-L1 adipocytes were grown with serum-free media for 48 hours. Primary human mammary epithelial cells, MCF10A, SUM149 and MCF7 cells were exposed to rhleptin (500 ng/ml), or adipocyte conditioned media and expanded in a non-adherent sphere forming assay for 10 days. Spheres were counted and size was quantified in Image J. Adipokine concentrations were assayed with the Proteome Profiler Adipokine Array. Other cultures were pre-treated with mTOR inhibitors rapamycin (100 nM) or everolimus (100 nM) for 2 hours prior to exposure to rhleptin or adipocyte conditioned media for 2 hours. S6 protein phosphorylation was quantified from Western blots.
Results: Data shown in Table 1 suggest that conditioned media from adipose tissue and from 3T3-L1 adipocytes increase human mammary stem cell self-renewal by 103% and 189%, respectively, whereas rhleptin increases stem cell self-renewal by 37%. Blockade of leptin activity with neutralizing antibodies or chimeric soluble receptors reduced the adipocyte conditioned media's stimulation of mammary epithelial cell self-renewal by 10-15%. Media conditioned by the mouse 3T3-L1 adipocytes or primary rat visceral adipose explants increased pS6 protein by 170% in MCF10A cells. mTOR inhibitors reduced rhleptin and adipocyte conditioned media stimulation of self-renewal in MCF10A and normal human mammary stem cells by 78-85%.
Conclusion: Adipocyte secreted factors and rhleptin promote increased mammary epithelial cell self-renewal through a process involving the activation of mTOR. Leptin contributes to a small fraction of the activity in adipocyte conditioned media, and is sufficient but not required for mammary stem cell self-renewal.
Change in stem cell self-renewalrhLeptin3T3-L1 Adipocyte Conditioned MediaRat Adipose Tissue Conditioned MediaBaseline # Spheres% Change (± SEM)P Value% Change (± SEM)P Value% Change (± SEM)P ValuePrimary human organoids19737 ± 7.005104 ± 20.006190 ± 26.001MCF-10A cells28834 ± 16.043320 ± 32.002389 ± 27.002MCF-7 cells57638 ± 9.007142 ± 15.001262 ± 40.006SUM149 cells95435 ± 6.09174 ± 20.012167 ± 21.003
Citation Format: Ray Esper, Dame Michael, Zora Djuric, William Smith, Max Wicha, Dean Brenner. Adipokines modulate human mammary stem cell self-renewal through mTOR. [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 3037. doi:10.1158/1538-7445.AM2014-3037