bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3737: Identifying novel therapeutic targets for cancer stem cell differentiation.
Authors: Reyes Germán L. Vélez , Yang Haidi , Wilson Aaron , Henault Martin , Frias Elizabeth , Schlabach Michael , Mclaughlin Margaret , Ross Nathan , Hoffman Gregory , Chen Amy , Hild Marc , Jaffe Aron 
Published: August 2014

Abstract
A growing body of evidence supports a role for cancer stem cells in the initiation and maintenance of a wide range of tumors. Cancer stem cells appear to be less sensitive to current treatments, necessitating the discovery of novel strategies for targeting this cell type. We hypothesize that driving cancer stem cells to differentiate will be an effective approach for inhibiting tumor growth and recurrence. Indeed, this strategy is used for the treatment of Acute Promyelocytic Leukemia, which presents with an accumulation of promyelocytes. Treatment with all-trans retinoic acid drives these cells to differentiate into neutrophils and leads to complete remission in over 90% of patients.
The goal of our work is to identify druggable nodes to drive epithelial cancer stem cells to differentiate, leading to inhibition of tumor growth. We are currently focused on colorectal cancer, for which there is a high unmet medical need. Each year, more than 1.2 million new cases of colorectal adenocarcinoma are reported. It is estimated that 80% of colon tumors have mutations in the adenomatous polyposis coli (APC) gene, which results in constitutive activation of the Wnt pathway and nuclear accumulation of β-catenin. Wnt signaling activates the transcription of genes that drive cell proliferation. Recent studies have shown that β-catenin is necessary for the maintenance of colorectal adenocarcinomas with APC mutations. Indeed, β-catenin knockdown in colon cancer cells drives them to differentiate and decreases their proliferative capacity, reducing tumor size in vivo. We have developed a number of methods to monitor this process in vitro, and will present our efforts to screen for novel targets that can drive colon tumor stem cells to differentiate.
Citation Format: Germán L. Vélez Reyes, Haidi Yang, Aaron Wilson, Martin Henault, Elizabeth Frias, Michael Schlabach, Margaret Mclaughlin, Nathan Ross, Gregory Hoffman, Amy Chen, Marc Hild, Aron Jaffe. Identifying novel therapeutic targets for cancer stem cell differentiation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3737. doi:10.1158/1538-7445.AM2013-3737
Abstract 374: KDR amplification in NSCLC is associated with sensitivity to VEGFR tyrosine kinase inhibitors.
Authors: Nilsson Monique B. , Cascone Tina , Gudikote Jayanthi , Roarty Emily , Diao Lixia , Koo Andrew , Ramachandran Sumankalai , Riquelme Erick , Tran Hai , Wistuba Ignacio , Carbone David P. , Heymach John 
Published: August 2014

Abstract
Targeted therapies designed to inhibit the vascular endothelial growth factor (VEGF) pathway have been extensively evaluated in the treatment of malignancies including Non-Small Cell Lung Cancer (NSCLC). VEGF pathway inhibitors such as bevacizumab, or the multitargeted receptor tyrosine kinase inhibitors (TKIs) vandetanib and sorafenib, have been shown to prolong progression-free survival (PFS) and/or overall survival (OS). These benefits, however, have been modest, seen only in subsets of patients. Thus, predictive markers for identifying which patients are likely to benefit are critically needed. Although expression of VEGF receptor-2 (VEGFR-2, also known as KDR) was initially thought to primarily occur in endothelial cells, VEGFR-2 has been detected on malignant cells, including lung cancer cells, and in NSCLC, overexpression of VEGFR-2 on tumor cells is associated with a poor clinical outcome. Amplification of KDR has been detected in lung cancer specimens at a relatively high frequency (9% and 32%). The consequences of KDR copy number gains (CNGs) are not yet understood. Recently, we have shown that NSCLC cell lines with KDR copy number gains (CNGs) were associated with in vitro resistance to platinum chemotherapy, and KDR CNG predicted worse overall survival in patients who received platinum adjuvant therapy but not in untreated patients. We investigated the hypothesis that NSCLC tumor cells with KDR CNG display increased sensitivity to VEGFR TKIs compared to tumor cells without KDR CNG. In tumor cell lines with KDR CNG, treatment with exogenous VEGF ligand enhanced cell motility and this was inhibited by VEGFR blockade with TKIs. Multiple receptor tyrosine kinases have been shown to drive HIF-1α levels, and NSCLC cells with KDR CNG express elevated levels of HIF-1α in normoxic conditions compared to NSCLC cell lines without KDR CNG. Here, we show that in NSCLC cell lines with KDR CNG, VEGFR TKIs decreased protein levels of HIF-1α and HIF-1α- regulated proteins. Furthermore, we report a clinical case in which a NSCLC patient with KDR CNG as determined by SNP array had a partial response to VEGFR inhibition with sorafenib.
Citation Format: Monique B. Nilsson, Tina Cascone, Jayanthi Gudikote, Emily Roarty, Lixia Diao, Andrew Koo, Sumankalai Ramachandran, Erick Riquelme, Hai Tran, Ignacio Wistuba, David P. Carbone, John Heymach. KDR amplification in NSCLC is associated with sensitivity to VEGFR tyrosine kinase inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 374. doi:10.1158/1538-7445.AM2013-374
Abstract 3743: Effect of folic acid supplementation on epigenetics and cancer stem cell populations in established colorectal cancer cell lines.
Authors: Farias Nathan , Coomber Brenda 
Published: August 2014

Abstract
Mandated fortification of folic acid, a B vitamin involved in nucleotide synthesis and DNA CpG methylation, has led to a subsequent increase in blood folate concentration as well as a simultaneous increase in colorectal cancer incidence in North America. Recent findings suggest that a proportion of tumor cells, termed cancer stem cells (CSC), share properties with native stem cells and are vital in the development and perpetuation of tumor metastasis. Both epigenetic DNA modifications as well as the activation of established stem cell signaling pathways are responsible for the activation and maintenance of (CSC). CSC share properties with native stem cells and are vital in the development of primary lesions and the perpetuation of tumor metastasis. We hypothesize that folate, a CpG methylation altering agent, and extracellular microenvironment factors can influence the development and maintenance of CSCs. By isolating and characterizing the CSC fraction in established human colorectal cancer cell lines HCT116, Caco2, and SW480, LS174T and PC7, a subline of DLD-1, we have assessed the effect of folate on CSC signaling pathways and global DNA methylation. Cell lines were grown in suspension and supplemented with specialized stem cell media to promote the growth and expansion of the CSC fraction. Western blot analysis and immunofluorescence were used to characterize the protein expression and nuclear localization of proteins associated with established CSC maintenance pathways, respectively. Global DNA methylation status was assessed using an ELISA-based assay. HCT116 and SW480 show an increased ability to form colonospheres in culture compared to Caco2 and IEC18 (normal rat intestinal cell line). Cells grown in suspension show variable activation of stem cell renewal pathways compared to monolayer. Low folic acid levels led to reduced methylation status and colonosphere yield while high folic acid levels led to increased global methylation and an increased in colonosphere yield. Thus, altered folic acid exposure in vitro can influence the methylation status and CSC self-renewal ability of human colorectal cancer cells. The relationship between folic acid and cancer stem cell maintenance may be an important factor in the apparent duel modulatory effect of folic acid on colorectal cancer and warrants further investigation.
Citation Format: Nathan Farias, Brenda Coomber. Effect of folic acid supplementation on epigenetics and cancer stem cell populations in established colorectal cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3743. doi:10.1158/1538-7445.AM2013-3743
Abstract 3751: Characterization of melanospheres from BRAFV600E mutated A2058 melanoma cell line.
Authors: Liao Yi-Hua , Deng Jhu-Yun , Kuo Min-Liang 
Published: August 2014

Abstract
Increasing evidence suggests that there is a unique cell subpopulation in melanomas that possess stem cell-like activities and play important roles in tumor maintenance, metastasis, and chemo- or radio-resistance. It has been found that a subset of cells in human melanomas can form nonadherent melanospheres under serum-free stem cell medium. These sphere-forming cells have been demonstrated to have the capabilities of self-renewal and multi-differentiation similar to cancer stem cells. The goal of the study was to understand the features associated with tumorigenesis and melanoma progression in melanospheres compared to that in the adherent parental melanoma cells. We demonstrated that melanospheres had a higher tumorigenic ability than parental melanoma cells in that as few as 100 cells injected subcutaneously could form tumors. The tumorigenic ability was more enhanced in serially transplanted xenografts in severe combined immunodeficient mice as revealed by soft agar colony formation assay. Melanospheres showed chemo-resistance to cisplatin-induced cytotoxicity, which was also enhanced in cells derived from serially transplanted xenografts. Moreover, upregulation of markers of epithelial to mesenchymal transition (EMT) was found in melanospheres. The sphere-forming cells showed decreased levels of E-cadherin and significantly increased expression of the transcription factor SLUG/SNAI2. Taken together, these results suggested that melanosphere cultures represent a useful methodology to enrich and investigate melanoma cells with higher tumorigenic and metastatic potentials.
Citation Format: Yi-Hua Liao, Jhu-Yun Deng, Min-Liang Kuo. Characterization of melanospheres from BRAFV600E mutated A2058 melanoma cell line. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3751. doi:10.1158/1538-7445.AM2013-3751
Abstract 3760: EGFL6 is a tumor vascular regulator of ovarian CSC asymmetric division and a novel therapeutic target.
Authors: Buckanovich Ronald J. , Bai Shoumei , Deng Ning , Ingram Patrick , Yoon Euisik 
Published: August 2014

Abstract
Cancer stem cells (CSC) are closely associated with tumor vasculature in the CSC niche. Tumor vascular cells are known to provide critical growth, differentiation, and survival cues for CSC. Unfortunately little is known about the specific factors produced by vascular cells. EGFL6 is a factor specifically secreted by ovarian tumor vascular cells. EGFL6 is reported to regulate the differentiation of normal stem cells. We examined the impact of EGFL6 on ovarian cancer cell growth. We found that EGFL6 significantly promoted ovarian cancer cell growth in vitro. Ovarian cancer cell proliferation was associated with a decrease in the percentage of ALDH+ ovarian CSC. Using a novel single cell microfluidic culture system we found that EGFL6 acts specifically on ALDH+ CSC to promote proliferation via asymmetric division. We used a in vivo novel model of human tumor vasculature to express EGFL6 in vivo and demonstrate that EGFL6 significantly promotes ovarian tumor growth. Finally we generated an EGFL6 blocking antibody and found that anti-EGFL6 antibodies could restrict tumor growth and delay disease recurrences. Thus EGFL6 is an import vascular regulator of ovarian CSC and EGL6 blocking antibodies represent a potentially important ovarian CSC targeting therapeutic.
Citation Format: Ronald J. Buckanovich, Shoumei Bai, Ning Deng, Patrick Ingram, Euisik Yoon. EGFL6 is a tumor vascular regulator of ovarian CSC asymmetric division and a novel therapeutic target. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3760. doi:10.1158/1538-7445.AM2013-3760
Abstract 3764: Loss of β2SP (ELF) enhances the stem-like traits and invasiveness of HCC cells.
Authors: Zhi Xiuling , Lin Ling , Shivapurkar Narayan , Jogunoori Wilma , Mishra Lopa , He Aiwu R 
Published: August 2014

Abstract
β2SP(ELF) is one of adapter proteins for Smad3/Smad4 complex formation during TGF-β signal transduction. 40% of β2SP+/- mice spontaneously develop hepatocellular carcinoma (HCC) and most cases of human HCC, gastric cancer, and lung cancer demonstrate significant reductions in β2SP expression. In our study, we investigated the possible mechanism for loss of β2SP induced HCC tumorigenesis. Recent studies have highlighted the involvement of cancer stem cells during the formation and progression of various types of cancers, epithelial cells that have undergone EMT (epithelial mesenchymal transition) acquire stem-cell properties during cancer development. Giving the role of TGF-beta signaling in stem cell differentiation and EMT during embryonic development, we hypothesize loss of β2SP results in alteration of liver stem cell that may contribute to the development of HCC in β2SP+/− mice. It has been shown that EpCAM-positive adult liver cells has stem cell property and can differentiate into functional hepatocytes in xenograft model. We found that EpCAM-positive hepatocyte number doubled in β2SP+/− mouse compared to wild type by fluorescence-activated cell sorter (FACS). Furthermore EpCAM level in β2SP+/− mouse liver was three times higher than that in the liver of wild type mouse. To study the mechanism by which Epcam is regulated by β2SP, HCC cells were transfected by β2SP siRNA. Inhibition of β2SP increased the expression of Epcam, and EMT markers vimentin was increased and E-cadherin expression was decreased in PLC/PRF/5 and SNU449 cells, while TGF-β1 and Smad3 rescued the expression of Epcam and E-cadherin, but not vimentin. We also found that suppression of β2SP expression promotes adhesion, migration and cloning formation of PLC/PRF/5 and SNU449 cells. Our data suggests loss of β2SP enhances the stem-like traits and invasiveness of HCC cells.
Citation Format: Xiuling Zhi, Ling Lin, Narayan Shivapurkar, Wilma Jogunoori, Lopa Mishra, Aiwu R He. Loss of β2SP (ELF) enhances the stem-like traits and invasiveness of HCC cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3764. doi:10.1158/1538-7445.AM2013-3764
Abstract 3768: Autophagy: a mechanism of resistance to therapy in breast cancer.
Authors: Dave Bhuvanesh , Mitra Sucharita 
Published: August 2014

Abstract
Autophagy is an evolutionarily conserved lysosomal pathway for degradation of cytoplasmic proteins, macromolecules, and organelles. It is defined as a cell survival pathway which allows cells to survive nutrient and environmental stress. Tumor initiating cells (TICs) survive radiation, endocrine therapy, and chemotherapy, making them the primary cause of relapse in breast cancer patients. Our previous studies have identified autophagy as the mechanism of survival in these treatment-resistant populations in letrozole- as well as chemotherapy-treated patient samples. In this study we confirmed our previous finding by using a real time PCR low density array of 84 genes related to autophagy in 9 paired pre- vs. post-letrozole treated clinical samples, where 60 out of 84 genes demonstrated a statically significant change (p&lt;0.05). Autophagy inhibitors like N-acetyl cysteine and catalase demonstrate a significant reduction in TICs using mammosphere forming efficiency (MSFE) (p&lt;0.05) and flow cytometry of CD44+/CD24- (p&lt;0.05) cells in three triple negative breast cancer cell lines (MDA-MB231, SUM159 and BT549). Recent evidence from our group had determined a role for hypoxia and reactive nitrogen species in TIC inhibition. Here we demonstrate that both catalase and N-acetyl cysteine inhibit TICs by a mechanism that significantly reduces inducible nitric oxide synthase and HIF-1α, implicating both hypoxia and reactive nitrogen species in the process. We will be confirming our finding in-vivo using patient-derived and cell line human xenografts and further examine the cross talk between hypoxia and reactive nitrogen species as it relates to autophagy. The understanding of this process may allow us to target TICs in a novel mechanistic way.
Citation Format: Bhuvanesh Dave, Sucharita Mitra. Autophagy: a mechanism of resistance to therapy in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3768. doi:10.1158/1538-7445.AM2013-3768
Abstract 3771: Establishment of primary cultures of cancer stem cells from patients with Li-Fraumeni Syndrome, carrier of TP53 p.R337H Brazilian founder mutation.
Authors: Mambelli Lisley I. , Kerkis Irina , Hainaut Pierre , Achatz Maria Isabel W. 
Published: August 2014

Abstract
Li-Fraumeni syndrome (LFS), an inherited cancer predisposition syndrome, is associated with germline mutations in TP53. It is characterized by high risk of multiple, early cancers. In Brazil, a variant form of LFS is exceedingly frequent due to a widespread founder TP53 mutation, p.R337H, detected in about 0.3% of the general population in Southern Brazil. This mutation occurs in p53 oligomerization domain and its effect on p53 oligomerization is supposed to be dependent upon pH conditions. Recent studies indicate that p53 plays a critical role in regulating differentiation and asymmetric divisions of stem cells. The main objective of this study is to isolate and to characterize Cancer Stem Cells (CSC) in patients with germline mutations in TP53 gene with Li-Fraumeni syndrome and Li-Fraumeni-like Syndrome. We have isolated and characterized CSC from tumors of p.R337H mutation carriers. After informed consent, surgical resection fragments were dissociated and brought in culture. Adherent cells and spheroids were derived from different tumor types. Spheroids and stromal cells derived from a breast cancer (BC) were further analyzed by immunofluorescence and flow cytometry to demonstrate positive immunolabeling for CD44+, CD24−, Oct4, Ki67 and Sox2 antibodies. Time-lapse videomicroscopy showed rapid growth, frequent asymmetric division and absence of senescent phenotypes for least 17 passages. Moreover, we showed by Colony Forming Units assay (CFU) that stromal cells are very clonogenic, once 103 cells initially plated were able to form 442 new colonies after 15 days in culture. It was also verified the differentiation potential of stromal cells for the following lineages: adipogenic, osteogenic and muscle-like cells. The adherent stromal cells as well as oncoesferas are able to self-renew and to proliferate in vitro for long periods without losing its main features. These properties are similar to stem cell possessing the p53 inactive. However, we observed that treatment of adherent cells with doxorubicin (DNA damaging agent) causes accumulation of p53 and causing induction of cell cycle arrest with low doses of this drug, and cell death / apoptosis in higher doses. Our findings using CSC-p.R337H can provide a very useful model for better understanding the role of specific mutation, as well as the TP53 tumor biology.
Citation Format: Lisley I. Mambelli, Irina Kerkis, Pierre Hainaut, Maria Isabel W. Achatz. Establishment of primary cultures of cancer stem cells from patients with Li-Fraumeni Syndrome, carrier of TP53 p.R337H Brazilian founder mutation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3771. doi:10.1158/1538-7445.AM2013-3771
Abstract 3780: Tumorigenicity and partial clear cell conversion of the epithelioid, but not fibroblastoid, subset of a sarcomatoid renal carcinoma cell line.
Authors: Hsieh Chin-Hsuan , Chen Hung-Chang , Chuang Cheng-Keng , Pang See-Tong , Chang Ying-Hsu , Liao Shuen-Kuei 
Published: August 2014

Abstract
The biology of sarcomatoid renal cell carcinoma (RCC) and its conversion from and to the clear cell RCC cells are not fully understood. In this study, we analyzed the sarcomatoid RCC cell line, RCC52, derived from a clear cell RCC lesion with extensive sarcomatoid differentiation. When grown as monolayers, RCC52 cells consisted of mostly epithelioid cells and partly fibroblastoid cells, and were all PAX-2 negative, suggestive of in vitro growth of the sarcomatoid, but not clear cell, component. Immunohistology of xenografts resulted from subcutaneous injection of tumor cells revealed that only the parental line and all epithelioid sublines tested could develop solid tumors consisting of mostly sarcomatoid cells and PAX-2+ clear cells in areas. Our findings revealed (i) the coexistence of the two phenotypically distinct epithelioid and fibroblastoid subsets in this sarcomatoid RCC52 cell line, (ii) the dissociation of the abilities to display tumorigenicity and migratory/invasive potential by the epithelioid and fibroblastoid subsets, respectively, (iii) the capability of only epithelioid subset to undergo partial conversion to a clear cell type, and (iv) the identification of epithelioid subset as the niche for cancer stem cells within the RCC52 cell line. Importantly, using CD44 and CD24 markers in cytofluorometric analysis, we identified the phenotypes of the epithelioid and fibroblastoid subsets to be CD44+/CD24− and CD44+/CD24+, respectively. Collectively, our findings highlight the phenotypical and functional properties of the two distinct subsets in a sarcomatoid RCC. Thus, improved understanding of tumor heterogeneity, metastatic niche and stromal progression has profound consequence of metastatic disease, and promises to open up new strategies for therapy of cancer.
Citation Format: Chin-Hsuan Hsieh, Hung-Chang Chen, Cheng-Keng Chuang, See-Tong Pang, Ying-Hsu Chang, Shuen-Kuei Liao. Tumorigenicity and partial clear cell conversion of the epithelioid, but not fibroblastoid, subset of a sarcomatoid renal carcinoma cell line. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3780. doi:10.1158/1538-7445.AM2013-3780