bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1503: HP1-gamma's expression correlates with glioma grade and survival and is a putative marker of glioma stem like cells
Authors: Rajcevic Uros , Fritah Sabrina , Nazarov Petr V. , Popovic Mara , Kavalar Rajko , Strojnik Tadej , Podergajs Neza , Knol Jaco C. , Pham Thang V. , Piersma Sander R. , Jimenez Connie R. , Niclou Simone P. 
Published: August 2015

Abstract
Genetic and signaling pathways involved in the development of glioblastoma have been relatively well characterized. Gene/protein expression profiles of glioblastoma have been described that reflect stem-like phenotype of the tumor. However, no reliable individual markers exist up-to-date that differentiate glioblastoma stem-like cells from the neural stem cells. Glioblastoma appears to be of heterogenous cellular population, but detailed cellular origin of these tumors is unknown. Using a label-free proteomic approach, we analyzed two different glioma models with proven de novo tumorigenic properties, and compared them with primary neurospheres. Of almost 2000 identified proteins, we found 482 to be significantly differentially expressed among the three groups. Among the identified substrates, the clusters of proteins with highest density of protein-protein interactions were functionally enriched in RNA processing related to development and metabolic processes. We then focused on two putative quantitative markers of glioma stem-like cells, HP1-gamma (Heterochromatin Protein 1- gamma) - CBX3 (chrome box 3), an epigenetic regulator involved in RNA processing, and LDHA (Lactate Dehydrogenase A), a key metabolic enzyme of anaerobic glycolysis. We quantitated their expression in glioma tissue of different grades in a large set of patient samples and were able to show that the expression of HP1-gamma, highly upregulated in glioblastoma stem-like cells, correlates to glioma grade. Independent analysis of publicly available glioma patient data showed that LDHA expression is linked to IDH1 mutation status both in high grade and low grade gliomas. The same analysis reinforced our findings towards an increased involvement of CBX3/HP1-gamma in high grade gliomas. Altogether, CBX3/HP1-gamma and LDHA are novel biomarkers for cancer stem cell phenotype with different clinical importance in gliomas.
Citation Format: Uros Rajcevic, Sabrina Fritah, Petr V. Nazarov, Mara Popovic, Rajko Kavalar, Tadej Strojnik, Neza Podergajs, Jaco C. Knol, Thang V. Pham, Sander R. Piersma, Connie R. Jimenez, Simone P. Niclou. HP1-gamma's expression correlates with glioma grade and survival and is a putative marker of glioma stem like cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1503. doi:10.1158/1538-7445.AM2015-1503
Abstract 1506: Frequent loss of function mutations in TGFβR1 and TGFβR2 identify hair follicle bulge stem cells as the cell of origin for cutaneous squamous cell carcinoma
Authors: Cammareri Patrizia , Rose Aidan M. , Vincent David F. , Libertini Silvana , Ridgway Rachel A. , Athineos Dimitris , Coates Philip , McHugh Angela , Pourreyron Celine , Larsson Jonas , Spender Lindsay C. , Sapkota Gopal , Purdie Karin , Proby Charlotte , Harwood Catherine A. , Leigh Irene M. , Clevers Hans , Barker Nicholas , Karlsson Stefan , Pritchard Catrin , Marais Richard , South Andrew P. , Sansom Owen J. , Inman Gareth J. 
Published: August 2015

Abstract
Solid tumors are typically considered to arise from the accumulation of mutations within either stem or differentiated cells and to evolve over several years. However, melanoma patients treated with inhibitors of oncogenic BRAF frequently present with keratoacanthomas and/or cutaneous squamous cell carcinoma (cSCC) within weeks of treatment, possibly driven by paradoxical RAS/RAF MAPK pathway activation. Here, we identify frequent HRAS, TGFβR1 and TGFβR2 mutations in skin lesions from vemurafenib treated patients. Analysis of 98 human sporadic cSCC tumor samples and 21 cSCC cell lines revealed mutation of TGFβ receptors in 42% of samples and activating RAS mutations in 9% of samples. Functional analysis indicates that TGFβ receptor mutations frequently result in loss of canonical signaling. Analysis of normal human skin revealed localised TGFβ signaling in hair follicle bulge stem cells. In murine skin autocrine TGFβ signaling was highly localised to Lgr5+ve stem cells. We modelled hyperactivation of the MAPK pathway (through knockin of BRafV600E or KRASG12D) and the consequences of TGFβ signalling ablation (through the deletion of Tgfβr1) in Lgr5+ve cells. Whist BRaf or KRAS activation alone did not lead to cancer, homozygous deletion of Tgfβr1 enabled rapid cSCC development. Taken together, our results indicate that Lgr5+ve stem cells can act as the cell of origin for cSCC and that hyperactivation of the RAS-RAF-MAPK pathway, coupled with loss of TGFβ signalling, are driving events of skin tumorigenesis.
Citation Format: Patrizia Cammareri, Aidan M. Rose, David F. Vincent, Silvana Libertini, Rachel A. Ridgway, Dimitris Athineos, Philip Coates, Angela McHugh, Celine Pourreyron, Jonas Larsson, Lindsay C. Spender, Gopal Sapkota, Karin Purdie, Charlotte Proby, Catherine A. Harwood, Irene M. Leigh, Hans Clevers, Nicholas Barker, Stefan Karlsson, Catrin Pritchard, Richard Marais, Andrew P. South, Owen J. Sansom, Gareth J. Inman. Frequent loss of function mutations in TGFβR1 and TGFβR2 identify hair follicle bulge stem cells as the cell of origin for cutaneous squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1506. doi:10.1158/1538-7445.AM2015-1506
Abstract 1507: Heterogeneity of CD34 and CD38 expression in adult acute B lymphoblastic leukemia cells is reversible and not hierarchically organized
Authors: Jiang Zhiwu , Deng Manman , Lu Yi , Xu Bing , Li Peng 
Published: August 2015

Abstract
The existence and identification of leukemia stem cells in adult acute B lymphoblastic leukemia (B-ALL) remain controversial. We examined whether adult B-ALL is hierarchically organized into phenotypically distinct subpopulations of leukemogenic and non-leukemogenic cells or whether most B-ALL cells retain leukemogenic capacity, irrespective of their immunophenotypes. Cells from CD34+CD38-, CD34+CD38+, and CD34-CD38+ subpopulations of primary adult B-ALL xenografts were shown to be capable of reconstituting the original leukemia in NOD-scid-IL2Rg-/- mice. We found that primary leukemia cells from 11 of 25 adult B-ALL patients with different expression profiles of CD34 and CD38 proliferated robustly and became CD34-CD38+ after being co-cultured with OP9 stromal cells. Surprisingly, cultured CD34-CD38+ B-ALL cells were able to reestablish the complete leukemic phenotype in xenografts. Transcriptomic analysis of CD34+CD38-, CD34+CD38+, and CD34-CD38+ fractions purified directly from xenografts and CD34-CD38+ cells from culture revealed no significantly distinct expression profiles of transcription factors among these populations. Furthermore, 5.7% of single adult primary B-ALL cells engrafted in vivo. These observations suggest that adult B-ALL follows the stochastic stem cell model and that the heterogeneity of CD34 and CD38 expression in B-ALL is reversibly dependent on the microenvironment and is not hierarchically organized.
Citation Format: Zhiwu Jiang, Manman Deng, Yi Lu, Bing Xu, Peng Li. Heterogeneity of CD34 and CD38 expression in adult acute B lymphoblastic leukemia cells is reversible and not hierarchically organized. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1507. doi:10.1158/1538-7445.AM2015-1507
Abstract 1508: UV-induced Wnt7a in the human skin microenvironment specifies the fate of neural crest -like cells via suppression of Notch
Authors: Fukunaga-Kalabis Mizuho , Hristova Denitsa , Wang Joshua , Li Ling , Heppt Markus , Wei Zhi , Gyurdieva Alexandra , Webster Marie , Oka Masahiro , Weeraratna Ashani , Herlyn Meenhard 
Published: August 2015

Abstract
Multipotent stem cells with neural crest-like properties have been identified in the dermis of human skin. These neural crest stem cell (NCSC)-like cells display self-renewal capacity and differentiate into neural crest derivatives including epidermal pigment-producing melanocytes. NCSC-like cells share many properties with aggressive melanoma cells, such as high migratory capabilities and expression of the neural crest markers. However, little is known about which intrinsic or extrinsic signals determine the proliferation or differentiation of these neural crest-like stem cells. Here, we show that in NCSC-like cells, Notch signaling is highly activated, similar to melanoma cells. Inhibition of Notch signaling reduced proliferation of NCSC-like cells, induced cell death, and down-regulated non-canonical Wnt5a, suggesting that the Notch pathway contributes to the maintenance and motility of these stem cells. In three-dimensional skin reconstructs, canonical Wnt signaling promoted the differentiation of NCSC-like cells into melanocytes. This differentiation was triggered by the endogenous Notch inhibitor Numb, which is up-regulated in the stem cells by Wnt7a derived from UV-irradiated keratinocytes. Together, these data reveal a novel crosstalk between the two conserved developmental pathways in postnatal human skin, and highlight the role of the skin microenvironment in specifying the fate of stem cells.
Citation Format: Mizuho Fukunaga-Kalabis, Denitsa Hristova, Joshua Wang, Ling Li, Markus Heppt, Zhi Wei, Alexandra Gyurdieva, Marie Webster, Masahiro Oka, Ashani Weeraratna, Meenhard Herlyn. UV-induced Wnt7a in the human skin microenvironment specifies the fate of neural crest -like cells via suppression of Notch. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1508. doi:10.1158/1538-7445.AM2015-1508
Abstract 1512: Cancer stemness property incurred by inflammatory cytokine confers poor prognosis of hepatocellular carcinoma
Authors: Chang Te-Sheng , Wu Yu-Chih , Tsai Ying-Huang , Huang Yen-Hua 
Published: August 2015

Abstract
Purpose: To unravel the role of inflammatory cytokine IL-6 and IGF-1 receptor (IGF-1R) in expressing stemness-related properties and to evaluate the prognostic values of pluripotent transcription factor OCT4/NANOG, and IGF-1R in hepatocellular carcinoma (HCC).
Experimental Design: Frozen liver and HCC tissue samples were obtained from 191 patients who received curative hepatectomy between 2004 and 2012. Serum levels of IL-6 were detected using ELISA assays (n = 120). The effects of IL-6/IGF-1 on stemness expression in HCC were examined using OCT4/NANOG promoter luciferase reporter, RNA interference, secondary sphere formation, side population, and xenograft animal models. The OCT4/NANOG protein and phospho-IGF-1 receptor (p-IGF-1R) in tissues were detected by western blotting (n = 8) and immunohistochemical staining (n = 85). OCT4, NANOG, and IGF-1R expression levels in tissues (n = 191) were analyzed by real-time Q-PCR and was correlated with early tumor recurrence using Kaplan-Meier survival analysis.
Results: A high positive correlation between the expression levels of OCT4/NANOG and IGF-1R/p-IGF-1R in human HCC tissues was observed. The concurrent expression of OCT4/NANOG/IGF-1R was mostly confined to HBV-related HCC (HBV-HCC) and was significantly correlated with early tumor recurrence. High serum levels of IL-6 were significantly correlated with high OCT4/NANOG expression. IL-6 stimulated an autocrine IGF-1/IGF-1R expression STAT3-dependently, which stimulated stemness-related properties in both the cell lines and the xenografted mouse tumors. The inhibition of IGF-1R activation by either RNA interference or by treatment with the inhibitor picropodophyllin (PPP) significantly suppressed the IL-6-induced stemness-related properties both in vitro and in vivo.
Conclusions: The expression of pluripotency-related genes is associated with early tumor recurrence and is regulated by IL-6-induced IGF/IGF-1R activation, particularly in HBV-HCC.
Citation Format: Te-Sheng Chang, Yu-Chih Wu, Ying-Huang Tsai, Yen-Hua Huang. Cancer stemness property incurred by inflammatory cytokine confers poor prognosis of hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1512. doi:10.1158/1538-7445.AM2015-1512
Abstract 1513: ALDH1 and podoplanin expression in oral leukoplakia: Correlate with malignant transformaion risk
Authors: Habiba Umma , Shindoh Masanobu 
Published: August 2015

Abstract
Oral leukoplakia (OL) is the clinically diagnosed preneoplastic lesion in the oral cavity with an increased oral cancer risk. However, the risk of malignant transformation of OL is still difficult to assess. The objective of this study was to examine the expression patterns of ALDH1 and Podoplanin (PD) and determine their role in predicting oral cancer development in patients with OL. In a retrospective follow-up study, the expression patterns of ALDH1 and PD were determined using immunohistochemistry in samples from 79 patients with OL, including patients with untransformed lesions (n = 42) and patients with malignant transformed lesions (n = 37). The association between protein expression patterns and clinicopathologic parameters including oral cancer free survival (OCFS) was analyzed during a mean follow up period of 3.5 years. ALDH1 and PD expression was observed in 48 (61%) and 53 (67%) patients respectively. Kaplan-Meier analysis showed that the expression of ALDH1 and PD was correlated with the risk of progression to oral cancer (P = &lt; 0.05). Multivariate analysis revealed that ALDH1 and PD expression was associated with 3.02 folds and 2.62 folds of increase risk of malignant transformation, respectively. Meanwhile, the malignant transformation risk of OL was considerably higher in cases with both ALDH1 and PD expression (P = 0.000). Taken together, our data indicated that ALDH1 and PD expression patterns in OL were associated with oral cancer development, suggesting that ALDH1 and PD could be useful biomarkers to identify OL patient with substantially high oral cancer risk.
Citation Format: Umma Habiba, Masanobu Shindoh. ALDH1 and podoplanin expression in oral leukoplakia: Correlate with malignant transformaion risk. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1513. doi:10.1158/1538-7445.AM2015-1513
Abstract 1515: Inhibition of the IKK/NF-κB pathway impairs glioma stem cell function
Authors: Rinkenbaugh Amanda L. , Cogswell Patricia C. , Baldwin Albert S. 
Published: August 2015

Abstract
Glioma, the most frequently occurring primary brain tumor, has a median survival of less than 15 months, despite multimodal treatment combining surgery, radiation, and chemotherapy. It has been suggested that the presence of cancer stem cells (CSCs) within these tumors are responsible for resistance to treatment and high probability of recurrence. As a result, there is increasing interest in specifically targeting CSCs with new therapies to improve treatment of this disease. NF-κB has been implicated in numerous forms of cancer, as its target genes regulate hallmarks of cancer such as cell proliferation, survival, and invasion. Both glioma cell lines and tumor samples show high levels of phosphorylated p65, a marker of NF-κB activation. When comparing populations from tumor explants, NF-κB is preferentially activated in the CSC subset. We are examining the effects of IKK/NF-κB inhibition on both heterogeneous glioma explants and purified (CD133+) CSCs from these explants. Inhibition of NF-κB through either genetic or pharmacological means abrogates neurosphere formation, an in vitro measure of stem cell function. Additionally, real-time PCR analysis indicates that inhibition of NF-κB leads to a decrease in target genes implicated in glioma CSC biology, such as A20 and IL-6. Through gene expression analysis, we have identified a set of NF-κB-dependent genes that potentially contribute to the CSC phenotype, including invasion. We are using ex vivo brain slices and in vivo xenograft models to examine our findings in a pre-clinical setting. Our studies indicate a significant role for the NF-κB pathway in the biology of glioma CSCs, with possible parallels in CSCs of other tumor types.
Citation Format: Amanda L. Rinkenbaugh, Patricia C. Cogswell, Albert S. Baldwin. Inhibition of the IKK/NF-κB pathway impairs glioma stem cell function. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1515. doi:10.1158/1538-7445.AM2015-1515
Abstract 1516: YAP1 regulates Oct4 activity and Sox2 expression, facilitating self-renewal and vascular mimicry of stem-like cells
Authors: Bora Singhal Namrata , Nguyen Jonathan , Schaal Courtney , Perumal Deepak , Singh Sandeep , Coppola Domenico , Chellappan Srikumar 
Published: August 2015

Abstract
Non-small cell lung cancer (NSCLC) is highly correlated with smoking and has very low survival rates. Multiple studies have shown that cancer stem-like cells (CSCs) contribute to the genesis and progression of NSCLC. These cells have been shown to form differentiated tumor cells upon receiving appropriate microenvironmental cues and can give rise to multiple components of the tumor, including the vasculature. Earlier work from our laboratory had shown that Hoechst 33342 dye excluding side-population (SP) cells are enriched in cells having stem-like properties. SP cells displayed high self-renewal capacity, were highly drug resistant, and could form metastatic tumors in immunocompromised mice. The present study shows that the transcriptional co-activator YAP1, which is the oncogenic component of the Hippo signaling pathway, is elevated in the stem-like cells from NSCLC and contributes to their self-renewal and ability to form angiogenic tubules in matrigel. Inhibition of YAP1 by a small molecule inhibitor Visudyne or depletion of YAP1 by siRNAs suppressed self-renewal and vascular mimicry of stem-like cells. These effects of YAP1 were mediated through the embryonic stem cell transcription factor Sox2. YAP1 could associate with the Sox2 promoter and could transcriptionally induce Sox2 as seen by qRT-PCRs, ChIP assays and promoter luciferase assays; this induction was through a physical interaction of YAP1 with Oct4 protein. The binding of Oct4 to YAP1 could be detected in cell lines as well as NSCLC tumor tissues as seen by immunofluorescence, proximity ligation assays (PLA), immunoprecipitation-western blot experiments and GST binding assays. Interestingly, the interaction was elevated in NSCLC samples compared to normal tissue as seen by PLA. A peptide that could disrupt the interaction between YAP1 and Oct4 abrogated Sox2 expression, self-renewal and vascular mimicry. Depleting YAP1 reduced the expression of EMT genes and prevented the growth and metastasis of tumor xenografts in mice, while overexpression of Sox2 in YAP1 depleted cells could rescue self-renewal of stem-like cells. In conclusion, our results demonstrate that YAP1 can modulate the stem-like functions of cancer stem cells by regulating Sox2, and this regulatory pathway can potentially be targeted for combating NSCLC.
Citation Format: Namrata Bora Singhal, Jonathan Nguyen, Courtney Schaal, Deepak Perumal, Sandeep Singh, Domenico Coppola, Srikumar Chellappan. YAP1 regulates Oct4 activity and Sox2 expression, facilitating self-renewal and vascular mimicry of stem-like cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1516. doi:10.1158/1538-7445.AM2015-1516
Abstract 1529: MYC and HIF-2alpha cooperates in oral squamous carcinoma cell self-renewal during hypoxia
Authors: Li Hong , Talukdar Joyeeta , Sandhya Sora , Bhuyan Seema , Gayan Sukanya , Sarma Anupam , Mokhtari Reza Bayat , Felsher Dean W. , Yeger Herman , Das Bikul 
Published: August 2015

Abstract
Oral squamous cell carcinoma (OSCC) is a global health challenge. The overall survival rate of this devastating disease has not significantly changed, and the biology of this type of cancer also remain largely unexplored. To enhance the understanding of this disease through global heath cancer research collaborative effort, we have set up an international collaboration between Forsyth Institute, Cambridge, and KaviKrishna laboratory, which is located in Kamrup district of Assam, having highest incidence of oral cancer in the world. Through this collaborative effort we intend to explore the role of hypoxia in oral cancer progression, metastasis and therapy resistance. Method: We used an oral squamous cell carcinoma cell line SSC25 for this purpose, and performed several experiments using a well-described in vitro assay of CSC self-renewal under hypoxia. Results: We identified a rare ABCG2+ expressing, highly tumorigenic cell population in SSC-25 having cancer stem cell (CSC) like characteristics in the in vivo serial transplantation assay, as well as high metastatic activity to bone marrow of NOD/SCID mice. The ABCG2+ cells, when exposed to hypoxia (&lt;0.1% O2, 24 hours), exhibited enhanced expression and transcriptional activity of MYC, and HIF-2alpha. ChIP assay revealed that HIF-2alpha directly binds to MYC in ABCG2+ cells. siRNA inhibition of HIF-2alpha significantly reduced hypoxia-induced MYC expression and transcriptional activity in ABCG2+ cells. Finally, in clinical OSCC specimens, we confirmed the expression of MYC, HIF-2alpha and ABCG2 expression by immunohistochemistry. Conclusion: These data indicate that MYC oncogene play important role in the self-renewal of oral cancer cells during hypoxia.
Citation Format: Hong Li, Joyeeta Talukdar, Sora Sandhya, Seema Bhuyan, Sukanya Gayan, Anupam Sarma, Reza Bayat Mokhtari, Dean W. Felsher, Herman Yeger, Bikul Das. MYC and HIF-2alpha cooperates in oral squamous carcinoma cell self-renewal during hypoxia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1529. doi:10.1158/1538-7445.AM2015-1529