bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1714: The role of Hedgehog signaling in the regulation of human colon cancer stem cells
Authors: Regan Joseph L. , Staudte Stephanie , Schumacher Dirk , Keilholz Ulrich , Haybaeck Johannes , Lehrach Hans , Yaspo Marie-Laure , Henderson David , Steffen Andreas , Toedling Joern , Lesche Ralf , Schaefer Reinhold , Regenbrecht Christian R. , Mumberg Dominik , Lange Martin 
Published: July 2016

Abstract
Recent data support a hierarchical model of colon cancer in which tumor growth is driven by a subpopulation of cancer stem cells (CSCs) that may also be the source of relapse following treatment. Elucidation of the cellular heterogeneity within a tumor would therefore facilitate better characterization of patient subtypes and lead to more personalized and effective treatments. Here, as part of the OncoTrack* consortium, we report the use of Matrigel-based 3D in vitro models of patient-derived colon cancer for the characterization of molecular pathways important in the regulation of CSC self-renewal and survival.
Cellular subpopulations were isolated from patient-derived 3D-culture models based on expression of the CSC marker aldehyde dehydrogenase (ALDH) and then functionally tested for tumor initiation and self-renewal capacity by limiting dilution serial xenotransplantation. These studies demonstrate CSCs to be ALDH+. ALDH+ and ALDH- cells from 3D-culture and xenograft models were then subjected to RNA sequencing for whole transcriptome analysis.
These analyses demonstrated ALDH+ CSCs cells to be enriched for stem cell associated genes (ALDH1A1, LGR5, BMI1, CD44, CD166), developmental processes (embryonic, tissue development, EMT) and signaling pathways (Wnt signaling). In particular, the Hedgehog signaling pathway was found to be enriched in both 3D in vitro and xenograft models.
The role of Hedgehog signaling in colon cancer remains controversial. It has been reported as a negative regulator of Wnt signaling and to be inactive in colon cancer cells lines. Here, using small molecule inhibitors and lentivirus mediated gene knockdown, we report on the role of Hedgehog signaling in the regulation of colon CSC self-renewal and identify non-canonical Hedgehog signaling as a positive regulator of Wnt signaling.
*The research leading to these results has received funding from the European Union's Seventh Framework Program (FP7/2007-2013) for the Innovative Medicine Initiative under grant agreement n°115234.
Citation Format: Joseph L. Regan, Stephanie Staudte, Dirk Schumacher, Ulrich Keilholz, Johannes Haybaeck, Hans Lehrach, Marie-Laure Yaspo, David Henderson, Andreas Steffen, Joern Toedling, Ralf Lesche, Reinhold Schaefer, Christian R. Regenbrecht, Dominik Mumberg, Martin Lange. The role of Hedgehog signaling in the regulation of human colon cancer stem cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1714.
Abstract 1715: Whole transcriptome analysis of patient-derived 3D in vitro and xenograft models of colon cancer identifies placental genes required for the survival of cancer stem cells
Authors: Regan Joseph L. , Staudte Stephanie , Schumacher Dirk , Keilholz Ulrich , Haybaeck Johannes , Lehrach Hans , Yaspo Marie-Laure , Henderson David , Steffen Andreas , Toedling Joern , Lesche Ralf , Schaefer Reinhold , Regenbrecht Christian R. , Mumberg Dominik , Lange Martin 
Published: July 2016

Abstract
Growing evidence supports a subpopulation of cancer stem cells (CSCs) as both the drivers of tumor growth and the source of relapse following treatment. The identification of genes and pathways required for the survival of CSCs may therefore lead to better treatment outcomes. Here, as part of the OncoTrack* consortium, we report the use of 3D in vitro and xenograft models of patient-derived colon cancer for the identification of novel regulators of CSCs.
Increased aldehyde dehydrogenase (ALDH) activity has been demonstrated to be a marker of normal intestinal stem cells and colon CSCs. We therefore isolated and functionally tested ALDH+ cells for CSC properties using 3D in vitro models and xenografts of patient derived colon cancer. These studies revealed ALDH+ cells to be highly enriched for CSCs. In addition, there was a positive correlation between CSC frequency in the models and tumor grade at time of surgical resection.
ALDH+ CSCs were subjected to RNA sequencing for whole transcriptome analysis. These analyses demonstrated ALDH+ CSCs to be enriched for stem cell associated genes (ALDH1A1, BMI1, LGR5, CD44, CD166), signaling pathways (Wnt, Hedgehog) and developmental (embryonic, placental, tissue development, EMT) and metabolic processes (retinol metabolism, drug metabolism, hypoxia).
Lentivirus mediated gene knockdown was carried out on a panel of genes that were differentially expressed in ALDH+ cells from 3D in vitro models and xenografts. These studies led to the identification of genes required for the self-renewal and survival of colon CSCs. Interestingly, these genes have been reported as important regulators of early embryonic and placental development but have not previously been reported in the regulation of cancer stem cells.
*The research leading to these results has received funding from the European Union's Seventh Framework Program (FP7/2007-2013) for the Innovative Medicine Initiative under grant agreement n°115234.
Citation Format: Joseph L. Regan, Stephanie Staudte, Dirk Schumacher, Ulrich Keilholz, Johannes Haybaeck, Hans Lehrach, Marie-Laure Yaspo, David Henderson, Andreas Steffen, Joern Toedling, Ralf Lesche, Reinhold Schaefer, Christian R. Regenbrecht, Dominik Mumberg, Martin Lange. Whole transcriptome analysis of patient-derived 3D in vitro and xenograft models of colon cancer identifies placental genes required for the survival of cancer stem cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1715.
Abstract 1716: The role of CD44v9+ colorectal cancer stem cells in the resistance to cetuximab treatment
Authors: Hung Chia-Nung , Chang Ching-Yu , Hsiao Jou , Wei Wan-Chen , Chao Wei-Ting 
Published: July 2016

Abstract
Recent studies found that conventional therapy combined with cetuximab treatment (EGFR inhibitor) to treat metastatic colorectal cancer, had no improvement of patient survival rate in some population. One of possibilities might be cancer stem cells (CSCs) population resist to cetuximab treatment and modulate metastasis, however, the detail mechanism has not been addressed in colorectal cancer. Thus, our study is to decipher the mechanism of resistance to cetuximab in CD44v9+ specific colorectal cancer stem cells. First, to reveal clinical significance of CD44v9, the tumor samples of colorectal cancer patients were analyzed by immunohistochemistry to evaluate CD44v9 expression status in patients. To further investigate the biological mechanism, single cell analysis in CD44v9+ population of HT29 cells was performed with Fluidigm Biomark™ HD system. The results showed that 67% patients had highly expressed CD44v9 with lower survival rate. In vitro studies showed that when HT29 cells were in 5uM cetuximab treatment for 48 hours, CD44v9, Oct4, CD133, CD24, Lgr5, CSCs markers, were up-regulated in RNA level. Furthermore, CD44v9+/Oct4+ cancer cell population was increased but CD44v9+/pEGFR+ cancer cells were eliminated according to immunofluorescence results. The results of single cell analysis demonstrated that CD44v9+/Oct4+ cancer cells highly expressed proliferation markers consistently with cetuximab treatment. Trans-well migration results showed that CD44v9+/Oct4+ cancer cells migrated collectively via mediating E-cadherin dynamics. Furthermore, in clinical outcome, CD44v9 and E-cadherin co-expression were associated with recurrence and metastasis and decreased survival rate significantly. In conclusion, cetuximab failed to target CD44v9+/Oct4+ cancer cells, which characterized as cancer stem cells and might modulate collective cell migration. This finding suggested that new therapeutic strategy to against CSCs would be the potential clinical treatment in colon cancer.
Citation Format: Chia-Nung Hung, Ching-Yu Chang, Jou Hsiao, Wan-Chen Wei, Wei-Ting Chao. The role of CD44v9+ colorectal cancer stem cells in the resistance to cetuximab treatment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1716.
Abstract 1718: Characteristics of carbonic anhydrase 9-expressing cells in the human intestinal crypt base
Authors: Suzuki Yozo , Takahashi Hidekazu , Tanemura Masahiro , Nishimura Junichi , Haraguchi Naotsugu , Ohtsuka Masahisa , Miyazaki Susumu , Uemura Mamoru , Hata Taishi , Mizushima Tsunekazu , Yamamoto Hirofumi , Doki Yuichiro , Mori Masaki 
Published: July 2016

Abstract
Background/Aims: In many tissues, stem cells are sequestered in hypoxic microenvironments. However, little is known about the relationship between hypoxia and the intestinal crypt base, the presumed location of intestinal stem cells. This study investigated the expression of carbonic anhydrase 9 (CA9), a hypoxia-inducible membrane-tethered protein, in normal intestinal crypt base cells and in adenoma and early colorectal cancer.
Methods: Using surgically resected human colorectal cancer specimens, we investigated the expression pattern and functional associations of CA9 in human adult normal intestinal epithelia and in adenoma and early colorectal cancer using immunofluorescence, immunohistochemical staining, flow cytometry, and quantitative real-time polymerase chain reaction.
Results: Almost all slender cells in the crypt base in the ileum were CA9+. In the right and left colon, 25% and 40% of all cells, respectively, were CA9+. Notably, CA9+ cells had eosinophilic structures in their basal cytoplasm. Adenomas and T1 colorectal cancer showed broad CA9 expression. Flow cytometry analysis indicated that CA9+ cells had increased mRNA levels of AXIN2, a Wnt signaling factor.
Conclusion: These observations indicate that CA9 expression in normal crypt base cells is associated with intestinal epithelial stemness. CA9 expression may be involved in the carcinogenesis of colorectal cancer.
Citation Format: Yozo Suzuki, Hidekazu Takahashi, Masahiro Tanemura, Junichi Nishimura, Naotsugu Haraguchi, Masahisa Ohtsuka, Susumu Miyazaki, Mamoru Uemura, Taishi Hata, Tsunekazu Mizushima, Hirofumi Yamamoto, Yuichiro Doki, Masaki Mori. Characteristics of carbonic anhydrase 9-expressing cells in the human intestinal crypt base. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1718.
Abstract 1719: CD133 attenuates ROS accumulation via a steady increase in the expression of the cystine/glutamate transporter xCT: Consequence on chemoresistance in hepatocellular carcinoma
Authors: Seo Haengran 
Published: July 2016

Abstract
CD133+ cells in hepatocellular carcinoma (HCC) exhibit cancer stem cell (CSC)-like properties as well as resistance to chemotherapeutic agents and ionizing radiation; however, their function remains unknown. In this study, we tried to define new target and compound for enhancement of chemotherapy efficiency in HCC through elucidation of mechanism of CD133-induced chemoresistance.
Here, we show that CD133+ HCC cells exhibit strong resistance to reactive oxygen species (ROS) via persistent maintenance of the ROS-induced increase in xCT expression that upregulates glutathione (GSH) levels, and thereby play a central role in resistance to liver cancer therapy.
ROS are generally known to act as mediators of apoptosis induced by various anti-cancer drugs. We found that increased CD133 expression enhanced the capacity for ROS defense by enhancing cellular GSH levels, and ablation of CD133 attenuated not only the capacity for defense against ROS, but also chemoresistance, in HCC. Sulfasalazine, a potent xCT inhibitor, impaired the ROS defense system and increased the therapeutic efficacy of anticancer therapies in CD133+ HCC but not CD133−HCC in vivo and in vitro. Furthermore, we found that CD133 sustained the ROS stress-induced increase in the expression of xCT, a cystine/glutamate transporter that plays an important role in maintaining GSH levels, and thereby in preventing cell death via anticancer therapies. These results strongly indicate functional roles for CD133 in ROS defense and in evading anticancer therapies in HCC, and suggest that sulfasalazine, administered in combination with conventional chemotherapy, might be an effective treatment for CD133-targeted liver cancer therapy.
Citation Format: Haengran Seo. CD133 attenuates ROS accumulation via a steady increase in the expression of the cystine/glutamate transporter xCT: Consequence on chemoresistance in hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1719.
Abstract 1733: Inhibition of embryonic stem cells gene expression in pancreatic cancer: Effects of metformin and indole-3-carbinol
Authors: Lyn-Cook Beverly D. , Joseph Stancy , Word Beverly , Hammons George 
Published: July 2016

Abstract
Pancreatic cancer is among the top five deadliest cancers in developing countries and is rapidly increasing in minority populations, particularly African Americans. Understanding molecular mechanisms involved in the etiology and progression of this cancer can greatly improve patient prognosis. Cancer stem cells have been identified in pancreatic tumors and have been shown to contribute to its progression and resistance to standard treatments. Pancreatic cancer stem cells are subject to regulation by key embryonic stem cell transcription factors that are known to be aberrantly expressed in pancreatic cancer, such as SOX2, OCT4 and NANOG. Overexpression of OCT4, SOX2 and NANOG together or separately led to tumor transformation and tumor metastasis. These stem cell factors are known to promote self-renewal by interacting with other transcription factors. Using a human embryonic stem cell RT2 Profiler gene array, numerous stem cell genes were expressed in pancreatic cancer cell lines (MIAPaca2, Panc1). Both cell lines expressed high levels of SOX2, NANOG, CD44, GATA2, POU5F1 (OCT4) and other genes. Panc1 expressed high levels of SOX 17, while MIAPaCa2 expressed high levels of SOX 3,15 and 17. Treatment of cells with indole-3-carbinol alone at 100 and 200μM inhibited or decreased the expression of SOX2, NANOG, CD44, SOX15 and STAT3. However, treatment with metformin alone increased expression of SOX 15 and STAT3 in Panc1 cells but not in MIAPaCa2. Combination of metformin and indole-3-carbinol inhibited the expression of SOX2, NANOG, STAT3, and CD44. SOX2, POU5F1(OCT4) and NANOG are thought to be important players in various human cancers. OCT4 has been found to be expressed in 69% of PDAC and expression was shown too correlated to status and clinical state. High levels of OCT4 and NANOG has been found to correlate to worse prognosis and furthermore, contribute to multidrug-resistance and metastasis. This study have shown that the dietary agent, indole-3-carbinol alone and in combination with metformin down-regulate critical stem cell genes involved in maintenance of pluripotency and self-renewal of cancer stem cells.
Citation Format: Beverly D. Lyn-Cook, Stancy Joseph, Beverly Word, George Hammons. Inhibition of embryonic stem cells gene expression in pancreatic cancer: Effects of metformin and indole-3-carbinol. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1733.
Abstract 1734: Body mass index, physical activity and risk of colorectal cancer in the Korean Multi-center Cancer Cohort (KMCC)
Authors: Cho Sooyoung , Shin Aesun , Park Sue K. , Shin Hai-Rim , Chang Soung-Hoon , Yoo Keun-Young 
Published: July 2016

Abstract
Objectives: To examine the association between body mass index (BMI), physical activity and colorectal cancer risk among Korean adults.
Methods: Data from the Korean Multi-center Cancer Cohort (KMCC) between 1993 and 2005 were analyzed. The study population comprised 12,379 subjects aged above 20 years old. The subjects were followed until December 31, 2011 (median follow-up of 10.1 years). Measured weight and height values was used to calculate BMI and self-reported total time spent for physical activity were used. The Cox proportional hazard model was used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) of BMI and physical activity for colorectal cancer risk.
Results: Men who did moderate physical activity showed a lower risk for colorectal cancer (HR 0.35, 95% CI: 0.19-0.65 for 30-419 minutes compared to who spend less than 30 minutes a week doing moderate activities). We did not find any association between the total time of vigorous activities and muscle-strengthening activities and colorectal cancer risk in both men and women. Men with BMI of 25 or higher showed an increased risk for colorectal cancer compared to men with BMI of 18.5 to 22.9 (HR 1.64, 95% CI 0.94-2.88 for 25.0-29.9 kg/m2; HR 1.64, 95% CI 0.94-2.88 for greater than 30.0 kg/m2).
Conclusions: Moderate physical activities were associated with lower colorectal cancer risk among Korean men.
Citation Format: Sooyoung Cho, Aesun Shin, Sue K. Park, Hai-Rim Shin, Soung-Hoon Chang, Keun-Young Yoo. Body mass index, physical activity and risk of colorectal cancer in the Korean Multi-center Cancer Cohort (KMCC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1734.
Abstract 1752: Dietary fat intake during adolescence and breast density among young women
Authors: Jung Seungyoun 
Published: July 2016

Abstract
BACKGROUND: Lack of association between fat intake and breast cancer risk in cohort studies might be attributed to disregard of temporal effects during adolescence when breasts develop and are particularly sensitive to stimuli. We prospectively examined associations between adolescent fat intakes and breast density.
METHOD: Among 177 women who participated in the Dietary Intervention Study in Children, dietary intakes at ages 10-18 were assessed on five occasions by 24-hour recalls and averaged. We calculated geometric mean and 95% confidence intervals for MRI-measured breast density at ages 25-29 across quartiles of fat intake using linear mixed-effect regression.
RESULTS: Comparing women in the extreme quartiles of adolescent fat intakes, percent dense breast volume (%DBV) was positively associated with saturated fat (mean = 16.4% vs. 21.5%; Ptrend&lt;0.001). Conversely,%DBV was inversely associated with monounsaturated fat (25.0% vs. 15.8%; Ptrend&lt;0.001) and the ratio of polyunsaturated fat to saturated fat (P/S ratio; 19.1% vs. 14.3%; Ptrend:&lt;0.001). When examining intake by pubertal stages,%DBV was inversely associated with intake of polyunsaturated fat (20.8% vs. 16.4%; Ptrend = 0.04), long-chain omega-3 fat (17.8% vs. 15.8%; Ptrend&lt;0.001), and P/S ratio (22.5% vs. 16.1%; Ptrend&lt;0.001) before menarche, but not after. These associations observed with%DBV were consistently observed with absolute dense breast volume but not with absolute non-dense breast volume.
CONCLUSIONS: In our study, adolescent intakes of higher saturated fat and lower mono- and polyunsaturated fat are associated with higher breast density measured approximately 15 years later.
IMPACT: The fat subtype composition in adolescent diet may be important in early breast cancer prevention.
Citation Format: Seungyoun Jung. Dietary fat intake during adolescence and breast density among young women. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1752.
Abstract 176: Development of 1- and 3-phosphohistidine monoclonal antibodies utilized as novel tools to study histidine phosphorylation
Authors: Speckmann Wayne A. , Santos Mark , Shea Reshmie , Geiman Sheri , Saadat Arazo , Hoberg James , Zheng Wei 
Published: July 2016

Abstract
Phosphorylation of proteins is one of the most common forms of post-translational modification (PTMs) and is a mechanism for regulating enzyme activity or protein function. There are several amino acids that can be phosphorylated but despite its importance in cancer and tumor metastasis histidine phosphorylation (pHis) has been highly overlooked. One of the key reasons is the inherent challenge associated with studying pHis legitimately, due largely in part to the lack in availability of specific antibodies. Unlike serine, threonine, and tyrosine which all form acid-stable phosphoester (P-O) bonds upon phosphorylation, histidine forms heat and acid-labile phosphoramidate (P-N) bonds. Because of the instability of the P-N bond, it is nearly impossible to assess the prevalence of pHis accurately.
Here, we outline the development of selective, sequence independent anti-1-pHis and anti-3-pHis monoclonal antibodies which have addressed this current need for specific antibodies to detect the phosphorylation of histidine. The antibodies developed specifically recognize 1-pHis and 3-pHis and are isomer specific. In addition, they do not cross-react with phospho-tyrosine (pTyr), whereas, the first and second generation “pan-pHis” polyclonal antibodies against 3-pHis have been reported to do so. Moreover, it has been suggested that pHis could be as abundant as pTyr, comprising of approximately 1% of all known phosphorylation in cells, making specific monoclonal antibodies for detection highly desirable.
Validation data of the four monoclonal phospho-Histidine antibodies developed (clones SC50-3 and SC1-1 for assessment of 1-pHis activities; clones SC56-2 and SC39-6 for assessment of 3-pHis activities) demonstrate the specificity and broad utility of these monoclonal antibodies when identifying pHis substrates, making them useful tools in a variety of immunological and biological assays.
Citation Format: Wayne A. Speckmann, Mark Santos, Reshmie Shea, Sheri Geiman, Arazo Saadat, James Hoberg, Wei Zheng. Development of 1- and 3-phosphohistidine monoclonal antibodies utilized as novel tools to study histidine phosphorylation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 176.