bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3859: MicoRNAs in regulation of colon cancer stem cells
Authors: Yu Yingjie , Pratima Nangia-Makker , Rajendra Sindhu , Levi Edi , Majumdar Adhip P. N. 
Published: May 2015

Abstract
Accumulating evidence supports the contention that epithelial cancers, including sporadic colorectal cancer (CRC), the incidence of which increases sharply after the age of 50 years, are diseases driven by self-renewing cancer stem/stem-like cells (CSCs). We have reported that CSC population in the colonic mucosa increases with advancing age. This was accompanied by a concomitant rise in microRNA-21 (miR-21) and reduction in miR-145 in the colonic mucosa. Interestingly, increased levels of miR-21 and reduction in miR-145 were noted in the colonic mucosa of patients with adenomatous polyps or CRC. These observations prompted us to speculate a role for miR-21 and miR-145 in regulating CSCs in the colonic mucosa. Indeed, we found that overexpression of miR-21 in colon cancer cells greatly increases CSCs and also induces tumor growth. An opposite phenomenon was noted in colon cancer cells where miR-145 was upregulated through stable transfection. In addition, studies utilizing SCID mice xenograft model of colon cancer showed that administration of either antagomir-21 (anti-sense miR-21) or excess miR-145 greatly inhibited the growth of tumors of colon cancer cells, when compared with the controls.
This reduction in growth was associated with decreased expression of CD44, B-catenin and Sox-2 and induction of CK-20. In vitro cell culture studies have further demonstrated miR-21 to regulate miR-145 and vice versa. Although the precise mechanism(s) by which miR-21 or miR-145 regulates CSCs in the colonic mucosa during the progression of CRC is unknown, our in vitro studies suggest that they induce differentiation of colon CSCs. The latter was evidenced by the increased expression of CK-20 in colon cancer cells following downregulation of miR-21 and upregulation of 145. In contrast, Sox-2 expression is decreased following overexpression of miR-145. In conclusion, our current observations suggest that miR-21 and miR-145, that are upregulated and downregulated, respectively, in the colonic mucosa during aging and CRC, play critical roles in regulating CSCs in the colon.
Citation Format: Yingjie Yu, Nangia-Makker Pratima, Sindhu Rajendra, Edi Levi, Adhip P. N. Majumdar. MicoRNAs in regulation of colon cancer 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 3859. doi:10.1158/1538-7445.AM2014-3859
Abstract 3863: The stemness of gastric cancer stem cells is sustained by TGFβ produced from cancer-associated fibroblasts
Authors: Yashiro Masakazu , Hasegawa Tsuyoshi , Fukuoka Tatsunari , Kinoshita Haruhito , Morisaki Tamami , Kasashima Hiroaki , Masuda Go , Kubo Naoshi , Hirakawa Kosei 
Published: May 2015

Abstract
Purpose: Cancer-associated fibroblasts (CAFs) have recently been implicated in tumor growth and metastasis in gastric cancer. Cancer stem cells. (CSCs) have been proposed to have an important role in cancer progression. CSCs are known to display stem cell properties, “stemness”, the ability to sustain self-renewal. Because CAFs are abundant in the stroma of gastric cancer, CAFs are supposed to affect CSC characteristics of gastric cancer. However, the effects of CAFs on the characteristics of gastric cancer CSCs have not been clarified. The aim of this study was to clarify the effect of CAFs on CSCs characteristics in gastric tumor microenvironment.
Experimental Design: Four gastric cancer cell lines, OCUM-12, OCUM-2MD3, MKN-45, and MKN-74, were used. Side population (SP) cells were sorted by flow cytometry as CSC-rich cells from each parent cell line. CaF-37 was established from the tumoral gastric specimens as CAFs. Flow cytometric analysis of SP fraction, spheroid colony assay, and RT-PCR analysis of CSC markers, ABCG2, ALDH1, CD44, CD133, NANOG, and OCT3/4, were performed to identify CSCs properties. Effect of CAFs on the tumorigenicity by OCUM-12/SP cells was examined using nude mice.
Results: CaF-37 significantly increased the percentages of the SP fraction of scirrhous-type of gastric cancer cells, OCUM-12/SP and OCUM-2MD3/SP cells, but not that of non-scirrhous-type of gastric cancer cells, MKN-45/SP and MKN-74/SP cells. Taken together, CaF-37 significantly increased the number of spheroid colonies and the expression level of CSC markers of scirrhous-type of gastric cancer cells. These stimulating-activities by CaF-37 were significantly decreased by TGFβ inhibitors, but not FGFR and cMet inhibitor. Also, SP fractions of scirrhous-type of gastric cancer cells were significantly increased by TGFβ, but not by FGF2 and HGF. Tumorigenicity by subcutaneous co-inoculation of OCUM-12/SP cells with CaF-37 was significantly high in comparison with that by OCUM-12/SP cells alone. Phospho-Smad2 expression level was significantly increased by co-inoculation with CaF-37.
Conclusions: TGFβ from CAFs in the tumor microenvironment might sustain the stemness of CSCs of gastric cancer cells, especially in scirrhous-type of gastric cancer.
Citation Format: Masakazu Yashiro, Tsuyoshi Hasegawa, Tatsunari Fukuoka, Haruhito Kinoshita, Tamami Morisaki, Hiroaki Kasashima, Go Masuda, Naoshi Kubo, Kosei Hirakawa. The stemness of gastric cancer stem cells is sustained by TGFβ produced from cancer-associated fibroblasts. [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 3863. doi:10.1158/1538-7445.AM2014-3863
Abstract 3870: Effects of carbon ion beam, alone or in combination with cisplatin, on triple-negative breast cancer stem-like cells
Authors: Sai Sei , Karasawa Kumiko , Vares Guillaume Gueal , Shirai Toshiyuki 
Published: May 2015

Abstract
Aims
To investigate whether a carbon ion beam alone or in combination with cisplatin has beneficial effects compared to X-ray by targeting putative triple negative (TN) breast cancer stem cells (CSCs).
Materials and Methods
Human breast CSCs sorted from MDA MB231 cells were treated with carbon ion or X-ray irradiation alone or in combination with cisplatin, and then colony, spheroid and tumor formation assays, RT-PCR Array analysis as well as immunofluorescence γH2AX foci assay were performed.
Results
The colony, spheroid formation as well as tumorigenicity assays confirmed that CD44+/CD24- and CD44+/ESA+ cells exactly have CSC properties compared to CD44-/CD24- and CD44-/ESA- cells. CSCs were more highly enriched after X-ray or cisplatin compared to carbon ion beam. Carbon ion beam combined with cisplatin significantly suppressed colony and spheroid formation compared to that of X-ray combined with cisplatin as well as carbon ion alone. RT-PCR Array analysis showed that expression of DNA repair, apoptosis and autophagy related genes were differently altered between carbon ion beam and X-ray irradiation alone or in combination with cisplatin, and carbon ion beam combined with cisplatin more highly induced apoptosis and autophagy compared to X-ray combined with cisplatin. Immunofluorescence assay showed that not only the number but also the size of γH2AX foci in CSCs were lager 24 h after carbon ion beam combined with cisplatin compared to that of X-ray combined with cisplatin as well as carbon ion alone.
Conclusion
Carbon ion beam combined with cisplatin has superior potential to kill TN breast CSCs with unrepairable severe DNA damage and enhanced apoptosis as well as autophagy.
Citation Format: Sei Sai, Kumiko Karasawa, Guillaume Gueal Vares, Toshiyuki Shirai. Effects of carbon ion beam, alone or in combination with cisplatin, on triple-negative breast cancer stem-like 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 3870. doi:10.1158/1538-7445.AM2014-3870
Abstract 3871: Tie-2 regulates stemness and metastasis of prostate cancer cells
Authors: Tang Kai Dun , Ling Ming-Tat 
Published: May 2015

Abstract
Introduction: Prostate cancer is the most commonly diagnosed male cancer in Western countries. Currently, the major treatment challenge for prostate cancer patients is the development of tumor metastasis. Ample evidence supports the idea that tumor metastasis originates from a rare population of cancer cells known as cancer stem cells (CSCs) [1]. Unfortunately, little is known about the identity of these cells, making it difficult to target prostate tumor metastasis. Here we reported the identification of a rare population of prostate cancer cells which express the Tie-2 protein, a tyrosine kinase receptor required for the bone marrow homing and colonization of hematopoietic stem cells. Notably, this Tie-2 positive population exists exclusively in highly metastatic prostate cancer cell lines.
Methods:To study the role of Tie-2 in prostate tumor metastasis, we have performed fluorescence-activated cell sorting (FACS) to isolate the Tie-2+ population from a prostate cancer cell line (PC-3). We then performed cDNA microarray analysis to characterize the gene expression profile of these cells. Furthermore, we have performed cell adhesion assay to examine the ability of the Tie-2+ cells in adhering to osteoblasts and endothelial cells. Besides that, we have also performed quiescent staining and drug sensitivity assay to examine whether Tie-2+ cells are more quiescent, and thus become resistant to chemotherapeutic drug. Finally, we have injected both Tie-2+ and Tie-2- PC-3 cells intracardiacly into the NOD-SCID mice to determine if Tie-2 expression promote prostate tumor metastasis under in vivo condition.
Results: Data from our study revealed that Tie-2+ cells express higher level of prostate CSC markers when compared to the Tie-2- population. Meanwhile, Tie-2+ cells are highly adhesive to both osteoblasts and endothelial cells, a characteristic necessary for tumor metastasis. We also found that Tie-2+ cells are more quiescent and resistant to the chemotherapeutic drug cabazitaxel, further support that these cells possess CSC-like characteristics. More importantly, we found that Tie-2+ cells, but not the Tie-2- cells population, developed metastatic tumor in vivo.
Conclusions: Our data suggested that Tie-2 plays an importantly role in the development of drug resistance and prostate tumor metastasis. Thus, Tie-2 might be a novel therapeutic target for treatment of advanced prostate cancer patients.
References:[1] J.E. Visvader, G.J. Lindeman, Cancer stem cells in solid tumours: accumulating evidence and unresolved questions, Nature reviews. Cancer, 8 (2008) 755-768.
Citation Format: Kai Dun Tang, Ming-Tat Ling. Tie-2 regulates stemness and metastasis of prostate cancer 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 3871. doi:10.1158/1538-7445.AM2014-3871
Abstract 3876: Can Nanog activity identify aggressive breast cancer stem cell populations
Authors: Sayers Thomas J. , Kluyver Rachel de , Kaddoura Marcella , Stauffer Jim , Tewary Poonam , Brooks Alan D. 
Published: May 2015

Abstract
Many tumors have been demonstrated to contain cancer stem cells (CSC). We hypothesized that expression of transcription factors that are required for induction and maintenance of pluripotency would be a possible alternative to cell surface phenotype for identification of CSC populations. Therefore we evaluated Nanog expression in 4T1.2 murine breast carcinoma cells, as a biomarker for CSC sub-populations. Introduction of a Nanog promoter reporter that drives destabilized GFP into 4T1.2 cells resulted in a stable expression of GFP in about 1-3% of the cells. On in vitro cell culture of FACS sorted GFP+ populations, up to 80% of the cells became GFP- over a period of 4 weeks, whereas GFP- populations remained 100% GFP-. In vitro CSC surrogate assays show that Nanog-GFP+ cells exhibited CSC characteristics, with enhanced colony formation in methylcellulose and increased survival in serum-free media. Nanog-GFP+ cells were also more efficient at generating experimental lung metastases following intravenous injection. In addition Nanog-GFP+ cells were also more resistant to the chemotherapeutic drugs paclitaxel and bortezomib. However targeting the extrinsic apoptosis pathway in vitro with a combination of bortezomib and agonist antibodies to the TRAIL death receptor DR5 was equally effective against both Nanog-GFP+ and Nanog-GFP- cell populations. To monitor Nanog expression in human breast cancer cells (SUM159), we used lentiviral vectors to introduce DNA constructs of the Nanog response element driving GFP and luciferase. About 0.5% of the SUM159 cells were GFP+ by FACS, and these cells also demonstrated some CSC characteristics such as enhanced colony formation in methylcellulose. Levels of GFP were increased in the SUM159 cells following cell culture under hypoxic conditions. These findings suggest that Nanog activity may be useful as surrogate marker of aggressive breast CSC subpopulations.
Funded by NCI Contract HHSN261200800001E
Citation Format: Thomas J. Sayers, Rachel de Kluyver, Marcella Kaddoura, Jim Stauffer, Poonam Tewary, Alan D. Brooks. Can Nanog activity identify aggressive breast cancer stem cell populations. [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 3876. doi:10.1158/1538-7445.AM2014-3876
Abstract 388: Epigenome-wide profiling identified significant differences in DNA methylation between African-American and European-American men with prostate cancer
Authors: Kwabi-Addo Bernard , Wang Songping , Devaney Joseph 
Published: May 2015

Abstract
Background: DNA methylation is a dynamic epigenetic mark that is essential for mammalian organismal development. For human prostate cancer (PCa), abundant evidence has accumulated to suggest that somatic epigenetic alterations may appear early during cancer development, as well as more commonly and consistently, than genetic changes. Several cancer-associated genes have been reported to show significant differences in DNA methylation pattern in prostate tissues from African-American (AA) and European-American men, but the genome-wide pattern and extent of these differences are largely unknown. The current study investigated genome-wide DNA methylation differences in AA and EA prostate tissue samples with the aim of assessing the variation of genome-wide patterns of DNA methylation.
Methods: To comprehensively examine the DNA methylation pattern in AA and EA samples, we used illumina 450 K methylation platform (Infunium Chip) to conduct genome-wide large scale analysis of DNA methylation changes in 7 normal and 3 PCa tissue samples from AA versus 8 normal and 3 PCa tissue samples from EA. This chip interrogates &gt;485,000 CpG methylation sites per sample at single-nucleotide resolution and assigns each site an average beta value for quantitative methylation level.
Results: Pathway analysis of the genes with altered methylation patterns identified top canonical pathways for the involvement of cancer related network for genes involved in axonal guidance, antigen presentation, androgen signaling and protein ubiquitination pathways in prostate cancer tissues compared with normal prostate tissues obtained from AA men. On the other hand, the top canonical pathways identified in prostate cancer tissues compared with normal prostate tissues obtained from EA men are genes involved in epithelial-mesenchymal transition, p53 signaling, nucleotide sugars metabolism and germ cell-sertoli cell junction signaling pathways.
Conclusion: Using this quantitative sequencing-based approach, our work uncovers significant global DNA methylation alterations in AA versus EA prostate tissues and provides a mechanistic explanation for the disease disparity.
Citation Format: Bernard Kwabi-Addo, Songping Wang, Joseph Devaney. Epigenome-wide profiling identified significant differences in DNA methylation between African-American and European-American men with prostate 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 388. doi:10.1158/1538-7445.AM2014-388
Abstract 3889: Modulation of breast cancer stem cell marker CD44 by all-trans-retinoic acid (ATRA)
Authors: Kitadai Rui , Bednarczyk Robert , Tuli Neha , Hanly Elyse , Benrahoma Ghada , Suriano Robert , Mittelman Abraham , Tiwari Raj K. 
Published: May 2015

Abstract
Breast cancer stem cells (BCSCs), often characterized by cell surface marker expression as being CD44+/CD24- or CD44+/CD24low phenotypes, constitute a subpopulation of tumor cells that are highly tumorigenic. With respect to CD44, it has been reported that its expression is influenced by tumor microenvironment (TME) and that modulation of CD44 is detrimental to breast cancer stem cell self-renewal and differentiation. Interestingly, the factors that mitigate this effect are still unknown, which has led us to hypothesize that factors within the TME, comprising of differentiating agents, modulate the BCSC phenotype by regulating cell surface markers. MDA-MB 231 showed presence of BCSCs as CD44 positive cells were detected using immunofluorescence and Western blot analyses. The expression of CD44 on MDA-MB 231 was not responsive to the proinflammatory molecule IL-8 or estrogen. Both MDA-MB 231 and T47D were responsive to IL-8 and estrogen with respect to migration and invasion as examined in vitro using a Boyden Chamber assay suggesting that migration and invasion was independent of CD44 expression. Alternatively IL-8 responsiveness may be on a select clonal population of CD44- cells. The presence of differentiating agents within the TME has been explored. To examine the effect of differentiating agents, we used the classical all-trans-retinoic acid (ATRA) previously shown to promote tumor regression. CD44 expression was highly responsive to ATRA as it was down regulated following treatment. ATRA treatments also resulted in decreased migration and invasion of breast cancer cells. Our results led us to conclude that specific differentiating agents can affect breast cancer stem cell activity by directly down regulating key adhesion cell surface markers.
Citation Format: Rui Kitadai, Robert Bednarczyk, Neha Tuli, Elyse Hanly, Ghada Benrahoma, Robert Suriano, Abraham Mittelman, Raj K. Tiwari. Modulation of breast cancer stem cell marker CD44 by all-trans-retinoic acid (ATRA). [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 3889. doi:10.1158/1538-7445.AM2014-3889
Abstract 3892: Inhibitory effects and regulatory mechanism of nestin in pancreatic cancer
Authors: Matsuda Yoko , Ishiwata Toshiyuki , Yoshimura Hisashi , Yamashita Satoshi , Ushijima Toshikazu , Takubo Kaiyo , Arai Tomio 
Published: May 2015

Abstract
Introduction: Nestin, a progenitor/stem cell marker, is expressed in human pancreatic cancer, and we have previously shown that its expression positively correlates with invasiveness and metastasis of the cancer (Cancer Biol Ther, 2011; Am J Pathol. in press). Here, we examined the inhibitory effects of nestin expression using nestin-targeted small interfering RNA (siRNA) in pancreatic cancer cells. We also investigated the regulatory mechanism of nestin expression in pancreatic cancer. Methods: siRNA targeting nestin was transfected to the pancreatic cancer cell lines PANC-1 and PK-45H, and we analyzed the effect on cell behaviors including proliferation, migration, invasion, sphere-forming ability, and sensitivity to gemcitabine. Next, to clarify the mechanisms of nestin expression, pancreatic cancer cells were injected into the spleen of NOD.Cg-Prkdcscid Il2rgtm1Sug/Jic (NOG) mice, and pancreatic cancer cells were also collected from metastatic foci of NOG mice. We compared the methylation status of the promoter and the 1st and 2nd introns of the nestin gene in metastatic and parental cancer cells using bisulfite sequencing and pyrosequencing.
Results: Nestin siRNA inhibited the proliferation, migration, invasion, and sphere-forming ability of the pancreatic cancer cells in vitro. Co-treatment of pancreatic cancer cells with gemcitabine and nestin siRNA decreased cell viability compared to administration of gemcitabine or nestin siRNA alone. Cells derived from the metastatic nodules of NOG mice showed higher expression of nestin compared with parental cells, and methylation of the nestin promoter and the 1st and 2nd introns was lower in the metastatic cells. Compared to control siRNA-treated mice, nestin siRNA significantly inhibited primary and metastatic tumor formation derived from human pancreatic cancer cells in an orthotopic implantation model using NOG mice.
In summary, decreasing nestin expression in pancreatic cancer cells using nestin siRNA suppressed cell proliferation, migration, invasion, and sphere formation in vitro and primary and metastatic tumor formation in vivo. Furthermore, nestin siRNA had synergistic effects with gemcitabine in inhibiting pancreatic cancer cell growth. These findings suggest that nestin plays a key role in pancreatic cancer cell metastasis and stemness, and that administration of nestin siRNA is a novel therapeutic strategy for pancreatic cancer.
Citation Format: Yoko Matsuda, Toshiyuki Ishiwata, Hisashi Yoshimura, Satoshi Yamashita, Toshikazu Ushijima, Kaiyo Takubo, Tomio Arai. Inhibitory effects and regulatory mechanism of nestin in pancreatic 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 3892. doi:10.1158/1538-7445.AM2014-3892