bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4365: Glucosylceramide synthase promotes cancer stem cells accumulating in chemotherapy
Authors: Gupta Vineet , Bhinge Kaustubh N. , Liu Yong Yu 
Published: June 2012

Abstract
Cancer stem cells initiate tumorigenesis and are the causes of metastasis and relapse. Cancer stem cells, rather than other differentiated cells in tumors display resistance to cytotoxicity of anticancer drugs, but we do not know whether by-product of chemotherapy can induce cancer stem cells leading to chemotherapy failure. Glucosylceramide synthase (GCS) is a limiting enzyme regulating the synthesis of glycosphingolipids that play an essential role in the maintenance of embryonic stem cells. The purpose of this study was to identify and characterize the effect of ceramide glycosylation in the formation and maintenance of breast cancer stem cells (BCSCs). We have found that GCS overexpression was interrelated to the increment BCSCs and drug resistance in human breast cancer MCF-7 cell lines after doxorubicin induction. In MCF-7/Dox (doxorubicin-resistant) cells, GCS protein was increased by 39-fold accompanied with enhanced enzyme activity, as compared to wild-type MCF-7 cells. The BCSCs with CD24-/CD44+/ESA+ phenotype was increased by 5-fold in MCF-7/Dox cells as compared to MCF-7 cells. Silencing GCS by using mixed-backbone oligonucleotide (MBO-asGCS) significantly decreased the numbers of BCSCs more than 2-fold in MCF-7/Dox cells. In the soft agar colony formation assay, MCF-7/Dox cells showed significantly higher colonies formed as compare to the MCF-7 cells. BCSCs sorted from MCF-7/Dox cells displayed significantly higher GCS enzyme activity more than 3-fold and formed 2-fold more colonies, as compare with other non-stem cell subsets. The BCSCs cells showed significantly higher tumorigenicity and metastasibility as compared to non-stem cells (CD24-/CD44-) in athymic nude mice. More interestingly, doxorubicin treatment (1 mg/kg, once a week, and 40 days) considerably increased BCSCs 2-fold in tumors, and MBO-asGCS treatment eliminated the tumor growth and reduced metastasis due to reduction of BCSCs more than 2-fold in vivo. Comparison of glycosphingolipids and gene profile of stem cells indicated GCS or globo-series glycosphingolipids upregulates FGF1, FGFR1, ALDH2, ISL1, MSX1, SIGMAR1, PPARD and downregulates CXCL12, FRAT1, CCND1 to accumulate BCSCs during the course of chemotherapy. These results, for the first time, demonstrate that ceramide glycosylation by GCS accumulates BCSCs formation and causes aggressive tumor progression. Silencing of GCS that eliminates BCSCs can prevent and treat drug-resistant tumors and relapse.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4365. doi:10.1158/1538-7445.AM2011-4365
Abstract 4372: Radiation induces Notch-dependent de novo generation of breast cancer stem cells via expression of OCT-4/SOX2/NANOG
Authors: Lagadec Chann H. , Della Donna Lorenza , Vlashi Erina , Dekmezian Carmen , Brocks Tania , Pajonk Frank 
Published: June 2012

Abstract
Like in normal tissues, the self-renewal of cancer stem cells (CSCs) might be also under tight control of developmental pathway like the Notch, Wnt, Sonic Hedgehog or TGFβ pathways. The Notch pathway plays an important role in normal breast development, cell fate, and normal stem cell self-renewal, and its deregulation has been shown to play a role in cancer. Aberrant Notch signaling has been implicated in the development and progression of both preinvasive ductal carcinomas in situ and invasive breast cancers. Interestingly, in breast cancer, the Notch pathway plays major role for CSCs maintenance. We previously published that BCSCs (Breast Cancer Stem Cells) are relatively resistant to radiation and we demonstrated a link between BCSCs radio-resistance and the Notch pathway. Irradiation of MCF-7 and T47D cells increased the number of CSCs and this correlated with the induction of Notch signaling protein expression in a dose- and time-dependent manner. Jagged 1 expression was quickly (1h) increased 28-fold after 2Gy, DLL1 expression was increased 15-fold, 3 to 6h after irradiation with 2 or 4 Gy, Notch 2 expression was increased 16-fold 6h after 2, 4, 6 or 8 Gy, while DLL3 was increased 10-fold after the highest doses (6 to 12 Gy). Inhibition of Notch signaling pathway by a γ-secreatase inhibitor prevented enrichment for CSCs and reduced radiation-induced Notch protein expression. Most importantly, we demonstrated that radiation-induced Notch signaling contributes to the phenotype plasticity of BCSCs and their progeny. Using 2 different cancer stem cell markers (low proteasome activity and ALDH1) to found that radiation causes de novo generation of induced BCSCs (iBCSCs) from non-tumorigenic cells and this correlated with radiation-induced the expression of OCT-4, SOX2, and NANOG, key transcription factors of used to generate induced pluripotent stem cells (iPS cells).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4372. doi:10.1158/1538-7445.AM2011-4372
Abstract 4382: Matricellular protein Cyr61/CCN1 regulates the stemness of oral cancer stem-like cells
Authors: Chang Chih-Hao , Leu Shih-Jeng , Lo Jeng-Fan 
Published: June 2012

Abstract
Background: Cysteine-rich 61 (Cyr61 [CCN1]), a matricellular and plasma membrane protein that has disparate function dependent on cell type-specific manner, is closely related to proliferation, invasion, angiogenesis and epithelial-mesenchymal transition (EMT). Besides, EMT promotes stemness properties in normal and neoplastic cells. Therefore, we want to examine whether CCN1 plays a role in our previous enriched oral cancer stem-like cells (OC-SLCs).
Methods: Initially, the expression of CCN1 in OC-SLCs translationally was evaluated. Further, the cell surface CCN1 positive cells from oral cancer cells or OC-SLCs were sorted for further study. We will compare the difference of stemness properties and tumorigenicity between CCN1 positive and negative cells. Further, downregulation of CCN1 in oral cancer cells was achieved to evaluate the function of CCN1 on oral cancer tumorigenesis in vitro and in vivo. The molecular mechanisms mediated by CCN1 on regulating the oral cancer tumorigenicity will also be elucidated
Results: We found that CCN1 protein was upregulated in OC-SLCs. Comparing to CCN1 negative cells, CCN1 positive cells exhibited higher sphere formation ability and highly expressed stem cell markers, Nanog and Oct-4. Flow cytometry analyses showed that cytoplasmic membrane CCN1 positive OC-SLCs also co-expression with cancer stem-like cell makers, ABCG2, Grp78 and CD133. In addition, CCN1 knockdown cells decreased sphere formation ability and displayed morphological alternation with loss of EMT. Analysis of CCN1 knockdown cells found that EMT related markers were significantly changed. Overall, we demonstrated that CCN1 is involved in maintenance of stemness and acquisition of epithelial-mesenchymal transition in OC-SLCs.
Conclusion: Our data suggest that Cyr61 could be a potential oral cancer stem cell marker, and also the key molecule to regulate the stemness of oral cancer stem-like cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4382. doi:10.1158/1538-7445.AM2011-4382
Abstract 4383: Regulation of cancer cell differentiation in vivo by delta-like 1 homolog (Drosophila) DLK1
Authors: Begum Asma , Kim Yuri , Lin Qun , Yun Zhong 
Published: June 2012

Abstract
Malignant tumor progression from a benign growth to metastasis is often accompanied by an accumulation of multiple genetic and epigenetic changes occurring over a course of more than a decade. The stem cell-like characteristics, especially the self-renewal capacity, of tumor cells is essential for uninterrupted inheritance of these disparate genetic and epigenetic changes in the same originating tumor cell. Like normal stem cells, cancer cells can lose their stemness or self-renewal potential in response to environmental stresses. Therefore, tumor cell stemness needs to be actively maintained. However, the underlying mechanisms remain to be clearly understood. Our previous studies and others have suggested that the tumor microenvironment, including hypoxia, plays a significant role in the regulation of cancer stem cell characteristics. We have identified a previously uncharacterized stem cell pathway mediated by DLK1 or delta-like 1 homolog (Drosophila) that is upregulated by hypoxia and enhances cancer cell stemness and tumorigenicity in neuronal tumors. In this study, we investigated the role of DLK1 in the regulation of cancer cell differentiation in vivo using neuroblastoma (NB) xenografts as a model. Our findings have revealed that overexpression of DLK1 promotes tumor growth by increasing the number of mitotic or proliferative cells and inducing angiogenesis. On the other hand, tumors derived from NB cells with down regulation of DLK1 expression by RNA interference or with overexpression of dominant negative mutants of DLK1 sensitize NB cells to undergo differentiation, as shown by increased expression of neuronal and glial differentiation markers. These results demonstrate that DLK1 plays an important role in the maintenance of undifferentiated, stem cell-like phenotype of NB cells in vivo. Our findings also indicate that the tumor microenvironment, especially hypoxia, can exert a profound impact on the tumor cell fate in vivo by regulating specific stem cell pathways.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4383. doi:10.1158/1538-7445.AM2011-4383
Abstract 4391: OCTN1- and OCTN2-mediated uptake of oxaliplatin in rat dorsal root ganglion neurons and HEK293 cells over-expressing OCTN1 or OCTN2
Authors: Jong Nancy N. , Nakanishi Takeo , Liu Johnson J. , Tamai Ikumi , McKeage Mark J. 
Published: June 2012

Abstract
Purpose: Organic cation transporters (OCTs) have been recently implicated in the uptake and toxicity of oxaliplatin. Peripheral neuropathy is the dose-limiting toxicity of oxaliplatin due to accumulation of platinum in the dorsal root ganglia (DRG) and damage to sensory neurons. This study sought to determine the role of OCTs in the DRG neuronal uptake of oxaliplatin.
Experimental Design: [14C] Oxaliplatin uptake and cytotoxicity in HEK/rOctn1, HEK/rOctn2, HEK/hOCTN1, HEK/hOCTN2, and primary culture of DRG neurons was determined to evaluate the role of Octn1 and Octn2 in oxaliplatin transport and neurotoxicity. mRNA, protein and functional expression of organic cation transporters in rat lumbar DRG were characterised using RT-PCR, Western blotting and uptake of model OCT substrates [3H] MPP, [14C] TEA, [3H] ergothioneine and [3H] L-carnitine.
Results: HEK293 cells over-expressing rOctn1, rOctn2, hOCTN1 and hOCTN2 showed increased uptake and cytotoxicity of oxaliplatin compared to Mock-transfected HEK293 controls, and Octn2-mediated uptake of oxaliplatin was significantly higher than Octn1 in both human and rat. Uptake of ergothioneine mediated by Octn1, and L-carnitine mediated by Octn2, was decreased during oxaliplatin exposure. Rat DRG showed high Octn1 and Octn2 mRNA levels, and uptake of ergothioneine and L-carnitine that was temperature- and sodium-dependent and significantly inhibited by model substrates of Octn1 and Octn2. In contrast, DRG had negligible functional activity and low or undetectable mRNA levels of Oct1, Oct2, and Oct3. [14C] Oxaliplatin uptake by DRG neurons was temperature- and sodium-dependent and inhibited by ergothioneine and L-carnitine. Ergothioneine and L-carnitine uptake by DRG neurons was inhibited in the presence of oxaliplatin.
Conclusions: In conclusion, Octn1 and Octn2, but not Oct1, Oct2 or Oct3, are functionally expressed in rat DRG neurons. Oxaliplatin uptake by rat DRG neurons and HEK293 cells was mediated by Octn2 and to lesser extent by Octn1.
Supported by Grant-in-Aid for Scientific Research (B) (I. T.), Research Activity Start-up (T. N.), Auckland Medical Research Foundation (Doctoral Scholarship) and Cancer Society of New Zealand (Research Grant).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4391. doi:10.1158/1538-7445.AM2011-4391
Abstract 4404: Post-transcriptional regulation of dihydropyrimidine dehydrogenase (DPD) by the microRNAs mir27a and mir27b
Authors: Offer Steven M. , Wegner Natalie J. , Diasio Robert B. 
Published: June 2012

Abstract
The pyrimidine analog 5-fluorouracil (5-FU) and its prodrug capecitabine are prescribed widely for the management of several common cancers, including colorectal, breast, and pancreatic cancers. 5-FU is activated by conversion to cytotoxic metabolites via the pyrimidine anabolic pathway. In the opposing catabolic pathway, dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene) initiates rapid and irreversible conversion of greater than 80% of administered 5-FU to inactive metabolites and limits the pool of 5-FU available for anabolism. Deficiency of DPD has been associated with adverse effects to 5-FU treatment, including mucositis, severe diarrhea, neurotoxicity, and life-threatening hematological toxicity, making DPD activity a potentially important predictor of 5-FU toxicity. Despite considerable study of the DPYD gene and its promoter, little is known about the post-transcriptional regulation of DPD expression at the molecular level. The objective of this study was to determine if DPD expression undergoes microRNA-mediated regulation. Computational analysis of the DPYD 3’ untranslated region (UTR) revealed an evolutionarily conserved seed-binding region for the microRNAs mir27a and mir27b. This finding prompted the hypothesis that both mir27a and mir27b are capable of modulating DPD expression. To determine if mir27a and/or mir27b bind to the DPYD 3’ UTR, HCT116 cells lines were engineered to stably express luciferase reporter constructs wherein the luciferase gene was modified to contain the 3’ UTR sequence from DPYD. As controls, stable cells lines containing mutations in the putative microRNA-binding region were generated concurrently. Two colon cancer cell lines (HT29 and HCT15) were also utilized to determine if mir27a and/or mir27b could modulate endogenous DPD expression. In cell lines expressing the luciferase gene juxtaposed to the DPYD 3’UTR, mimics of mir27a or mir27b resulted in significantly reduced luciferase activity relative to scramble control microRNA. Luciferase levels in mir27a or mir27b transfected lines were also significantly reduced compared to stable luciferase-expressing cells harboring the mutant UTR construct. Over-expression of small RNA inhibitors directed toward mir27a or mir27b led to increased luciferase activity in cells containing the wildtype UTR construct. Finally, over-expression of mir27a or mir27b significantly reduced endogenous DPD expression in both HT29 and HCT15 cells. Based on these findings, we conclude that mir27a and mir27b are capable of post-transcriptional regulation of DPD. To our knowledge this is the first report to show microRNA-mediated modulation of DPD expression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4404. doi:10.1158/1538-7445.AM2011-4404
Abstract 4420: Analysis of functional role of interleukin-6 secreted by tumor-associated macrophages in ovarian cancer ascites
Authors: Isobe Aki , Sawada Kenjiro , Ooyagi Chifumi , Mabuchi Seiji , Wakabayashi Atsuko , Morishige Ken-Ichirou , Kimura Tadashi 
Published: June 2012

Abstract
Tumor-associated macrophages (TAMs) are known to contribute to tumor growth, invasion, and metastasis by producing various mediators. However, few studies have clarified the role of TAMs in human ovarian cancer patients. The aim of the present study was therefore to analyze the effect of TAM on ovarian cancer growth, invasion, and metastasis. Ascites were collected aseptically, and CD11b positive cells (TAMs) were purified by positive selection using magnetic-activate cell sorting (MACS) technology. Co-culture of ovarian cancer cell line, SKOV3ip1 cells, with TAMs significantly enhanced the invasive activity of cancer cells in Matrigel Boyden chamber assay. This enhancement was partially blolcked by the treatment of anti-interleukin (IL)-6 receptor antibody (Tocilizumab). Since SKOV3ip1 cells did not express IL-6 in mRNA and protein level, IL-6 secreted by TAMs were considered to play a key role in ovarian cancer invasion. In vivo ovarian cancer xenografts, i.p. treatment of Tocilizumab significantly reduced peritoneal dissemination and ascites formation. Those results suggested targeting IL-6 produced by TAMs could be a promising therapy for a subset of ovarian cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4420. doi:10.1158/1538-7445.AM2011-4420
Abstract 4421: Curucmin suppresses myeloid-derived suppressor cells and inhibits gastric cancer growth
Authors: Tu Shuiping , Jin Huanyu , Shi Jingdong , Suo Ya , Liu Anna , LU Gang , Yang Chung S. 
Published: June 2012

Abstract
Myeloid-derived suppressor cells (MDSCs) are accumulated in the spleen and tumor and contribute to tumor growth, angiogenesis and progression. In this study, we examined the effects of curcumin, a compound from turmeric, on MDSCs and gastric cancer growth in vivo. BABL/C nude mice injected subcutaneously with gastric cancer MKN-45 cells were fed with control diet or 2% curcumin diet or received curucmin through daily i.p. injection at 50mg/kg body weight. Cell apoptosis were determined by Flow cytometer and TUNEL staining. Protein expressions were determined by Western Blot and Immunohistochemistry staining. The frequencies of myeloid-derived suppress cells in the mice were analyzed by Flow cytometer. Cytokines were determined by ELISA. Tumors growth was significantly inhibited by both 2% curucumin diet and curcumin i.p. injection treatment. The frequencies of MDSCs in the spleen, blood and tumor tissues were significantly decreased in the tumor-bearing mice after a 5-days or a 4-weeks treatment with curcumin (in diet or by i.p. injection) compared to control treatment. MDSCs isolated from the spleen of curcumin-treated mice secreted lower levels of IL-6, compared to that from untreated mice. The treatment of MDSCs isolated from the spleen of the untreated tumor-bearing mice with curcumin had lower levels of IL-6, compared to that of control mice. Furthermore, curcumin treatment significantly reduced IL-6 level secreted by IL-1beta-induced MDSCs. Curucmin treatment also significantly induced apoptosis of gastric cancer cells in vitro and in vivo. Our results demonstrate for the first time that cucumin could inhibit MDSCs mobilization and activation and that curcumin inhibits gastric cancer partly through suppressing MDSCs mobilization and activation. MDSCs may be a new target of cucumin for gastric cancer therapy and prevention. (The project was supported by NIH grant R21CA149865 (Tu SP)).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4421. doi:10.1158/1538-7445.AM2011-4421
Abstract 4441: Intracellular delivery of therapeutic siRNA via an antennapedia-RNA-binding domain fusion peptide
Authors: Tsimon Myrsini , Kang Angray , Markiv Anatoliy , Kousparou Christina , Epenetos Agamemnon 
Published: June 2012

Abstract
A key characteristic in tumorigenesis is the aberrant expression of various oncogenes, whose cellular products drive various anti-apoptotic/pro-survival pathways. The RNAi pathway is an endogenous cellular pathway that transiently inhibits the translation of mRNA into protein. It therefore has the potential to selectively arrest the production of mutated proteins.
As the Intracellular delivery of bioactive molecules is still a major challenge, we are exploring the possible ability of the Antenapedia homeodomain (Antp) to act as an effective transporter of conjugated cargo across biological membranes. We have previously shown that Antp delivers both p21 into p21-null tumors in order to restore cell-cycle regulation, as well as a truncated form of MAML to inhibit Notch activation and induce apoptosis.
To test whether in silico-designed siRNA has the ability to silence mutated forms of genes, we have created a bifunctional fusion protein, TR7, which incorporates Antp and an RNA-binding protein. TR7 attempts to both neutralize the anionic nature of siRNA as well as introduce it to the cytoplasm, thus initiating the RNAi process in a non-cytotoxic manner.
In summary, this project, utilizing Antp, aims to solve the issue of systemic RNAi delivery, as well as harness the endogenous RNAi pathway to effectively halt the production of abnormal proteins in cancer and other life threatening illnesses.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4441. doi:10.1158/1538-7445.AM2011-4441