bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5170: Identification of factors secreted by melanoma exhibiting propensity for lung metastases
Authors: Huang Ruea-Yea , Odunsi Kunle , Wong Michael KK 
Published: June 2012

Abstract
Disseminated malignant melanoma is a result of widespread lymphatic and systemic metastases. We hypothesized that melanoma cells secret a cohort of factors that orchestrate tumor microenvironment to enable them to expand and metastasize. A proteomic approach was used to identify factors secreted by a lung metastatic and its parental primary melanoma cell lines as well as four primary cultured melanoma cell strains established from surgical material of melanoma patients. The lead factors identified were matricellular proteins, extracellular matrix proteins, tissue metalloproteinases, proteinase inhibitors, and insulin-like growth factor binding proteins. Several of these factors exhibit differential levels between the primary and the lung metastatic cell lines. To establish a melanoma lung metastasis signature, lung metastatic melanoma tumor cell lines derived from xenograph melanoma were selected. Protein secretion in culture medium by melanoma cells that exhibit a propensity to metastasize to the lung was analyzed using Western blot analysis. Our data show that decreased extracellular level of matrix metalloproteinases (MMP1, MMP2) and increased level of proteinase inhibitors (TIMP1, Glia-derived nexin) are associated with the development of melanoma lung metastases. These results suggest that these proteins can be useful markers in clinical testing for melanoma progression and as potential targets for intervening metastatic melanoma.
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 5170. doi:10.1158/1538-7445.AM2011-5170
Abstract 5182: Nicotine enhanced colon cancer migration through the change of epithelial-to-mesenchymal transition biomarkers
Authors: Chang Yu-Jia , Wei Po-Li , Huang Ming-Te , Liu Jun-Jen 
Published: June 2012

Abstract
Long-term cigarette smoking increases the risk of colorectal cancer mortality. Tobacco's addictive toxin, nicotine, was reported to increase DNA synthesis of colon cancer cells. Since metastasis is the major cause of cancer death, the influence of nicotine on the migration of colon cancer cells remains to be determined. The influence of nicotine on the migration of colon cancer cells was evaluated using trans-well assay. Nicotine receptor-mediated migration was studied by using both inhibitors and small interfering RNA (siRNA). The role of COX-2 signal was studied using pharmacological inhibitors. The expression of epithelial mesenchymal transition (EMT) marker and COX-2 signal was evaluated using real time PCR. Nicotine enhanced DLD-1 and SW480 cell migration in dose dependent manner. We used inhibitors and siRNA to demonstrate that α7-nAChR mediates nicotine-enhanced colon cancer cell migration and upregulates fibronectin expression, which is involved in nicotine-enhanced migration. Further, COX-2 signal was induced by nicotine treatment and is involved in nicotine-enhanced fibronectin expression. We concluded that nicotine, tobacco's additive toxin, enhances colon cancer metastasis through α7-nAChR and fibronectin, a mesenchymal marker for epithelial mesenchymal transition. Furthermore, COX-2 signal was also involved in the induction of fibronectin. Therefore, smoking may play role in the progression of colon cancer.
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 5182. doi:10.1158/1538-7445.AM2011-5182
Abstract 519: Blockade of PDGFR signaling impairs the tumor promoting effect of bone marrow-derived mesenchymal stem cells in colon cancer
Authors: Shinagawa Kei , Kitadai Yasuhiko , Ohnishi Mayu , Ohara Eiji , Tanaka Miwako , Sumida Tomonori , Tanaka Shinji , Yasui Wataru , Chayama Kazuaki 
Published: June 2012

Abstract
Bone marrow-derived mesenchymal stem cells (MSCs) are reported to migrate to tumor stroma as well as injured tissue. We reported recently that, in an orthotopic nude mice model of colon cancer, MSCs traveled to tumor stroma, where they differentiated into carcinoma-associated fibroblasts (CAF)-like cells. We have also found that CAFs express platelet-derived growth factor receptor (PDGFR) at a high level and that imatinib therapy targeting PDGFR in CAFs combined with administration of a cytotoxic drug significantly inhibits growth and metastasis of human colon cancer. These findings led us to examine whether the tumor promoting effect of MSCs is impaired by blockade of PDGFR signaling achieved with imatinib. KM12SM colon cancer cells alone or KM12SM cells mixed with MSCs in a 1:2 ratio were transplanted into the cecal wall of nude mice. Orthotopic transplantation of KM12SM cells mixed with MSCs, in comparison to transplantation of KM12SM cells alone, resulted in tumors of greater weight. The survival rate was significantly lower in the mixed-cell group. Co-injection of MSCs with tumor cells promotes tumor growth and metastasis of colon cancer by enhancing angiogenesis and tumor migration and invasion and by inhibiting tumor cell apoptosis. When tumor bearing animals were treated with imatinib (by gavage once daily at 50 mg/kg for 35 days), there was no significant increase in primary tumor volume or number of metastases with the KM12SM+MSC xenograft and the lower survival rate in the mixed-cell group was prolonged by the treatment. Moreover, migratory ability of MSCs to tumor stroma was impaired, and MSCs surviving in the tumor microenvironment were significantly decreased. In in vitro experiments, treatment with imatinib inhibited migration and proliferation of MSCs. Our data suggest that blockade of PDGFR signaling pathways influences the interaction between bone marrow-derived MSCs and tumor cells in the tumor microenvironment and, hence, inhibits the progressive growth of colon cancer.
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 519. doi:10.1158/1538-7445.AM2011-519
Abstract 5190: Biomarkers of sensitivity to PF-03084014, a γ-secretase Inhibitor, in a preclinical model of colorectal cancer
Authors: Powell Rebecca W. , Tan Aik Choon , Varella-Garcia Marileila , Touban Basel , Dasari Arvind , Puls Lauren , Pitts Todd , Kulikowski Gillian , Quackenbush Kevin , Messersmith Wells , Arcaroli John J. 
Published: June 2012

Abstract
Purpose: To evaluate the efficacy of PF-03084014, a γ-secretase inhibitor, in a preclinical model of colorectal cancer (CRC) and to identify biomarkers that predicts sensitivity to the compound.
Experimental Design: Fourteen patient-derived CRC explants were treated with PF-03084014 (150mg/kg/day- BID) for 28 days. Gene expression of the Notch pathway was evaluated at baseline and day 28 using RT-PCR. Additionally, baseline gene expression profiles were determined using gene array. An Aldefluor assay (stem cell technologies) was used to determine the effect of treatment on tumor initiating cells. Fluorescence in situ hybridization (FISH) was used to determine Notch 1 gene copy number.
Results: Three out of the fourteen explants showed sensitivity (cytostatic effects) to PF-03084014. Treatment reduced Notch pathway gene expression (Hes-1, Notch 1, Notch 3, and Jag1) in the sensitive tumors when evaluated by RT-PCR. Baseline gene array data showed an increase in IL-8 gene expression in resistant tumors and pathway analysis demonstrated an increase in focal adhesion, Jack-STAT, and MAPK signaling pathways in resistant explants. Evaluation of the ALDH+ cell population after 28 days of treatment showed that PF-03084014 reduced the ALDH+ cell population in the most sensitive explant (CRC001) when compared to the vehicle group. Evaluation of Notch 1 gene copy number in four CRC explants by FISH showed increased gene copy number in two sensitive explants (CRC027 and CRC001) and one intermediate explant (CRC036) and no gain in gene copy number in one resistant explant (CRC042).
Conclusion: Treatment with PF-03084014 significantly reduced tumor growth in three CRC explants. In addition, treatment inhibited expression of the Notch pathway and reduced the tumorigenic ALDH+ population. These results indicate that a subset of patients may derive benefit from treatment with PF-03084014 and biomarkers could be identified that predict sensitivity to the compound.
Acknowledgements: This work was supported by a Pfizer IIR 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 5190. doi:10.1158/1538-7445.AM2011-5190
Abstract 5191: Dual roles for CDK8 in cancer and stem cell maintenance
Authors: McCleland Mark , Adler Adam , Firestein Ron 
Published: June 2012

Abstract
Cyclin Dependent Kinase 8 (CDK8) is a highly conserved member of the Mediator complex that is required for animal development and growth. Several groups have recently identified CDK8 as a colorectal oncogene (Firestein R., et al Nature 2008; Starr T. Science 2009). While, loss of CDK8 expression inhibits colon cancer cell line proliferation in vitro, the mechanism through which this occurs is unkown. In order to examine the role of CDK8 on tumor growth in vivo, we generated inducible knockdown cell lines in two colon cancer cell line models. We find that CDK8 is necessary for tumor progression in vivo and loss of CDK8 imparts a differentiated phenotype in xenografted colon cancer tumors. FACS analysis of these tumors shows that loss of CDK8 leads to a specific depletion of the tumor initating stem cell compartment. These observations were extended to mouse and human intestine, where CDK8 protein levels were found to be increased both in tumors and in the basal portion of the crypt where the intestinal stem cells reside To further explore the mechanism by which CDK8 leads to this depletion, we performed both microarray gene expression analysis and whole genome ChIP to identify CDK8 transcriptional targets. We find that many of CDK8 regulated targets overlap with gene signatures known to be upregulated in stem cells (p&lt;1×10−45). To determine the relevance of these transcriptional targets to colon cancer, we assessed their level of expression in colon tumors and performed a loss of function screen in a panel of 12 cell lines to determine which genes are required for colon cancer proliferation. Using this approach we identify a subset of CDK8 downstream genes with dual roles in cancer and embryonic maintenance. These data show that modulation of CDK8 induces differentiation in cancer cells by potentially targeting the stem cell properties of cancer.
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 5191. doi:10.1158/1538-7445.AM2011-5191
Abstract 5195: Progressive overpopulation of colonic stem cells during tumorigenesis is linked to delayed licensing of cells for DNA synthesis in the process of crypt cell maturation
Authors: Boman Bruce M. , Zhang Tao , Cofer Zenobia , Palazzo Juan , Fields Jeremy Z. 
Published: June 2012

Abstract
Since cancer stem cell (SC) overpopulation drives tumor growth, it is critical to identify mechanisms underlying SC overpopulation. Our hypothesis that SC overpopulation underlies development of colorectal cancer (CRC), which was based on our kinetic studies (Cancer Res 61: 3304-13, 2008), has since been supported by our biologic studies showing that ALDH1 is a specific marker for human colonic SC and can track SC overpopulation during tumor development (Cancer Res 69:3382-9, 2009). We then asked: What cellular mechanisms that normally control SC population size in colonic crypts become dysregulated during colon tumorigenesis? Accordingly, we measured the orderly, sequential phenotypic transitions in human crypts that colonocyte subpopulations undergo during their maturatio– a process involving both proliferation and differentiation. Quantitative immunohistochemical mapping of crypt cell subpopulations was done using markers for SC (ALDH1), proliferating cells (DNA-synthesis-licensing proteins: CDT1/geminin/MCM2), cell-cycle arrest (P21), and apoptosis (M30/TUNEL). Staining indices were used to evaluate changes in maturation during the step-wise progression to colon cancer. The rate of crypt cell maturation was measured using clearance of BrdU from pre-labeled wildtype (C57BL/6) and premalignant (ApcMin/+) mouse intestine. In normal human colon, the proportion of cells expressing licensing proteins was low at crypt bottom (where SC reside), high in the lower crypt where proliferating cells reside, and nil in the upper crypt (where differentiated/apoptotic cells reside). In FAP and adenomatous human crypts, SC and proliferating cell populations expanded towards the crypt top while differentiated/apoptotic subpopulations in the upper crypt contracted. ApcMin/+ mouse crypts had slower BrdU clearance than controls. Colonocytes become licensed for DNA synthesis in the transition from SC to proliferating cells; licensing is delayed in premalignant crypts. Moreover, all transitions between cell phenotypes occur more slowly in premalignant human colonic crypts, indicating that crypt cell maturation becomes progressively delayed during colon tumorigenesis. Since crypt cell maturation regulates colonic SC population size, as maturation becomes progressively delayed, crypt SC overpopulation will develop, leading to dysplasia and colon cancer.
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 5195. doi:10.1158/1538-7445.AM2011-5195
Abstract 5201: Distinctive distribution of expression of Lgr5, an intestinal stem cell marker, during each stage of colorectal tumorigenesis
Authors: Takeda Kayoko , Kinoshita Ichiro , Shimizu Yasushi , Matsuno Yoshihiro , Shichinohe Toshiaki , Dosaka-Akita Hirotoshi 
Published: June 2012

Abstract
Lgr5, an orphan G-protein coupled receptor and Wnt target gene, has been identified as a murine intestinal stem cell marker. To elucidate the role of Lgr5 during each stage of human colorectal tumorigenesis, we immunohistochemically analyzed 17 low-grade, 13 high-grade intraepithelial neoplasias and 30 adenocarcinomas. While there was only sporadic expression of Lgr5 at the crypt base in normal epithelia, the increased numbers of Lgr5-positive cells were found in most tumors, with clustering of the cells to form patches. An apparent difference in their distribution was observed among the different tumorigenesis stages. Lgr5 expression in luminal surface showed a negative association with the progressive grade of the tumors (p = 0.0004), while that in the lower crypt exhibited a positive association with grade (p = 0.0001). In adenocarcinomas, Lgr5 expression in the luminal surface was negatively associated with the pStage (p = 0.02), while it was almost invariably high in the lower crypt during advanced pStage disease. These results suggest that increases in putative stem cells with the Lgr5 expression occur early during colorectal tumorigenesis and that the shifts in their distribution towards the crypt base and/or invasive tumor front play a role in the development and progression of colorectal cancer.
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 5201. doi:10.1158/1538-7445.AM2011-5201
Abstract 5211: Development of a panel of colon cancer cell lines with cancer stem cell properties: a tool for cancer biology and target discovery
Authors: Roberts Penny , Young Peter , Smith Doug , Hooley Jeff , Li Jonathan , Chen Francine , Loo Deryk , Mather Jennie , Moore Paul A. 
Published: June 2012

Abstract
The cancer stem cell (CSC) hypothesis provides a foundation for understanding cancer development and carries significant implications relevant to drug discovery. The generation of cell lines with cancer stem cell properties would be an important advancement in the field. If CSC were capable of indefinite self-renewal without immortalization, it should be possible to develop conditions that select this minority population from a tumor for continuous culture as a line. By employing defined serum-free media and conditions that are strongly selective for fetal colon epithelial progenitor cells, we have been able to select a morphologically homogeneous minority population, hereafter we termed cancer stem-like cells (CSLC) from a repertoire of primary and metatstatic colon cancer specimens.
Six colon CSLC lines have been generated, some of which have been stably maintained in vitro for over 200 generations. When implanted subcutaneously, under the subrenal capsule, or orthotopically in immune deficient mice, all CLSC form tumors that are morphologically and phenotypically recapitulate the patient's original tumor. Furthermore, some of the lines form distant metastasis with consistent colorectal cancer morphology.
All lines express CEA; however, only a fraction expresses elevated levels of “canonical” CSC markers, including CD44 or CD133. Affymetrix U133 micro-array analysis identified a set of transcripts that were elevated in the CSLC lines compared to a series of control cell populations. These included ALDH1A1, a well known colon CSC marker, and OLFM4, a recently identified marker of normal colon crypt stem cells.
Whole-cell immunizations of mice with several lines has yielded a panel of CSLC-reactive monoclonal antibodies that recognize broadly expressed colon cancer antigens as well as surface proteins more discreetly represented within colon tumors and possibly representing CSC-specific markers.
These lines and their reactive antibodies provide the basis for developing and characterizing novel approaches aimed at targeting and the elimination of the CSC population.
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 5211. doi:10.1158/1538-7445.AM2011-5211
Abstract 5213: Overexpression of SIP1 and down-regulation of E-cadherin predict delayed neck metastasis in stage I/II oral tongue squamous cell carcinoma after partial glossectomy
Authors: Skakamoto Koji , Imanishi Yorihisa , Shimoda Masayuki , Kameyama Kaori , Tomita Toshiki , Ozawa Hiroyuki , Shinden Seiichi , Fujii Masato , Shibata Katsushi , Sakai Nobuya , Ogawa Kaoru 
Published: June 2012

Abstract
Neck lymph node involvement is considered as the most important adverse prognostic factor in head and neck squamous cell carcinoma (HNSCC). Patients with clinical stage I/II (T1-2N0M0) oral tongue carcinoma usually undergo partial glossectomy alone. However, 14 to 48% of these patients develop delayed neck metastasis (DNM) within 2 years and tend to result in unfavorable course. Clinicopathologic features and molecular biomarkers have been investigated to find the reliable predictor of DNM, however, it still remains to be elucidated. Recently E-cadherin and its transcriptional repressors are thought to play a crucial role in tumor progression and metastasis, the mechanism of which is called epithelial to mesenchymal transition (EMT). The present study was aimed to examine whether the molecular factors involved in the induction of EMT, as well as standard clinicopathologic factors, are predictive of DNM in stage I/II oral tongue squamous cell carcinoma. mRNA expressions of E-cadherin and its repressors (snail, SIP1 and twist) in 7 HNSCC cell lines were evaluated by quantitative real-time RT-PCR, which revealed significant inverse correlation between E-cadherin and SIP1 (p = 0.023). Immunohistochemical staining was performed to evaluate protein expressions of E-cadherin and its repressors in the specimens of the primary lesions of 37 stage I/II tongue carcinoma patients who had initially undergone only partial glossectomy in the Keio University Hospital without elective neck dissection. Univariate analysis showed that loss of E-cadherin (p = 0.004) and overexpression of SIP1 (p &lt; 0.001) were significantly correlated with DNM, although no inverse correlation was found between E-cadherin and each of its repressors. Regarding other clinicopathologic factors, mode of invasion 3/4 (p = 0.048), vascular invasion (p = 0.021) and muscular invasion (p = 0,012) were also significantly correlated with DNM. Multiple logistic regression analysis including clinicopathologic and the molecular factors elucidated that overexpression of SIP1 (p = 0.005), loss of E-cadherin (p = 0.046) and vascular invasion (p = 0.024) were independently correlated with DNM. These results suggest that DNM in the stage I/II oral tongue carcinoma is closely relating to EMT, and especially SIP1 and E-cadherin are considered as the useful markers to predict development of DNM.
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 5213. doi:10.1158/1538-7445.AM2011-5213