bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1338: Knockdown of CD24 prevents colorectal polyp formation in APCmin/CD24 double knockout transgenic mice
Authors: Naumov Inna , Zilberberg Alona , Rosin-Arbesfeld Rina , Ilan Aroch , Kazanov Dina , Arber Nadir , Kraus Sarah R. 
Published: August 2012

Abstract
Background: Previous studies in our lab have shown that CD24 is a potential oncogene in the colon. CD24, a mucin-like glycoprotein, is overexpressed in 90% of colorectal cancer (CRC) tumors at a fairly early stage in the multistep process of CR carcinogenesis (Sagiv et al., Gastroenterology, 2006). We have also shown that CD24 downregulation by shRNA interference (Sagiv et al., Can Res, 2008) or anti-CD24 mAb targeting (Shapira et al., Gastroenterology, 2011) retarded tumorigenicity of human CRC cell lines and/or reduced tumor volume in nude mice. The APCmin/+ is a popular animal model for studies of human colon carcinogenesis and the molecular changes associated with neoplasia in this system have been partially characterized. These mice have a germline nonsense mutation at codon 850 of the APC gene and spontaneously develop hundreds of polyps, mostly in the small intestine at the age of 10-12 weeks. Aim: To validate the importance of CD24 in intestinal carcinogenesis using a transgenic mouse model with a double knockout (KO) of CD24−/+ /CD24+/− and APCMin/+ alleles. Methods: We generated the CD24−/+/APCMin/+ double KO by crossing the mice with each of the single gene knockouts, in order to obtain both CD24+/−/APCMin/+ and CD24−/+ APCMin/+ genotypes. The double KO mice were followed up thrice a week and sacrificed at 12 weeks of age. Tumors from the entire small and large intestine were counted and verified by histological analysis Results: There was almost a complete absence of polyps in the small intestine in APCMin/+/CD24+/− double heterozygotes compared to that of the parental APCMin/+, CD24+/+ animals: 273±55.4 vs. 6±1.7 polyps, respectively (P=0.0001). APCMin/+and CD24−/+ homozygotes showed a striking lack of polyps (P&lt; 0.0001). This reduction occurred in all sections of the small intestine. Histophatological analysis confirmed the absence of malignant lesions in the double KO mice as compared to the parental mice. Conclusions: 1. A deficiency of only one CD24 allele is sufficient to suppress almost completely polyp formation in the APCMin/+ mice that normally develop hundreds of polyps. 2. Although the mechanism/s underlying the pathophysiologic role of CD24 in the development of CRC are still unknown, these studies suggest that CD24 plays a critical role in the proliferation and progression of CRC and is a potential important target for the prevention and treatment of intestinal neoplasia.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1338. doi:1538-7445.AM2012-1338
Abstract 134: miRNA-708 suppresses prostate cancer growth through Akt2 signaling pathways
Authors: Saini Sharanjot , Majid Shahana , Shahryari Varahram , Arora Sumit , Yamamura Soichiro , Chang Inik , Zaman Saif , Deng Guoren , Tanaka Yuichiro , Carroll Peter R. , Dahiya Rajvir 
Published: August 2012

Abstract
MicroRNAs have been implicated in the etiology, progression and metastasis of various malignancies. We identify miR-708, a little studied member of a set of microRNAs that have been implicated in stress control, as an important tumor suppressor in prostate cancer. In this study we identify that miR-708 expression is significantly attenuated in prostate cancer cell lines and human prostate clinical specimens. To evaluate the functional significance of decreased miR-708 expression, miR-708 was reintroduced in prostate cancer cell lines followed by functional assays. Restoration of miR-708 expression in prostate cancer cell lines decreased cell growth, clonability, invasion, migration and elicited a dramatic increase in apoptosis. Moreover, intratumoral delivery of miR-708 was sufficient to trigger in vivo regression of established tumors in a murine xenograft model of human prostate cancer. Further, analysis of putative miR-708 targets showed that miR-708 targets the serine/threonine kinase Akt2/PKBβ, a member of the PI3K/Akt signaling pathway that plays a key role in cellular survival. Phenocopy experiments in prostate cancer cell lines suggest that Akt2 is a functionally relevant target of miR-708 in prostate cancer. In conclusion, our data suggests that miR-708 is a tumor suppressor microRNA that inhibits prostate cancer growth both in vitro and in vivo through targeting Akt2 pathways.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 134. doi:1538-7445.AM2012-134
Abstract 1340: A mouse model of metastatic intestinal cancers associated with Fbw7- and p53-loss
Authors: Grim Jonathan E. , Knoblaugh Sue , Hagar Amanda , Hespelt Jessica , Swanger Jherek , Guthrie Katherine , Small Thomas , Grady William M. , Nakayama Keiichi , Clurman Bruce E. 
Published: August 2012

Abstract
Colon cancer is a leading cause of cancer deaths in the USA, where it accounts for up to 50,000 deaths per year. Mouse models that recapitulate the genetic changes seen in human colon cancers are useful tools for biological and preclinical applications, but most available models develop adenomatous lesions that rarely metastasize. The Fbw7 tumor suppressor is a core component of a ubiquitin ligase complex that negatively regulates a number of proteins associated with genomic instability and cancer, including cyclin E, c-myc, Mcl-1, and Notch. Our previous work shows that Fbw7 cooperates with the p53 tumor suppressor to control genetic instability in vitro, and both Fbw7 and p53 are frequently deregulated in human colon cancers. We hypothesized that coordinate deletion of these two tumor suppressors would promote intestinal cancers in mice. To accomplish intestine specific deletion of these pathways, we interbred genetically engineered mice encoding conditional Fbw7 and p53 alleles with the VillinCre strain. Examination of normal intestines from the resulting Fbw7(fl/fl); p53(fl/fl); villinCre (FPV) animals showed abnormal proliferation and differentiation along the crypt-villus axis compared to control animals. Strikingly, the majority (55%) of FPV mice developed adenocarcinomas in the small intestine and cecum (median survival 70 weeks of age), and these tumors frequently metastasized to the lymph nodes and liver (in 36% and 14% of tumor bearing animals, respectively). Analysis of cancer tissues showed clear evidence of genetic instability in the majority of tumors. Finally, FPV tumors were readily grown as cell lines in vitro which could, in turn, grow as allografts in both immunodeficient and immunocompetent recipients. Notably, comparison of primary tumors and allografted cell lines showed similar pathological features and patterns of metastasis. This work confirms the critical role of the Fbw7 and p53 pathways in suppressing genetic instability and cancer development. Furthermore, the described FPV models recapitulate critical features of human colon cancer and should prove useful for studies of cancer biology, prevention, and therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1340. doi:1538-7445.AM2012-1340
Abstract 1341: Mice expressing activated PI3K develop advanced colon cancer
Authors: Deming Dustin A. , Leystra Alyssa A. , Christopher Zahm D. , Farhoud Mohammed , Olson Terrah J. Paul , Hadac Jaime N. , Nettekoven Laura A. , Albrecht Dawn M. , Clipson Linda , Sullivan Ruth , Washington Mary Kay , Torrealba Jose R. , Weichert Jamey P. , Halberg Richard B. 
Published: August 2012

Abstract
Background: Mutations in PIK3CA are a common feature of human cancers and multiple new PI3K inhibitors are in clinical development. These mutations are present in 20-30% of colorectal cancers in humans; however, the effects of such mutations on the intestinal mucosa have not been previously studied in animal models. Here we demonstrate that the expression of a dominant active form of the PI3K protein in the mouse intestine results not only in hyperplasia but also advanced neoplasia. Methods: Mice carrying a transgene in which the fatty acid binding protein promoter is fused to Cre recombinase (FC) were crossed to mice carrying a transgene encoding a chimeric protein with the iSH2 domain of the p85 subunit fused to the N-terminus of p110 (PIK3ca*). Progeny carrying both transgenes (FC PIK3ca*) express this constitutively active form of p110 in epithelial cells of the distal small bowel and colon. Results: Invasive mucinous adenocarcinomas develop in the proximal colon by only 50 days of age. These tumors are very aggressive, spreading into the mesentery and adjacent organs, and their histological characteristics are strikingly similar to those of invasive colon cancers in humans. Neoplastic cells exhibit a high rate of cell proliferation as seen by increased Ki67 immunohistochemical staining and phosphorylation of AKT, pS6, and p4E-BP1 by western blot demonstrating downstream signaling of PI3K. Interestingly, these cells did not exhibit perturbations in ERK and WNT signaling. Consistent with the lack of aberrant WNT signaling, no benign polypoid intermediaries were identified. Together, the results indicate that tumors in this model form via a non-canonical mechanism. A cohort of FC PIK3ca* mice were imaged by FDG dual hybrid PET/CT colonography and mice with similar sized tumors were divided into control and experimental arms. The experimental arm was treated with rapamycin (6mg/kg/day) for 14 days. Both groups were re-imaged 14 days later. The full results of the rapamycin treatment will be presented. Conclusion: This unique model of advanced colonic invasive adenocarcinomas has the potential to further our understanding of human disease and facilitate the development of therapeutics, especially inhibitors targeting downstream of PI3K.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1341. doi:1538-7445.AM2012-1341
Abstract 1365: The PAMM (pulmonary assessment of metastatic morbidity) diagnostic: A novel non-invasive method for evaluating lung metastasis in murine models
Authors: Gharpure Radhika V. , Mendoza Arnulfo , Dennis John U. , Khanna Chand 
Published: August 2012

Abstract
Metastasis continues to be the most significant problem in the field of cancer. The biological complexity that characterizes metastasis requires relevant experimental systems for its study, necessitating the use of animal models. When using murine models for pulmonary metastasis, it is valuable to conduct longitudinal studies during which progression of metastatic burden in the lung occurs. Current methods for evaluating pulmonary metastatic burden in experimental mice are limited to advanced imaging approaches or to the development of morbidity linked to pulmonary metastasis. Unfortunately, clinical signs of morbidity are often vague and unpredictable. A novel, inexpensive, clinical method to detect advanced metastatic burden in mice before the development of significant morbidity or mortality would be beneficial to the study of metastasis in mice. With this goal in mind we have developed a novel, non-invasive technique for assessing pulmonary metastatic burden in laboratory mice. The PAMM (Pulmonary Assessment of Metastatic Morbidity) test is performed by restraining an awake mouse and gently applying pressure with the index finger under the xiphoid process. This pressure reduces the diaphragmatic component to respiration. Mice with advanced lung metastases will show signs of respiratory distress within 3 seconds of applying this pressure. Application of this method in 4 models of pulmonary metastasis (n=27 mice including sarcoma and mammary carcinoma histologies), amongst 3 independent “users,” yielded 100% positive and 100% negative predictive values that were validated by post mortem examination. In summary, the PAMM method is a simple, inexpensive, reproducible and efficient method to assist in the detection of advanced pulmonary metastasis. This method contributes to the humane care of mice included in longitudinal studies of pulmonary metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1365. doi:1538-7445.AM2012-1365
Abstract 1399: SRC-1 up-regulates CSF-1 expression to potentiate breast cancer metastasis
Authors: Qin Li , Wu Yelin , Li Dabing , Toneff Michael Joseph , Tien Jean Ching Yi , Xu Yixiang , Liao Lan , Feng Zhen , Li Yi , Xu Jianming 
Published: August 2012

Abstract
Steroid receptor coactivator-1 (SRC-1/NCOA1) has been reported to be overexpressed in a subset of human breast cancer (BC) and its overexpression correlates with Her2 expression, disease recurrence and endocrine therapy resistance. To determine the role and underlying mechanisms of SRC-1 overexpression in BC progression and metastasis, a transgenic mouse model with overexpression of human SRC-1 in mouse mammary epithelial cells was created. In vivo data revealed that overxpression of SRC-1 potentiated BC metastasis to lung in both MMTV/Neu and MMTV/TVA/PyMT tumor models. While SRC-1 overexpression did not obviously accelerate tumor growth in these BC mouse models, the number of tumor cells invaded into blood vessels and metastasis index in lung tissue significantly increased in these mice. In addition to the elevated Twist expression and activation of Her2 and AKT driven by SRC-1 overexpression in the tumors, CSF-1 level was significantly increased in SRC-1 overexpressed tumors. We also found that CSF-1 expression was decreased in two PyMT/SRC-1 KO tumor cell lines compared with the two PyMT/WT control cell lines. Knockdown of SRC-1 in PyMT/WT cells or human BC cells reduced CSF-1 levels, while adenoviral-mediated expression of SRC-1 in PyMT/SRC-1 KO cells or human BC cells significantly promoted CSF-1 expression. Furthermore SRC-1 was found to interact with transcription factors, c-jun and c-fos, to activate the csf-1 promoter. Both SRC-1 and c-fos were found to associate with the csf-1 promoter at AP-1 binding sites in human BC cells. This study provided compelling evidence that overexpression of SRC-1 promotes BC metastasis. Targeting SRC-1 might be a potential therapeutic strategy for controlling BC metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1399. doi:1538-7445.AM2012-1399
Abstract 1401: Dietary selenium and metastasis in a mouse model
Authors: Mastro Andrea M. , Chen Yu-Chi , Sosnoski Donna M. , Prabhu K Sandeep 
Published: August 2012

Abstract
The skeleton is a common site for breast cancer metastasis. Once breast cancer cells enter the bone microenvironment, they alter the homeostasis of the bone remodeling system in favor of osteoclasts, which results in osteolysis. Breast cancer cells induce an osteoblast inflammatory response resulting in the production of IL-6, IL-8, MCP-1, and COX-2, known to promote osteoclastogenesis. Therefore, down-regulation of the inflammatory response of the osteoblasts brought about by breast cancer cells may reduce the activation of osteoclasts and decrease osteolysis. IL-6, MCP-1, COX-2 are regulated by a common transcription factor, NF-κB which is sensitive to intracellular redox status; its activation can be inhibited by cellular antioxidant enzymes. Two major antioxidant enzymes, glutathione peroxidase and thioredoxin reductase are selenoenzymes. Their dependence on selenium (Se) offers a way to increase their expression and activity, block NF-κB activation and thus inhibit the expression of its target genes. The hypothesis was that inhibition of NF-κB through dietary selenium would prevent the osteoblast inflammatory response and metastasis. To test the effect of dietary selenium in breast cancer progression, one of five diets: three selenium supplementation diets (sodium selenite, selenomethionine, and methylseleninic acid) or a selenium-deficient or a selenium adequate diet was fed to Balb/c mice for 3 months before inoculation of a metastatic breast cancer cell line 4T1.2luc into the mammary gland. The growth and metastasis of the tumors were followed by IVIS imaging. After 4 weeks, organs were collected and prepared for Q-PCR analysis of the luciferase gene as an indicator of metastatic burden. There was no significant difference in the development or growth of the primary breast tumor and the metastatic patterns between mice receiving the selenium-deficient or selenium-adequate diets. On the other hand, selenium supplementation diets were shown to affect breast cancer progression differently. Mice with sodium selenite supplementation developed the most metastasis (15/15) and showed higher incidence of breast cancer kidney and bone metastasis. The selenomethionine supplementation diet (3ppm) reduced breast cancer primary tumor growth and decreased overall tumor burden in major organs, such as lung, liver, kidney and femur. Taken together, this study showed that dietary selenium affected tumor growth and metastasis and that the selenomethionine supplementation diet offered the most protective effect on breast cancer progression. Support: American Institute for Cancer Research with supplemental support from the National Foundation for Cancer Research.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1401. doi:1538-7445.AM2012-1401
Abstract 1408: Activation status and function of the canonical Wnt pathway in murine mammary tumor cells reexpressing Glypican-3 (GPC3)
Authors: Huvelle María A. Lago , Romero Silvina A. , Castillo Lilian , de Kier Joffé Elisa Bal , Peters María G. 
Published: August 2012

Abstract
GPC3 is a proteoglycan downregulated in breast cancer cells. We previously demonstrated that GPC3 reexpression inhibits in vivo metastatic potential of LM3 murine mammary adenocarcinoma cells. This event was associated in vitro with a lower motility and an increased aggregation, as well as with an enhanced senescence and apoptosis. We have previous evidence indicating that the canonical Wnt pathway is inhibited in LM3-GPC3 cells. The aim of this work was to validate the inhibition of canonical Wnt signaling in GPC3 reexpressing cells and to investigate whether differences in cell behavior are due to the regulation of GPC3 on this pathway. By means of western blots (WB) we established that LM3-GPC3 cells have 5-10 folds less phosphorylated GSK3B. Using cytoplasmic protein extracts and WB we also determined that GPC3 reexpressing cells present lower levels of cytoplasmic B-Catenin. This was further studied by immunofluorescence (IF), where it was found that while LM3-vector cells show positive signal for B-catenin mainly in nucleus and cytoplasm, this staining is restricted to the membrane and cytoplasm in LM3-GPC3 cells. In addition, a gene reporter assay employing OT/OF plasmids confirmed the canonical Wnt pathway inhibition induced by GPC3. To determine whether cell properties modulated by GPC3 are mediated by the canonical Wnt pathway, we treated cells with its activator LiCl (or NaCl as control). LiCl treatment increases 10-fold the phosphorylation of GSK3B, as compared to LM3-GPC3 cells treated with NaCl, and induces an enhance of about 50% of the canonical Wnt transcriptional activity (gene reporter assay). We confirm that although LiCl partially reverted senescence induced by GPC3 reexpression (Senescent X-Gal positive cells: LM3-GPC3+NaCl= 85% vs. LM3-GPC3+LiCl= 65%, p&lt;0.05), it had no effects on apoptosis. We established by wound healing assays that LM3-GPC3 cells +LiCl recover their ability to migrate (Coverage of the wound: LM3-GPC3+NaCl= 15% vs LM3-GPC3+LiCl= 75%, p&lt;0.05). Finally, LiCl treatment reduced LM3-GPC3 homotypic cell aggregation, reaching similar levels to LM3-vector clones (p&lt;0.05). In summary, we confirm by a new methodological approach that GPC3 inhibits the canonical Wnt signaling. Our results suggest that GPC3 would be modulating senescence, migration and cell aggregation of mammary tumor cells through this pathway inhibition.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1408. doi:1538-7445.AM2012-1408
Abstract 1416: An animal model to study the effects of primary tumor excision on metastatic potential and organ-tropism of residual breast cancer cells
Authors: Zhang Yun , Jernigan Danielle , Lioni Mercedes , Garcia Fernando , Fatatis Alessandro 
Published: August 2012

Abstract
Because of constant improvements in early detection, the majority of breast cancer patients are diagnosed when still in a localized or regional stage and considered to be viable candidates for breast-conserving surgery or lumpectomy. As only 37% of breasts are found tumor-free following initial lumpectomy, between 22 and 59% of patients currently need re-intervention because positive or close margins are detected. In addition, re-excision or adjuvant therapies, such as local irradiation, are normally started several weeks or even months after primary surgery. During this period, the stroma at the site of tumor removal, which is characterized by altered angiogenesis, immune cells infiltration and activation of cancer-associated fibroblasts, may be selecting for cancer stem phenotypes, increasing metastatic potential and promoting the dissemination to specific secondary organs. This study aims to: 1) establish whether surgery on primary breast tumors leads to the emergence of cellular phenotypes with higher malignancy, associated with an increase in local growth, invasiveness and metastatic potential; 2) determine whether breast surgery alters the organ-tropism of residual cancer cells. For our experiments, BALB/c mice were inoculated in the mammary fat pad with 4T1 murine breast cancer cells and developed tumors that were either allowed to progress or surgically excised. Approximately 50% of animals in the surgery group presented with local recurrence, although all the excised tumors had positive margins. Local recurrences showed higher Ki-67 staining compared to their respective primary tumors and these data were in agreement with human samples of primary and recurrent breast tumors. Interestingly, the overall survival of mice in the control and surgery with recurrence groups were similar. Furthermore, macroscopic lung metastases were detected in the control and local recurrence groups, whereas mice without post-surgery recurrence failed to develop lung metastatic lesions. Finally, differences in the dissemination and growth of 4T1 cells to brain and bone between control, surgery plus recurrence and surgery without recurrence groups were investigated.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1416. doi:1538-7445.AM2012-1416