bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2404: TMPRSS2, a type II transmembrane serine protease, alters the prostate tumor microenvironment and promotes metastasis
Authors: Sun Yu , Lucas Jared , Hernandez Susana , Nelson Peter 
Published: June 2012

Abstract
Introduction: Extracellular and cell surface proteases play indispensible roles in embryonic development and normal tissue homeostasis. They also contribute to tumor pathology involving cellular invasion and metastasis. As the majority of cancer-related deaths are associated with metastasis, understanding contributors to this process is essential for developing improved treatment strategies. TMPRSS2 is a Type II transmembrane serine protease (TTSP) regulated by androgenic hormones and is expressed preferentially in the human prostate. Recent studies have indicated that TMPRSS2 is expressed highly in primary and metastatic prostate cancers, though functional activities are poorly defined.
Methods: To determine the relevance and consequence of TMPRSS2 overexpression in prostate cancer, we generated four transgenic mouse models that overexpress wild-type or mutant variants of human and mouse TMPRSS2 under the control of the prostate-specific probasin promoter (PB-TMPRSS2). We further crossed PB-TMPRSS2 mice with the LADY model of prostate cancer, and evaluated tumor growth and the impact on metastasis.
Results: We confirmed that the PB-TMPRSS2 transgenic mouse lines have significantly elevated levels of TMPRSS2 protease in prostate epithelium. Although enhanced TMPRSS2 expression did not affect mouse fertility, we observed disorganization and disruption of the basement membrane of prostate glands, regardless of whether the overexpressed enzyme is of human or mouse origin. Immunohistochemical analysis identified dramatically altered levels of β4-integrin and collagen IV in the prostate glands of TMPRSS2-overexpressing mice, with the most significant changes occurring in ventral and anterior lobes. Histological changes in cell differentiation, proliferation or apoptosis were not observed. While a strain of LADY transgenic mice expressing SV40T antigen under the control of the probasin promoter (PB-SV40T) develop prostate cancer without metastatic spread, crosses with PB-TMPRSS2 mice produced offspring with high rates of metastasis to liver, lung, lymph node and bone.
Conclusions: Our study pinpoints a mechanistic pathway by which TMPRSS2 contributes to primary prostate cancer progression and promotes metastasis, paralleling the effects of Hepsin overexpression, a structurally similar protease known to promote metastasis. These results provide support for the development of therapeutic approaches to specifically limit TMPRSS2 proteolytic activity in prostate 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 2404. doi:10.1158/1538-7445.AM2011-2404
Abstract 2409: A precise orthotopic metastatic model of rectal cancer
Authors: Kishimoto Hiroyuki , Momiyama Masashi , Aki Ryoichi , Kimura Hiroaki , Suetsugu Atsushi , Bouvet Michael , Fujiwara Toshiyoshi , Hoffman Robert M. 
Published: June 2012

Abstract
We have developed a novel technique to orthotopically transplant rectal cancer cells. This model was established by intrarectal transplantation of mouse rectal cancer cells stably expressing fluorescent protein, followed by disrupting the epithelial cell layer of the rectal mucosa by soaking with an acetic acid solution. Early stage tumor was detected on the rectal mucosa from as early as 6 days after transplantation, which then became invasive into the submucosal tissue. The tumor incidence (%) on the rectal mucosa and size (mean volume ± SD) were 100% and 1232.4 ± 994.7 mm3 at 4 weeks after transplantation, respectively. Spontaneous lymph node metastasis and lung metastasis were also observed 4 weeks after transplantation in over 90% of mice. This rectal tumor model to mimic of the natural course of rectal cancer accurately. The model will be more useful for evaluation of the tumor environment, metastasis and agents which suppress or enhance the growth of tumor at early stages as well as metastasis.
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 2409. doi:10.1158/1538-7445.AM2011-2409
Abstract 2418: Establishment and characterization of a primary chordoma xenograft
Authors: Shah Preeti , Katuri Varalakshmi , Awad Ola , Gul Naheed , Metzer Paul S. , Loeb David 
Published: June 2012

Abstract
Chordomas are slow growing, malignant cancers believed to originate from notochord remnants. Chordoma accounts for 1% of cancers of the central nervous system with an annual incidence of 0.08 cases per 100,000 individuals. There are 3 different histologic subtypes- classic chordoma, chondroid chordoma, and dedifferentiated chordoma. Chordomas are characterized by the presence of physaliphorous cells with vacuolated cytoplasm and high expression of the transcription factor T Brachury. Management of chordoma is primarily surgical – chemotherapy and radiation therapy have limited effect. The development of effective treatments for this tumor is hampered by the lack of adequate animal models. We report here the establishment of the first primary xenograft model of chordoma. Tumor excised from a patient diagnosed with classic chordoma was implanted adjacent to the right proximal tibia in a NOD/SCID/IL2Rγ (null) mouse. The resulting tumor has been serially transplanted at least 10 times with no diminution in growth rate over time. Histologically, the xenograft does not appear to be a classic chordoma; interestingly, the patient from whom the xenograft was derived relapsed with a dedifferentiated morphology. To confirm the identity of the tumor xenograft, T brachyury expression was demonstrated by immunohistochemistry and PCR. We have begun to characterize this xenograft by gene expression profiling and comparative genomic hybridization. Expression profiling results were verified by RT-PCR. Cells isolated from xenografts were analyzed by the Aldefluor assay to assess the levels of expression of aldehyde dehydrogenase activity. A cell line was generated from this xenograft as well and is being characterized. In summary, we report here the establishment of the first primary chordoma xenograft. Initial molecular characterization of the xenograft and a cell line derived from this tumor is ongoing. These tools will shed valuable light on the pathophysiology of this rare tumor and allow the preclinical development of novel treatment strategies.
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 2418. doi:10.1158/1538-7445.AM2011-2418
Abstract 2429: Increased incidence of brain metastases in BRCA1 related ovarian cancers
Authors: Sekine Masayuki , Tanaka Kenichi 
Published: June 2012

Abstract
Objective: Brain metastasis to ovarian cancer is a very rare phenomenon. BRCA1 related ovarian cancers show specific pathobiological profiles, an advanced stage, and sensitivity to chemotherapeutic agents. However, no clear relationship to any known metastatic behavior has yet been found, so we examined the BRCA1 mutation and expression profiles in ovarian cancer cases with brain metastases.
Methods: We examined our clinical records of 320 ovarian cancer cases from 1983 to 2008 in order to ascertain cases with brain metastases. In the molecular genetic analyses, we performed loss of heterozygosity (LOH), direct sequence, and immunohistochemical staining analysis of BRCA1. For LOH analysis, 4 markers spanning the region of BRCA1 were selected for use. The entire exons, 23 exons in BRCA1 and 26 exons in BRCA2, and the intronic boundary regions were sequenced in both forward and reverse directions for detecting germline mutations. The immunohistochemical studies were performed with the BRCA1 C-terminal mouse monoclonal antibody (Ab-3, Calbiochem,×500)
Results: We ascertained 7 cases with brain metastases in 320 ovarian cancer cases (7/320=2.2%). Among the 7 cases, 3 cases had ovarian and/or breast cancer patients in third-degree relatives. We detected 4 LOH-positive cases and a germline mutation of BRCA1 in 2 of the 4 cases, Q934X and L63X respectively. Furthermore, the remaining 2 cases showed an absent staining of the BRCA1 protein. Therefore, 4 out of 7 cases with brain metastases were considered BRCA1-related ovarian cancers (4/7=57.1%). All 4 of the cases were serous adenocarcinoma of ovary.
Conclusions: This is the first report of a hospital population-based study in relation to brain metastasis and BRCA1-related ovarian cancers. Our results suggest that the loss of BRCA1 function may be involved in the phenomenon of brain metastasis to ovarian cancer. Further molecular biologic analyses will be required for a better understanding of this rare phenomenon.

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 2429. doi:10.1158/1538-7445.AM2011-2429
Abstract 2431: Inhibition of metastasis through therapeutic targeting of focal adhesion kinase (FAK) in pancreatic cancer
Authors: Dhani Neesha C. , Schwock Joerg , Cao Ping-Jiang M. , Tsao Ming-Sound , Hedley David W. 
Published: June 2012

Abstract
BACKGROUND: Cancer mortality is primarily caused by metastatic disease; it has therefore been suggested that the preclinical evaluation of novel therapies should include testing in metastatic models of disease. This is especially relevant in light of recent reports of both conventional and targeted therapies being associated with accelerated metastases despite maintenance of primary tumor control. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase which also acts as molecular scaffold, and localizes to focal adhesions, contact points between the cell and the extra-cellular matrix. Downstream of integrins and transmembrane receptors, FAK acts as a signaling hub, participating in processes integral to tumor progression including cell survival, proliferation, angiogenesis, migration and invasion. In this ongoing study, we explore the efficacy of selective genetic and pharmacologic FAK inhibition in preclinical models of human pancreatic cancer, including spontaneously metastasizing, cell-line derived and primary xenografts.
METHODS & RESULTS: We constructed modified pancreatic cancer cell lines using retroviral over-expression of the dominant negative FRNK (FAK related non-kinase). Pharmacologic inhibition of FAK was performed with PF-562271 (Pfizer), a selective FAK/Pyk2 inhibitor which recently completed Phase I testing. Adhesion, invasion and migration in vitro assays were conducted using the xCELLigence RTCA system. In vivo efficacy of FAK inhibition was evaluated in orthotopic xenograft models. In vitro studies demonstrated that both modalities of FAK inhibition resulted in impaired adhesion, invasion and migration and 3D colony formation, without comparable effects on viability, proliferation or colony formation in 2D. Expression of dominant-negative FRNK resulted in 49% smaller xenograft tumors (p=0.003), a 78% reduction in metastatic disease (p&lt; 0.001) and longer overall survival (p &lt; 0.001). There was a similar, 46% trend to reduction of metastatic burden (p=0.089) in orthotopic cell line xenograft models treated with PF-562271, despite a lack of significant primary tumor growth delay.
CONCLUSIONS: Our data suggest a potential utility of selective FAK inhibition in delaying metastatic progression of pancreatic cancer. This is particularly relevant clinically since patients frequently present with locally advanced, unresectable disease and subsequently develop metastases. Pharmacologic FAK inhibition (in combination with conventional therapies) is currently being evaluated in neo/adjuvant models of this disease.
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 2431. doi:10.1158/1538-7445.AM2011-2431
Abstract 2432: AMF/PGI modulates EGF-induced invasion of breast cancer cell line via positive feedback loop
Authors: Kho Dhonghyo , Raz Avraham 
Published: June 2012

Abstract
Phosphoglucose isomerase (PGI/AMF) is well established to promote cell migration as an autocrine motility factor. It remains to be established which microenvironmental signals enhance the secretion of AMF from tumor cells. Herein, we found that epithelial growth factor (EGF) enhances the secretion of AMF in the breast cancer cell line, T47D. Immunoprecipitation study shows that Caisen kinase 2α (CK2α) increases the phosphorylation of intracellular AMF. Therefore, increasing secretion of AMF and the extracellular AMF enhances the downstream cascade of EGF such as Phospho-ERK and β-catenin stabilization. In the transwell motility study, EGF-induced invasion increases synergistically with purified AMF. To confirm this, we demonstrate that the knockdown of AMF by siRNA treatment suppresses EGF-induced invasiveness. These findings imply that AMF may modulate the EGF-induced invasion in the tumor microenvironment.
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 2432. doi:10.1158/1538-7445.AM2011-2432
Abstract 2434: CXCR3-mediated cellular and molecular events involved in breast cancer metastasis
Authors: Li Yanchun , Reader Jocelyn , Ma Xinrong , Kundu Namita , Kao Joseph P. , Zhan Steven , Fulton Amy M. 
Published: June 2012

Abstract
We previously detected chemokine receptor CXCR3 in malignant epithelium of early stage breast cancers by immunohistochemistry and the expression levels were positively correlated with significantly poorer survival. We also showed that CXCR3 contributes to metastatic potential in a murine model of metastatic breast cancer. The goal of the present study is to determine the cellular and molecular mechanisms underlying CXCR3-mediated breast cancer metastasis. Treatment of the human breast cancer cell line MDA-MB-231 with the CXCR3 ligand CXCL10 induced calcium mobilization and Rac activation; both responses are essential for tumor cell chemotaxis. Not surprisingly, CXCL10 enhanced migration and invasion of MDA-MB-231 cells. We also showed that CXCL10 promoted anchorage independent growth of both human malignant mammary epithelial cells (MDA-MB-231 and MDA-MB-468) and murine malignant mammary epithelial cell line 66.1 in an ERK- dependent manner. In tumor cells, ERK1/2 is robustly activated after CXCR3 ligand stimulation, whereas the same pathway is inhibited or not changed in normal cells. In addition, CXCR3 activation provided some degree of anoikis resistance to 66.1 cells. There are two isoforms of CXCR3 in human cells. The “classical” CXCR3 receptor (CXCR3-A) mediates proliferation and migration of various cell lines, while CXCR3-B, a splice variant of CXCR3-A, has opposing functions. We determined the expression pattern of these two CXCR3 isoforms in a panel of human breast cancer cell lines by real-time quantitative PCR and showed that the CXCR3-B/CXCR3-A mRNA expression ratio is decreased (0.16-0.63) compared with normal epithelial cell line MCF-10A (2.16). Taken together, these data indicate that multiple molecular and cellular mechanisms may contribute to CXCR3-mediated breast cancer metastasis. Due to the distinct functions of CXCR3-A and CXCR3-B, the relative amounts of CXCR3-A and CXCR3-B may dictate cell behavior. Further studies will investigate how the balance between CXCR3-A and CXCR3-B regulates the metastatic potential of breast cancer cells and allow us to optimize therapeutic strategies targeting CXCR3.
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 2434. doi:10.1158/1538-7445.AM2011-2434
Abstract 2435: Chromogranin A and its N-terminal fragment affect the metastatic potential of circulating tumor cells in mice
Authors: Dondossola Eleonora , Crippa Luca , Colombo Barbara , Ferrero Elisabetta , Corti Angelo 
Published: June 2012

Abstract
Chromogranin A (CgA) is an acidic glycoprotein present within secretory vesicles of many normal and neoplastic endocrine and neuroendocrine cells. CgA is abnormally released in circulation in patients with neuroendocrine tumors and non neuroendocrine tumors, as in a subpopulation of patients with non small cell lung cancer (NSCLC), with important prognostic implications. We have previously demonstrated that CgA can preserve the barrier function of the vascular endothelium. Since hematogenous metastasis requires the seeding of malignant cancer cells in circulation, followed by cell extravasation and colonization of distant organs, we investigated the role of CgA on tumor cell extravasation and lung colony formation. We show that normal levels of endogenous CgA can reduce the number of lung colonies from mammary TS/A adenocarcinoma cells injected into the venous circulation of mice. Administration of omeprazole, a drug commonly used in the treatment of acid-peptic disorders, increased the blood levels of CgA and further inhibited the development of lung colonies in a CgA-dependent manner. Furthermore, administration of recombinant CgA or its N-terminal fragment (called vasostatin-1, VS-1) reduced the metastatic potential of circulating mammary TS/A adenocarcinoma and B16-F10 melanoma cells. Studies on the mechanism of action showed that CgA and VS-1 can inhibit the transendothelial migration of cancer cells, by preserving the VE-cadherin-dependent endothelial barrier function. These findings suggest that endogenous CgA can play a role as a modulator of the metastatic potential of circulating tumor 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 2435. doi:10.1158/1538-7445.AM2011-2435
Abstract 2442: XIAP mediates cancer cell motility via RhoGDI-dependent regulation of cytoskeleton
Authors: Yu Yonghui , Liu Jinyi , Zhang Dongyun , Luo Wenjing , Yu Jianxiu , Li Jingxia , Zhang Xinhai , Wu Xue-Ru , Acosta Germán R. , Huang Chuanshu 
Published: June 2012

Abstract
XIAP overexpression has been found to be associated with malignant cancer progression and aggression in individuals with many types of cancers. However, the molecular basis of XIAP in the regulation of cancer cell biological behavior remains largely unknown. In the current study, we found that the deficiency of XIAP expression in human cancer cells by approach of either knockout or knockdown led to a marked reduction of β-Actin polymerization and cytoskeleton formation. Consistently, cell migration and invasion were also decreased in XIAP-deficient cells in comparison to those in the parent wild type cells. Subsequent studies demonstrated that the regulation of cell motility by XIAP depended on its interaction with RhoGDI via XIAP's RING domain. Furthermore, XIAP was found to negatively regulate RhoGDI SUMOylation, which might affect its activity in controlling cell motility. Collectively, our studies provide novel insights into the molecular mechanisms by which XIAP regulates cancer invasion, and offer further theoretical basis for setting XIAP as a potential prognostic marker and specific target for treatment of cancers with metastatic property.
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 2442. doi:10.1158/1538-7445.AM2011-2442
Abstract 2445: CD24+ liver tumor-initiating cells drives self-renewal and tumor initiation through Stat3-mediated Nanog regulation
Authors: Lee Kin Wah , Castilho Antonia , Cheung Vincent Chi-Ho , Tang Kwan Ho , Ma Stephanie , Ng Irene Oi-Lin 
Published: June 2012

Abstract
Tumor-initiating cells (TICs) are a subpopulation of chemoresistant tumor cells that have been shown clinically to cause tumor recurrence upon chemotherapy. Identification of T-ICs and their related pathways are therefore priorities for the development of novel therapeutic paradigms. We established chemoresistant hepatocellular carcinoma (HCC) xenograft tumors in immunocompromised mice in which an enriched T-IC population was capable of tumor initiation and self-renewal. Using this model, we found CD24 to be up-regulated in residual chemoresistant tumor tissue when compared with bulk tumor upon cisplatin treatment. The determine whether CD24 is a candidate TIC marker for HCC, cell sorting approach was employed to separate CD24-/CD24+ populations derived from HCC cell lines and clinical samples. CD24+ HCC cells were found to be critical for the maintenance of tumor growth, self-renewal, differentiation, chemoresistance and metastasis of tumors. Using quantitative PCR, CD24 was over-expressed in HCCs when compared with their non-tumor counterparts, and CD24 expression was significantly correlated with poor patients’ survival.
Using a lentiviral-based knockdown approach, CD24 was found to be a functional liver T-IC marker that drives tumor initiation and self-renewal. Notably, whether by cell sorting or gene-knockdown approach, it was shown by quantitative PCR that the CD24-enriched population consistently overexpressed Nanog. Upon transfection of Nanog cDNA into CD24-knockdown cells, self-renewal and tumor formation were functionally recovered, suggesting Nanog as the downstream effecter of CD24. By Ingenuity Pathway analysis, ‘acute phase response signaling’ was found to be the most significantly altered upon CD24 knockdown in which phosphorylation of Stat3 at the Tyrosine705 residue is critical. Using Stat3 inhibitor (S3I-201), we found that Nanog promoter and its protein were down-regulated in dose-dependent manner in CD24+ HCC cells. CD24 was found to be a functional liver T-IC marker that drives T-IC genesis through Stat3-mediated Nanog regulation.
In conclusion, we identified CD24+ HCC cells within bulky tumor, and they functioned to initiate tumor growth and self-renewal through Stat3-mediated Nanog up-regulation. The identification of novel CD24 signaling pathways provides an attractive therapeutic strategy against this deadly disease.
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 2445. doi:10.1158/1538-7445.AM2011-2445