bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1339: The role of TNF-α in PGE2-induced tumorigenesis in gastric cancer mouse model
Authors: Oshima Hiroko , Ishikawa Tomo-o , Oshima Masanobu 
Published: August 2012

Abstract
Accumulating evidence has indicated that chronic inflammation is associated with cancer development. Mouse genetic studies have shown that the proinflammatory mediator, PGE2, plays an essential role in gastrointestinal tumorigenesis. Moreover, the proinflammatory cytokine TNF-α also plays a key role in tumorigenesis, including colitis-associated colon cancer. However, the relationship between PGE2 and TNF-α in tumorigenesis has not yet been fully investigated. We previously constructed a gastric tumor mouse model, Gan mice, that recapitulates human intestinal-type gastric cancer, in which both the PGE2 pathway and Wnt signaling are activated simultaneously in the stomach by transgenic expression of the COX-2, mPGES-1, and Wnt1 genes. The induction of the PGE2 pathway triggers an inflammatory response in the Gan mouse stomach, and the expression of proinflammatory cytokines and chemokines is induced in gastric tumor tissues. We herein examined the role of TNF-α in the PGE2-induced inflammation-associated gastric tumorigenesis by crossing Gan mice with TNF-α knockout mice. Importantly, the gastric tumorigenesis in the Gan TNF-α (-/-) compound mice was significantly suppressed in comparison to the control Gan mice. Moreover, the β-catenin level decreased significantly in the gastric tumors of Gan TNF-α (-/-) mice, suggesting a role for TNF-α in the promotion of Wnt signaling. Interestingly, inflammatory cells, including macrophages and CD4+ T cells, still infiltrated into the Gan TNF-α (-/-) mouse tumors, and the expression levels of IL-1α and IL-6 were almost the same as those in the control Gan mouse tumors. Accordingly, it is possible that TNF-α is an important tumor-promoting factor for gastric tumorigenesis, although TNF-α is not essential for PGE2-induced inflammation in the stomach. Notably, macrophages in the Gan TNF-α (-/-) mouse tumors lost their expression of the M2 marker CD206. It has been suggested that macrophages polarized to the M2(-like) type are important for tissue remodeling and tumorigenesis. It is therefore possible that TNF-α is required for macrophage polarization to a pro-tumorigenic status, which may be important for Wnt activation and gastric tumor promotion.
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 1339. doi:1538-7445.AM2012-1339
Abstract 1352: Shp2 is required for CML initiation and maintenance
Authors: Gu Shengqing , Chan Gordon , Neel Benjamin G. 
Published: August 2012

Abstract
Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm (MPN) caused by the constitutively activated BCR-ABL tyrosine kinase. CML progresses from an initial chronic phase, through an accelerated phase, to a final and fatal blast crisis. Current first-line therapy for CML involves tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib, or nilotinibs. However, TKIs don't completely cure CML, as revealed by low complete molecular response rate and frequent disease relapse upon drug withdrawal. Studies of patient samples and mouse models indicate that this most likely results from lack of dependence of CML stem cells (CML-SCs) on BCR-ABL for survival. It is important to further identify potential targets of CML-SC. Shp2 is a non-receptor protein tyrosine phosphatase involed in RTK, cytokine, and integrine signaling pathways, and is a target of Abl kinase during cell proliferation. It is required for survival and maintenance of normal hematopoietic stem cells (HSCs). In the context of CML, BCR-ABL constitutively phosphorylates Gab2, which then binds to Shp2, resulting in its inappropriate activation of downstream pathways, including the Ras-Erk cascade. Gab2 is required for CML initiation in vivo. We hypothesized that Shp2 is required for CML development from the stem cell level and might be an effective target for treatment of CML. Using our induced Shp2 deletion tools, we found that Shp2 is required for CML initiation and maintenance in a bone marrow transplant model of CML. Moreover, primitive CML cells undergo elevated cell death upon Shp2 knockout. This implicates Shp2 as a potential target for CML therapy in future.
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 1352. doi:1538-7445.AM2012-1352
Abstract 1367: Characterization of spontaneous metastases in Champions TumorGraft™ models
Authors: Albee Lee D. , Lu Bin , Anderson Nathan , James Meredith , Friedman Jay , Bruckheimer Elizabeth M. 
Published: August 2012

Abstract
Oncology drug development is challenged by an absence of model systems that accurately mimic the full metastatic processes during disease progression. Methods for establishing metastases generally involve orthotopic implantation or intravenous delivery of cell line-based xenografts. These cell line-based models can capture the seeding phase of the metastatic process but do not address the processes involved in remodeling of the extracellular matrix to allow for invasion into nearby tissues or dissemination to distance sites throughout the body via the lymphatic or the circulatory system. Extensive characterization of Champions TumorGraft™ models demonstrates that spontaneous metastasis in our platform may not be a rare event as it has been verified in 8 different models and preliminary data indicates multiple additional occurrences. Further, the capacity for spontaneous metastasis is not indication specific as it has been observed in Champions TumorGrafts derived from patients with multiple cancer types (e.g. ovarian, breast, H&N, and lung). The development and incidence rate of TumorGraft metastasis seems to correlate with the aggressiveness of disease and occurrence of metastases in the patient. For example, 83% of mice implanted with Champions TumorGraft breast cancer model CTG-0033 develop liver and/or spleen metastases. This Champions TumorGraft was derived from a patient with aggressive disease that failed to respond to first and second line treatments, and developed metastases in multiple organs including the liver. In this report, growth rates, metastases formation and molecular characterization in primary subcutaneous Champions TumorGraft models were compared with their corresponding metastatic lesions to identify changes that may correlate with the formation of metastases. Overall, this study further demonstrates that Champions Oncology TumorGraft platform preserves the biological properties of the original human tumor including spontaneous metastatic behavior and is therefore ideal for oncology drug development programs focused on the inhibition of metastases.
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 1367. doi:1538-7445.AM2012-1367
Abstract 1368: Investigating the tumorigenicity of disseminated tumor cells
Authors: Hall Carolyn S. , Laubacher Barbara , Anderson Amber , Kuerer Henry , Bedrosian Isabelle , Krishnamurthy Savitri , Lucci Anthony 
Published: August 2012

Abstract
Background: Tumor cells that disseminate to the bone marrow (disseminated tumor cells, DTCs) have been identified in 30% of stage I - III breast cancer (BC) patients and independently predict outcome. Because DTCs are a rare, heterogeneous population of cells, little is known regarding their characteristics; such as their clinical significance with regard to disease progression, and targets that can be utilized for their eradication. DTC Identification is typically achieved using antibodies to epithelial cell adhesion molecule (EpCAM), and cytokeratin (CK). However, EpCAM and CK can be down-regulated during epithelial–mesenchymal transition (EMT). To date, no published report has assessed the tumorigenicity of DTCs isolated from patient samples using an in vivo animal model. The purpose of this study was to investigate the tumorigenicity of DTCs in vivo. Methods: Thirteen clinical stage I-III BC patients provided informed consent to participate in an IRB-approved study involving collection of bone marrow at the time of primary surgery. Following Ficoll centrifugation, bone marrow aspirates were cultured using breast cancer stem cell enriching conditions for 21 days. At 21 days, viability of floating cells with high nuclear: cytoplasmic ratios were confirmed with Tryphan blue staining and cytokeratin expression was identified using pan-cytokeratin immunostaining. 200 cells were co-injected with Matrigel into the mammary fat pads (3 mice/patient) of female nude mice. Mice were monitored daily for tumor formation. Results: Viable floating cells with large nuclear: cytoplasmic ratios were observed in 10/13 cases. Both CK+ and CK- DTCs were identified in 8 out of 10 cases, and CK- DTCs only were identified in 2 out of 10 cases. One of the 10 samples was tumorigenic in vivo; all 3 mice injected with this patient's cells developed breast tumors within ≤ 55 days. This sample was obtained from a 40-year old T2N2 patient with a grade 2 estrogen receptor positive, progesterone receptor negative, Her2/neu negative tumor. Interestingly, CK expression was not detected in this patient's cultured cells. Conclusions: DTCs can be isolated and propagated using breast cancer stem cell enriching conditions, enabling the characterization and assessment of DTCs that are in the process of (or have undergone) EMT. In addition, the tumorigenetic potential of DTCs can be assessed on a patient-by-patient basis by employing an in vivo mouse model. Further studies are needed to develop targeted therapies for the eradication of micrometastatic disease in stage I-III BC patients.
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 1368. doi:1538-7445.AM2012-1368
Abstract 1372: Microvessel proliferation by co-expression of endothelial nestin and Ki-67 is associated with a basal-like phenotype and aggressive features in breast cancer
Authors: Krüger Kristi , Stefansson Ingunn Marie , Collett Karin , Arnes Jarle Birger , Aas Turid , Akslen Lars Andreas 
Published: August 2012

Abstract
Angiogenesis, the formation of new blood vessels from pre-existing ones, is essential in tumour growth and metastasis. Microvessel density (MVD) is the most widely used method for quantification of tumour angiogenesis. We here present a novel angiogenesis marker, microvessel proliferation (MVP) based on a dual immunohistochemical stain of nestin and Ki-67. Nestin is an intermediate filament protein expressed in a variety of undifferentiated cells, including newly synthesized endothelial cells (1-3), and used in this study to stain the vasculature. Proliferating cells were recognized by their Ki-67 positivity, and immature microvessels were recognized by their nestin positivity combined with their morphology. Proliferating microvessels contains endothelial cells co-expressing nestin and Ki-67. Microvessel proliferation was estimated by vascular proliferation index (VPI), the ratio of vessels containing immature proliferating endothelial cells, and the total number of immature vessels. VPI was evaluated in 178 breast cancer tissue sections. High VPI showed significant association to several markers of aggressive breast cancer, including negative estrogen receptor (ER) status (p=0.003), high tumour cell proliferation by Ki-67 (p=0.004), high p53 expression (p=0.001), five immunohistochemical profiles for the basal-like phenotype (odds ratios (OR); range 2.8-6.3), and the triple negative phenotype (TNP)(p=0.040). Concerning the mode of detection, high VPI was three times more likely to be presented in an interval detected breast cancer compared with a screening detected (OR: 3.0, p&lt;0.0005). Both in univariate and multivariate analysis, high VPI was significantly associated with poor survival (p=0.034 and p=0.022, respectively). In conclusion, activated angiogenesis, estimated by microvessel proliferation, is associated with several markers of aggressive breast cancer phenotype, basal-like breast cancer, interval detection, and a significant predictor of prognosis in this series of breast cancer. 1. Lendahl U, Zimmerman LB, McKay RD. CNS stem cells express a new class of intermediate filament protein. Cell. 1990 Feb 23;60(4):585-95. 2. Mokry J, Cizkova D, Filip S, Ehrmann J, Osterreicher J, Kolar Z, et al. Nestin expression by newly formed human blood vessels. Stem Cells Dev. 2004 Dec;13(6):658-64. 3. Mokry J, Ehrmann J, Karbanova J, Cizkova D, Soukup T, Suchanek J, et al. Expression of intermediate filament nestin in blood vessels of neural and non-neural tissues. Acta Medica (Hradec Kralove). 2008;51(3):173-9.
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 1372. doi:1538-7445.AM2012-1372
Abstract 1376: TIMP-2 inhibits angiogenesis induced by tumor associated myeloid-suppressor cells
Authors: Guedez Liliana , Stetler-Stevenson William G. 
Published: August 2012

Abstract
Among the mechanisms of resistance to cancer treatment is the recruitment by tumors of inflammatory myeloid (CD11b+, Gr-1+) suppressor cells, promoting angiogenesis and tumor progression. Here, we report the effects of tissue inhibitor of metalloproteases(TIMP)-2 on the recruitment of CD11b+, Gr-1+ cells and subsequent suppression of tumor angiogenesis. Previously, we showed that xenografts of A549 cells with up-regulated TIMP-2 demonstrated significant reduction in the number of CD11b+, Gr-1+ cells, expression of VEGF-R2, and αvβ3 as well as reduced angiogenesis. Here, the effect of TIMP-2 on the growth of Luciferase-tagged-A549 cells was tested in vivo using the direct in vivo angiogenesis (DIVA) assay implanted subcutaneously containing 400 nM TIMP-2 or PBS. TIMP-2 decreased A549-cell proliferation in vivo as determined by quantitating bioluminescence emission. Immuno-histochemistry analysis of the tissue in TIMP-2 treated DIVAs demonstrated a drastic reduction in inflammation, fewer CD11b+, Gr-1+ cells were recruited into the TIMP-2 DIVA compared with untreated DIVA controls, as well as significant lower number of angiogenic vessels and invading endothelial cells were seen. Moreover, bone marrow from mice carrying DIVA with TIMP-2-treated A549 cells demonstrated a relative decrease in cell progenitors as compared with PBS treated tumor cells, suggesting that TIMP-2 blocked the release of tumor factors affecting the mobilization of bone marrow progenitors. These findings support TIMP-2 as anti-angiogenesis and anti-inflammatory factor. By targeting tumor-myeloid suppressors cells, TIMP-2 may have a therapeutic utility in the resistance of tumors to angiogenesis inhibitors.
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 1376. doi:1538-7445.AM2012-1376
Abstract 1378: Concurrent inhibition of c-Met and VEGF signaling suppresses tumor invasion in orthotopic Panc-1 pancreatic carcinomas in mice
Authors: Sennino Barbara , Williamson Casey W. , Bhagwandin Vikash , Christensen James G. , McDonald Donald M. 
Published: August 2012

Abstract
Multiple factors can contribute to evasive resistance that develops during treatment with angiogenesis inhibitors that target the vascular endothelial growth factor (VEGF) pathway. Evidence from studies of neuroendocrine tumors in RIP-Tag2 transgenic mice indicates that hypoxia-induced activation of pro-invasive pathways involving the receptor for hepatocyte growth factor, c-Met, can participate. The present study sought to determine whether this mechanism also applies to other types of tumors. Our approach was to ask whether growth and invasiveness of Panc-1 pancreatic adenocarcinomas implanted orthotopically in nude mice were reduced by inhibition of c-Met during concurrent treatment with an angiogenesis inhibitor for 3 weeks. Panc-1 tumors in mice treated with the angiogenesis inhibitor sunitinib, a tyrosine kinase inhibitor that blocks VEGFR and related receptors, had a 75% reduction in vascularity and grew more slowly than controls but had twice as much of intratumoral hypoxia, assessed by pimonidazole staining. Unlike the faint c-Met immunoreactivity in most tumor cells of vehicle-treated Panc-1 tumors, c-Met staining was stronger in tumor cells after treatment with sunitinib. Tumors in mice treated with the selective c-Met inhibitor PF-04217903 alone had little change in tumor vascularity or intratumoral hypoxia and grew faster than those treated with sunitinib. However, tumors treated with sunitinib plus PF-04217903 together grew more slowly than after sunitinib alone but had similar amounts of vascular pruning and hypoxia. Tumor invasiveness, reflected by amylase-positive acinar cells of the exocrine pancreas located within tumors, was exaggerated after sunitinib treatment but, importantly, was significantly less in tumors treated with sunitinib plus PF-04217903. These findings indicate that sunitinib used alone reduced the growth of Panc-1 tumors but increased intratumoral hypoxia, c-Met expression, and local invasion into the surrounding normal pancreas. By comparison, sunitinib administered concurrently with the c-Met inhibitor PF-04217903 resulted in further slowing of tumor growth and less tumor invasiveness.
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 1378. doi:1538-7445.AM2012-1378
Abstract 1394: Acute bacterial infection increases lung cancer metastasis via toll-like receptors 2 and 4
Authors: Chow Simon C. , Chan Carlos HF , Rousseau Mathieu C. , Cools-Lartigue Jonathan , Roussel Lucie , Giannias Betty , Yoon Heewon , Chen Crystal , Ferri Lorenzo E. 
Published: August 2012

Abstract
INTRODUCTION: Surgery is required for curative treatment of lung cancer but is associated with a high rate of bacterial infections such as pneumonia. There is emerging clinical evidence to suggest that infectious complications may decrease survival after cancer surgery, but the mechanism is unclear. Interactions between bacteria and host cells are mediated by specialized pathogen recognition receptors, of which the Toll-like receptors (TLRs) are best characterized. We and others have shown that cancer cells express TLRs, but their function is largely unknown. The aim of this study is to investigate the mechanisms of bacterial infection-facilitated lung cancer metastasis with a particular focus on the role of TLRs. METHODS: Two lung cancer cell lines (murine H-59 and human A549) were incubated a) directly with heat-inactivated bacteria (S.pneumonia or E.coli) or purified bacterial antigens (lipopolysaccharide or lipoteichoic acid), or b) indirectly with an in vitro pneumonia model using conditioned media from pulmonary bronchial epithelial cells incubated with heat-inactivated bacteria or bacterial antigens. Migratory and metastatic ability of thus treated cells were determined in vitro (adhesion, migration) and in vivo (hepatic intravital microscopy and intra-splenic liver metastasis). A clinically relevant in vivo model of severe infection, cecal ligation and puncture (CLP) or sham control, was employed in some animals. To assess the role of TLRs, we used transgenic TLR4 knockout mice, and small molecule inhibiting molecules or antibodies of TLRs. RESULTS: Direct and indirect (in vitro pneumonia) infection of H-59 and A549 increased adhesion to extracellular matrix components approximately 2-8 fold and 2-4 fold over negative control, respectively. In vitro pneumonia increased in vitro migration of H-59 approximately 2-5 fold. Direct and indirect incubation of H-59 with S.pneumonia and E.coli increased the in vivo adhesion to liver sinusoids 2-4 fold. CLP (in vivo infection model) enhanced the in vivo adhesion of H-59 3-fold and increased number of liver metastases at 2 weeks post-injection approximately 12 fold. These effects were attenuated in TLR4 -/- mice and with TLR2 and TLR4 inhibition. CONCLUSION: Activation of TLR2 or TLR4 on lung cancer cells, either directly by S.pneumonia and E.coli, indirectly though activated bronchial epithelial cells, or via an in vivo infection, increases cancer cell adhesion, migration and metastasis. TLRs thus represent a potential therapeutic target in bacterial infection facilitated cancer 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 1394. doi:1538-7445.AM2012-1394