bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5235: Uncovering tumor-host molecular and cellular interactions involved in tumor dormancy using microRNAs
Authors: Tiram Galia , Segal Ehud , Sherberk Roni , Bachar Gal , Ofek Paula , Udagawa Taturo , Edry Liat , Shomron Noam , Satchi-Fainaro Ronit 
Published: August 2012

Abstract
There is an increasing interest in elucidating the mechanisms of the earlier stages in tumor progression, the point at which a dormant tumor acquires the ability to grow and metastasize. Although the tumor dormancy phenomenon has important implications for early detection and treatment of cancer, its biology and genetic characteristics are poorly understood. microRNAs (miRs), small non-coding RNA molecules which regulate gene expression at the post transcriptional level, are emerging as key regulators in physiological and pathological processes, including tumorigenesis. We hypothesized that specific miRs may also play a key role in the regulation of tumor dormancy and the angiogenic switch. We therefore established a pair of cell lines that generate dormant avascular and fast-growing angiogenic osteosarcomas in SCID mice (Saos-2-D and Saos-2-E respectively). Although these cells share similar growth rate in vitro, when inoculated into mice, Saos-2-E cells establish vascularized and palpable tumors within one month, while Saos-2-D cells remain avascular and non-palpable for a year. Following our hypothesis, miR array of Saos-2-D and Saos-2-E cells, was performed. Several miRs that were differentially-expressed in the dormant versus fast-growing-tumor-forming cells were selected for further evaluation. Out of those miRs, miR200c and miR93 (representing either a mild or a substantial difference in the expression profile respectively) reverted cells forming fast-growing tumors to a dormant non-angiogenic phenotype, both in vitro and in vivo. Preliminary in vitro analysis of human brain, breast and prostate cancer cell lines revealed a similar phenotypic effect following overexpression of those miRs. We therefore propose that miR200c and miR93 play a role in the switch from dormancy. Further analysis on the target genes of those miRs is required in order to fully elucidate their role in tumor dormancy. Uncovering new molecular targets involved in the tumor dormancy phenomenon could provide important tools for novel dormancy-directed tumor therapy strategies.
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 5235. doi:1538-7445.AM2012-5235
Abstract 5238: Impaired angiogenesis as a hallmark of prolonged tumor dormancy in a mouse model of human glioblastoma
Authors: Ferber Shiran , Segal Ehud , Almog Nava , Satchi-Fainaro Ronit 
Published: August 2012

Abstract
Small sized, microscopic, non-invasive, avascular and therefore asymptomatic tumors can remain in their dormant stage for considerable period of time depending on numerous processes. One crucial mechanism underlying the transformation from a dormant phenotype to a fast-growing phenotype is the ability of the tumor cells to induce angiogenesis, a phenomenon termed as the “angiogenic switch”. Suspected dormant tumor-generating clone, derived from aggressive tumor-forming U-87 MG human glioblastoma cell line, was isolated using single-cell clone and identified by gene expression signature of dormant tumors (Almog et al., Cancer Research 2009). In order to evaluate the phenotypic differences between cell lines that generate dormant avascular tumors or fast-growing angiogenic tumors, we established a pair of mCherry-labeled human glioblastoma cell lines, U-87-D (Dormant) derived from the parental U-87-F (Fast-growing). While the two cell lines share similar growth rate in vitro, we found profound differences in tumor growth pattern when injected into mice. U-87-F established palpable and vascularized tumors only few days following inoculation, whereas U-87-D-generated tumors remained at a small size for more than 100 days. We further characterized both cell lines using migration, invasion and capillary-like tube formation assays in vitro. Major differences in invasiveness via a monolayer of human umbilical vein endothelial cells (HUVEC) were found. Furthermore, considerably increased number of tube-like structures formed from HUVEC were observed in the presence of U-87-F conditioned media (CM), compared with those formed in the presence of U-87-D CM. Similarly, HUVEC migration towards U-87-F CM was significantly higher compared with that towards U-87-D CM. Next, we utilized non-invasive intravital imaging to evaluate tumor progression, and non-invasive endo-microscopy imaging, as well as microbubbles contrast-enhanced ultrasound imaging, to track the blood flow within the tumor and blood vessels morphology at the tumor microenvironment. We concluded that the dormant and fast-growing tumors displayed distinct differences in their angiogenic potential leading to highly diverse tumor progression profiles when injected into mice.
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 5238. doi:1538-7445.AM2012-5238
Abstract 5241: Development of a single Listeria monocytogene-based vaccine simultaneously targeting two antigens
Authors: Wallecha Anu , Malinina Inga , Ramos Kimberly , Singh Reshma 
Published: August 2012

Abstract
Previously published studies reported that recombinant Listeria monocytogenes (Lm-LLO)-based vaccines expressing either tumor associated antigens (TAA) or angiogenesis associated antigens fused to an immunogenic fragment of listeriolysin O (LLO) have demonstrated efficacy in mouse models with several types of tumors such as lung, breast, prostate or melanoma. Therefore, we hypothesized that an Lm-LLO vaccine capable of delivering two disparate antigens with two different therapeutic mechanisms would likely have a synergistic effect on decreasing tumor growth by 1) targeting blood vessels, which may enhance effector T cell infiltration into the tumor and 2) improving the therapeutic efficacy of the vaccine. In addition, a dual vaccine construct creates a flexible platform for future use. The Lm-LLO-cHER2 vaccine was developed using a chimeric HER2/neu (cHER2) construct, and was found to regress tumors, elicit a strong T cell immune response and break immune tolerance towards the HER2/neu self-antigen in experimental animals. The Lm-LLO-VEGR2 vaccine has been shown to eradicate established breast tumors, reduce microvascular density, protect against tumor rechallange and metastases, and induce epitope spreading to various regions of the TAA such as HER2/neu. A dual Lm-LLO vaccine was developed that expresses and secretes both the VEGFR2 and cHER2 antigens as LLO-based proteins and is based on a highly attenuated Listeria monocytogenes backbone Lm Δ dal dat actA, which is cleared 48 hours post-injection in interferon gamma knock-out mice. Initial characterization of the dual vaccine indicates that the two antigens cHER2 and VEGFR2 are stably expressed and secreted after two in vivo mouse passages. Currently, we are evaluating the anti-tumor effects and antigen specific immune responses generated by the dual vaccine in mouse models. If successful, this dual vaccine may offer a new immunotherapy for the treatment of cancer in humans.
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 5241. doi:1538-7445.AM2012-5241
Abstract 5242: Pancreatic cancer cell type specific oxygen dependent growth and drug sensitivity
Authors: Gouw Arvin M. , Hsieh Annie L. , Le Anne , Maitra Anirban , Dang Chi V. 
Published: August 2012

Abstract
Most cell are cultured at 37°C, in 4% CO2 and 20% O2. Studies have shown that changing the temperature of the cell culture will lead to either cold shock or heat shock. Others have also shown that level of CO2 is crucial for pH balance in cell growth. Although cultured cells are exposed to 20% O2, oxygen tension in vivo is significantly lower in normal tissues ranging from 5 to 8% O2. Furthermore cancer tissues tend to be more hypoxic because of the poorly developed neo-vasculature. Hence, we sought to determine if pancreas cancer cells will grow and/or respond to drugs differently under 20% vs. 6% oxygen tension. Methods: Six pancreatic cancer cell lines were cultured in DMEM media with 10% FBS and 5% Penicillin in 4% CO2, 37°C with variable O2 conditions: 20% and 6%. Cells are plated onto 6-well plates. Triplicates of cells were trypsinized daily for 4 days for cell counts which was done by using hematocytometer. To test drug sensitivity, we used a known Lactate Dehydrogenase A (LDHA) inhibitor, FX11. LDHA inhibition has been shown to suppress tumor growth both in vitro and in vivo. Some cells were treated with an LDHA inhibitor, FX11 in varying concentrations: 5mM, 10mM and 20mM, while the controls were exposed to DMSO. Results: 1. Pancreas cancer cell lines E3, P215 and A6L grow better in 6% than in 20% oxygen level. 2. Pancreas cancer cell line A6L shows higher sensitivity to FX11 in 6% compared to 20% oxygen. 3. Pancreas cell line P215 shows lower sensitivity to FX11 in 6% compared to in 20% oxygen. Conclusion: The artificial nature of standard culture condition does not account for the significantly lower oxygen tension in vivo. Because cancer cell lines are established from tumors which tend to be hypoxic, measurements of cell growth rates and respond to therapeutic agents at 20% O2 may not reflect responses at 6% O2 and specifically not to in vivo conditions.
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 5242. doi:1538-7445.AM2012-5242
Abstract 5243: Reductions in hypoxia in the tumor microenvironment after Listeria monocytogenes-LLO based immunotherapy
Authors: Singh Reshma , Wallecha Anu 
Published: August 2012

Abstract
As a consequence of increasing growth and outpacing blood supply, tumors become hypoxic as they get larger, with the interior of the tumor becoming extremely hypoxic. This makes therapeutic immune responses difficult, as lymphocytes do not typically infiltrate the interior regions of large tumors due to the hypoxic nature of these tumors. Initial observations in preclinical studies after Listeria monocytogenes (Lm)-LLO based immunotherapy specifically targeted to the hypoxia marker CA9 show the hypoxic nature of the interior of the tumor microenvironment is altered. Initially the tumors are extremely hypoxic (as evidenced by HIF-1α and HIF-2α staining) however, after Lm-LLO-CA9 vaccination they show reduced expression of these hypoxic markers. This change in hypoxia is seen with irrelevant Lm vaccines that overexpress listeriolysin O (LLO) and also with Lm vaccines targeting CA9 fused to LLO: however the change is much more dramatic and complete in the case of the Lm-LLO-CA9 immunotherapy. The irrelevant Lm-LLO effect may be seen due to the fact that the irrelevant vaccine is actually specific for a tumor associated antigen being expressed by the tumor. This does limit the growth of the tumor and may not allow it to reach the same level of hypoxia as an untreated tumor. In current studies, an additional truly irrelevant Lm-LLO vaccine is being added to see if there is a truly Listeria-driven component to the hypoxic changes being observed. As compared to the naïve untreated tumors or an irrelevant Lm-LLO control, tumors treated with the CA9 Lm-LLO immunotherapy show an increase in lymphocyte infiltration into the interior areas of the tumor. Studies are underway to determine if this increase in infiltration has an impact on the regression of these tumors by combining the Lm-LLO-CA9 vaccine with a vaccine that is specific for a tumor associated antigen. In addition, the function of these infiltrating lymphocytes are being studied under normoxic and hypoxic conditions, to determine if the infiltrating cells are functional CTLs after the tumor's hypoxic levels change. Finally, studies are being conducted to determine the exact signaling mechanism involved in the hypoxic changes of the tumor microenvironment.
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 5243. doi:1538-7445.AM2012-5243
Abstract 5244: The Heme binding protein HRG-1 controls pH and enhances the invasive potential of cancer cells
Authors: Fogarty Fionola , Keeffe Jean O’ , Connor Rosemary O’ 
Published: August 2012

Abstract
The Heme regulated gene (HRG)-1 encodes a 16kD transmembrane protein that is induced by IGF-1 in transformed cells and is associated with the Vacuolar - (H+) ATPase (V-ATPase) protein complex. V-ATPases pump protons across the membrane of endosomal compartments or into the extracellular environment to regulate acidification. V-ATPase expression and activity at the plasma membrane of cancer cells has been associated with an invasive phenotype. We previously showed that HRG-1 is essential for V-ATPase activity in endosomal acidification, so therefore we hypothesised that HRG-1 may also regulate extracellular pH to enhance cancer cell invasion. To test this we investigated HRG-1 expression in phenotypically distinct cancer cell lines and investigated whether it is required for V-ATPase- mediated extracellular acidification. We found that in highly invasive and migratory cell lines HRG-1 and the a1 subunit of the V-ATPase are both expressed at the plasma membrane. In less-aggressive cancer cells and in non transformed cells HRG-1 is not expressed at the cell membrane, and is restricted to the endocytic pathway. To investigate whether HRG-1 is required for V-ATPase function at the plasma membrane we stably over-expressed HRG-1 (HA-HRG-1) and empty vector (HA-EV) in MCF-7 cells and measured proton extrusion. MCF-7/HA-HRG-1 cells exhibited a greater effect on lowering the pH of the extracellular milieu compared to empty vector control cells and also exhibited a concomitant increase in cytosolic pH. The observed extracellular pH change in MCF-7/HRG-1 cells could be suppressed by the V-ATPase inhibitor Bafilomyocin A, demonstrating that this effect is V-ATPase dependent. We also observed that the expression level and activity of matrix metalloproteinase-2, a pH dependent degrading protease whose expression can be correlated with metastatic potential, was increased in MCF-7/HA-HRG-1 cells compared with control cells. Taken together, our findings suggest that HRG-1 expression at the plasma membrane of cancer cells enhances V-ATPase activity and this facilitates cell migration and invasion. Thus HRG-1 may be a suitable cell surface target for selectively disrupting V-ATPase activity and the invasive potential of cancer cells.
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 5244. doi:1538-7445.AM2012-5244
Abstract 5248: A novel ovarian cancer imaging agent based on integrin ligation
Authors: Swenson Stephen D. , Li Zibo , Minea Radu , Markland Francis S. 
Published: August 2012

Abstract
Ovarian cancer diagnosis and subsequent evaluation of disease progression is difficult due to the location of tumor mass and access to the organs affected. Ultrasound and surgical exposure are required to confirm disease and response to treatment. In an effort to develop a non-invasive radiologic method for both diagnostic assessment and to follow disease progression we have produced a integrin ligand, vicrostatin (VCN) that can be radiolabeled and imaged upon binding to active integrins over-expressed on the tumor. VCN displays a high affinity for integrins which are active and pivotal in tumor growth and progression. In the present studies we utilized an animal model employing the luciferase expressing cell line OVCAR-3luc. This procedure allows us to observe both the tumor itself in a living animal, and also co-register the PET image with the optical image enabling us to detect tumors in the intraperitoneal (IP) space. For these experiments we injected OVCAR-3luc cells IP and allowed the tumors to age for 28 days. At this point, with no obvious sign of disease, we imaged the tumors using the optical imaging system to detect the presence of luciferase. Since luciferase is only found in the tumor, this enables us to specifically image the tumor. Following these images 64Cu-DOTA-VCN is injected into the tail vein of the study animals and allowed to circulate for 90 minutes. At this time the animal is placed onto the mounting tray of the PET imaging instrument. There is a specific accumulation of 64Cu-DOTA-VCN in an area in the lower abdomen that correlates with a location of luciferase activity seen in the optical image. Both of these positions were confirmed by dissection and exposure of the tumor in the sacrificed animal. Experiments in which a larger number of cells are injected IP produced unusable optical images, as the tumors grew very large and coated much of the surface in the IP space yielding bright and indistinguishable images in the mouse abdomen. One problem of note is the high level of uptake by the kidneys at the 90 minute time point. The kidneys shield the ability to view an ovarian tumor via a dorsal or ventral total slice view. When viewed transversely, there is clear separation between the kidneys and the tumor mass which binds the 64Cu-DOTA-VCN. A three dimensional reconstruction yields a three dimensional model that can be rotated and rendered to observe the position of the tumor in relationship to the kidneys in space. These studies show that VCN can be utilized to image early stage OC and could possibly be used to monitor residual disease after surgical or therapeutic intervention.
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 5248. doi:1538-7445.AM2012-5248
Abstract 5250: Optimization of an orthotopic mouse model for in vivo fluorescent uPA imaging in breast cancer
Authors: Ides Johan , Wouters An , Messagie Jonas , Vangestel Christel , Pauwels Bea , Joossens Jurgen , Veken Pieter Van der , Augustyns Koen , Peeters Marc , Lardon Filip 
Published: August 2012

Abstract
The urokinase plasminogen activator (uPA) system is one of the serine protease systems involved in extracellular matrix degradation, which will facilitate tumor cell invasion and intravasation. Recently, the Medicinal Chemistry group of the University of Antwerp (UAMC) developed some very selective covalently binding uPA inhibitors. Besides its function as possible therapeutic target, uPA and its endogenous inhibitor PAI-1 are described as prognostic biomarkers for breast cancer with the highest level of evidence. Commercial ELISA and PCR kits are available for the screening of uPA in breast tumors. These ex vivo assays measure or predict the total uPA content (active and inactive). We present here a more advanced technique, which will be able to monitor the actual enzymatic uPA activity in a non-invasive manner. The technology is based on the modification of the UAMC inhibitors towards activity based probes containing a fluorescent label. Currently, we are evaluating these probes as imaging tools for uPA monitoring. The developed imaging probes will be profoundly tested in an orthotopic model of human MDA-MB-231 and MCF7 breast cancer cells since these cell lines show a high and low uPA expression respectively. We will use these models to study the potential beneficial characteristics of activity based probes in the field of bio-imaging applications targeted to uPA as a validated biomarker. The current protocol, which is still under evaluation, can be described as followed: Cell suspensions (2.106 cells/100μl) of each cell line were implanted in the mammary fat pads at both flanks of 7 mice, alternatively with and without Matrigel. Tumor size was monitored using bioluminescent imaging (BLI) and caliper measurements. When the tumor volume reached 200 - 400mm3, the rhodamine labeled uPA-inhibitor (uPA-probe) was administered (0.3 mg / kg i.v.). Fluorescent images were taken at 1, 2, 4, 6, 8, 12, 24 and 48 hours after injection. At 48 hours, the mice were sacrificed and the tumor, liver and lung were excised for ex vivo bioluminescent or fluorescent imaging and stored for histological examination. In this presentation, we describe the evaluation of the model and the first promising results. Considering the role of uPA in migration and invasion, the uPA-probe will also be tested in the future for the detection of micrometastases.
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 5250. doi:1538-7445.AM2012-5250