bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1518: Gene expression profiling reveals acidosis/GPR4-induced inflammatory responses in vascular endothelial cells
Authors: Dong Lixue , Castellone Reid D. , Chi Jen-Tsan , Yang Li V. 
Published: June 2012

Abstract
Due to deficient blood perfusion, hypoxia, and glycolytic metabolism, acidic tissue microenvironments commonly exist in solid tumors, inflammation, and many other pathological conditions. However, the molecular mechanisms by which cells respond to acidic microenvironments are not well understood. GPR4 has recently been identified as a novel proton-sensing receptor expressed in endothelial cells, cancer cells, and other cell types. GPR4 is activated by acidic extracellular pH but has lower activation at the physiological pH 7.4 and minimal activation at more alkaline pH. To delineate the function and signaling pathways of GPR4 in endothelial cells under acidic conditions, we performed gene expression microarray analyses. Primary human umbilical vein endothelial cells (HUVEC) that express endogenous GPR4 were stably transduced with the MSCV-IRES-GFP control vector (designated as HUVEC/Vector cells) or the MSCV-GPR4-IRES-GFP construct (designated as HUVEC/GPR4 cells). HUVEC/Vector and HUVEC/GPR4 cells were treated with pH 6.4 (400 nM H+) for 5 hours to activate GPR4 or with pH 8.4 (4 nM H+) as a negative control. RNAs were isolated, labeled, and hybridized with the Agilent Whole Genome Microarray Chip to compare gene expression. The results demonstrated that the acidic pH treatment of HUVEC/Vector cells stimulated the expression of a number of inflammatory genes, which represent a predominant signature in the microarray dataset. The induction of most of the acid-responsive inflammatory genes were further enhanced by GPR4 overexpression in HUVEC/GPR4 cells at pH 6.4, suggesting these genes are responsive to varying levels of GPR4 signaling. The inflammatory genes with substantial up-regulation by acidosis/GPR4 include chemokines, cytokines, adhesion molecules, genes involved in the TNFα and NF-κB pathways, prostaglandin-endoperoxidase synthase, and EGR transcription factors. The up-regulation of the genes at pH 6.4, compared to pH 7.4 and pH 8.4, was further confirmed by real-time RT-PCR. Taken together, our results show that activation of GPR4 by acidosis stimulates the expression of a wide range of inflammatory genes in endothelial cells. Since the inflammatory response of endothelial cells is important for blood vessels to interact with immune cells and tumor cells in the microenvironment, the acidosis/GPR4 signaling may play a role in the processes such as tumor immunity and 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 1518. doi:10.1158/1538-7445.AM2011-1518
Abstract 1551: Soluble tissue transglutaminase modulates cellular adhesion to matrix and peritoneal metastasis in ovarian cancer
Authors: Yakubov Bakhtiyor , Chelladurai Bhadrani , Turchi John , Matei Daniela E. 
Published: June 2012

Abstract
Background: Tissue transglutaminase (TG2) is a secreted protein that binds fibronectin (FN) and exerts protein transamidating activity in the presence of Ca2+. We previously reported that TG2 is upregulated in ovarian cancer (OC) cells and enhances intraperitoneal (ip) metastasis. TG2 is secreted abundantly in OC ascites, yet the function of soluble (s) TG2 remains unknown. We hypothesized that sTG2 acts as a permissive factor in the ECM by promoting cancer cell proliferation and adhesion to the matrix.
Materials and Methods: Recombinant his6-tagged full length human TG2 and its inactive enzymatic mutant C277S were purified by immobilized metal (Co2+) affinity and anion exchange chromatography. OV90 and A2780 OC cells that do not express endogenous TG2 were used. Solid phase adhesion assay measured adhesion to ECM proteins, MTT assay measured cell proliferation and an ip xenograft model quantified tumor formation and metastasis.
Results: S-TG2 enhanced cell adhesion to FN (p = 0.01) and vitronectin (VN, p = 0.01), but not to collagen and laminin. A neutralizing antibody to α5β1 and to αVβ3 blocked sTG2 induced cell adhesion to FN or to VN, respectively, suggesting that sTG2 modulates cell interaction with the matrix via integrins. Digestion of FN with matrix metallo-proteinase 2 blocked OC cell adhesion to digested fragments of FN, while addition of sTG2 restored OC cells’ binding to this protease-digested matrix (p = 0.02). This suggests that the soluble enzyme may facilitate the interaction of OC cells with a protease-remodeled matrix remodeled, similar to the tumor ECM. Enzymatically inactive soluble C277S TG2 enhanced OC cell adhesion to FN to the same extent as wild type TG2. In contrast, an antibody raised against the FN-binding domain of TG2 blocked sTG2 induced OC cell adhesion to FN (p =0.01). These data suggest that the interaction between TG2 and FN, but not the transamidating activity, is important to sTG2-mediated cell interaction with the ECM. When added to conditioned media, sTG2 (2.5ug/mL) increased OC cell proliferation by 20% (p = 0.01). Biweekly ip inoculation of 2.5ug sTG2 increased peritoneal dissemination of OV90 cells in nude mice (11.38 vs. 27.75, p = 0.02), but did not affect tumor volume (412.3 vs. 578.2 mm3, p = 0.34).
Conclusions: These data demonstrate that sTG2 increases OC cell adhesion to the ECM and peritoneal metastasis. The key mechanism involved in this process is the interaction between sTG2, FN, and integrins.
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 1551. doi:10.1158/1538-7445.AM2011-1551
Abstract 1557: Tumor Galectin-1 mediates lung cancer growth and metastasis through immunoregulation of T-cell apoptosis
Authors: Banh Alice , Zhang Jing , Cao Hongbin , Bouley Donna , Kwok Shirley , Kong Christina , Giaccia Amato , Koong Albert , Le Quynh-Thu 
Published: June 2012

Abstract
Studies have shown that Galectin-1 (Gal-1), a carbohydrate-binding protein whose secretion is enhanced under hypoxia, can promote tumor aggressiveness through its effect on angiogenesis and T-cell apoptosis. However, the importance of tumor versus host Gal-1 in tumor progression is unclear. Using matched Gal-1 wild-type and null mice together with Lewis lung carcinoma cells stably knocked-down of Gal-1 (shGal-1) or scramble control (Scr), we show that tumor Gal-1 is more critical that host Gal-1 in promoting tumor growth and spontaneous metastasis. Scr tumors had higher growth and metastasis rates compared to shGal-1 tumors, regardless of the host genotype. The enhanced growth and metastasis associated with Gal-1 appears to be related to its immunomodulatory function since it was abolished in immune-deficient mice. In contrast, angiogenesis, as assessed by microvessel density count, was similar between shGal-1 and Scr tumors when they were allowed to reach comparable size. These data indicated that tumor Gal-1 is more important than host Gal-1 in mediating tumor progression and that its effect was exerted through intratumoral T-cell modulation. These findings have broad implications in developing novel targeting strategies for Gal-1 in 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 1557. doi:10.1158/1538-7445.AM2011-1557
Abstract 1565: API 31510 as a potential agent in management of CNS leukemia
Authors: Narain Niven R. , Mauro Lucia M. , Perez Paula P. , Caperton Caroline V. , Sarangarajan Rangaprasad , Jimenez Joaquin J. , McCook John P. 
Published: June 2012

Abstract
Infiltration of cancer cells into the cerebrospinal milieu remains a challenge to oncologists. Thus, prophylactic therapy to avoid CNS tumors is now standard of care to avoid the development of tumors in the central nervous system (CNS). Despite the advances in oncological care, this issue remains poorly understood. In this regard, we have created a model of CNS chloroleukemia using Fischer 344 rats, in which chloroleukemic cells were injected when they are newborns and lipopolysaccharide (LPS) is given as a first-line of treatment. The cure rate with this regimen is 50%, and approximately 10% of survivors develop CNS leukemia as judged by their motor skills and the presence of quadriplegia and paraplegia. For this study, we injected 2400 Fischer 344 neonates with MIAC51 and treated them with LPS. All animals with overt signs of leukemia were sacrificed by day 26. By day 35, survivors started exhibiting CNS abnormalities. Of that cohort, we selected 150 animals with hind leg paraplegia on day 40. These animals were then re-randomized into 5 groups: group 1 received no treatment, group 2 received excipient control IV, group 3 received 5mg/kg API 31510 IV, group 4 received 25mg/kg IV, and group 5 received 100 mg/kg IV for 4 weeks, 3 times daily. Rats in groups 1, 2, 3 and 4 did not exhibit any signs of improvement and were sacrificed due to metastatic malignancy. These findings were recorded by MRI positive for tumor cells. In sharp contrast, animals injected with 100mg/kg IV exhibited a significant recovery of their motor skills and regained their ability to walk. MRI distinctly shows the lack of tumor cells in this group. Taken together, these results strongly indicate that API 31510 may provide a cure for CNS leukemia and may also be an effective prophylactic agent to prevent the extravasation of leukemic cells into the CNS.
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 1565. doi:10.1158/1538-7445.AM2011-1565
Abstract 1570: Thermal ablation improves oxygenation in remaining viable tumor
Authors: Griffin Robert J. , Przybyla Beata D. , Pagan Jonathon D. , Chen Xin , Shafirstein Gal , Webber Jessica S. , Moros Eduardo G. 
Published: June 2012

Abstract
To increase the use and effectiveness of thermal therapy of various solid cancers, it is necessary to understand how tumor remaining viable after ablation responds and repairs. Tumor oxygenation and angiogenesis are critical for tumor recurrence and therefore we are studying the changes in tumor oxygenation and migration pattern of endothelial progenitor cells (EPCs), one component of angiogenesis, after local thermal ablation of tumors in mice. Tumor cells in sublethal ablation zones may release a unique set of chemokines in an attempt to attract cells to repair and regrow the tumor. The location and mechanisms by which these cells are recruited to the tumor may be distinct from other methods of thermal therapy which suggests that specific targets to improve ablation outcomes may be identified. If the oxygenation is changed in tumor that remains viable after ablation, concomitant application of chemotherapy or radiation therapy may be an effective way to improve tumor control. Murine FSaII fibrosarcoma and 4T1 breast carcinoma tumors were ablated with a conductance probe or high intensity ultrasound at an average peak temperature of 60-90C for 1.5 min. One group of mice was immediately injected IV with near infrared emitting indocyanine green (ICG)-labeled EPCs, while the other group was injected with EPCs labeled with a stable in situ dye (PKH). The mice injected with ICG-labeled EPC were optically imaged at various time points up to 72 hours. These images were then compared to those of untreated tumors to observe the migration patterns of EPC in mice that had received HIFU ablation. In other mice, pimonidazole was injected 72 h post ablation and tumors were excised and stained for pimonidazole adducts as evidence of hypoxia. We routinely ablated approximately 50% of tumor tissue, leaving the other 50% peripheral tumor tissue viable. We were able to detect an increased amount of ICG signal in the tumor that received ablation ablation, when compared to controls. Histological examination revealed the presence of EPC cells in the tumor after ablation, while the control showed no signs of EPC presence. The tumor oxygenation in viable tissue after ablation was found to increase from control tumors where 27% of the tumor was pimonidazole positive to only 5% in thermally ablated tumors. The role of endothelial progenitors and tumor oxygenation changes in overall tumor response to ablation alone and combined with other modalities is being actively studied by our group. This work was supported by NIH grant CA44114 and Central Arkansas Radiation Therapy Institute.
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 1570. doi:10.1158/1538-7445.AM2011-1570
Abstract 1610: Predicting NSCLC outcomes based on tumor growth in SCID mice
Authors: Hennon Mark W. , Hylander Bonnie , Morrison Carl , Miller Austin , Groman Adrienne , Dexter Elisabeth , Yendamuri Sai , Demmy Todd L. , Adjei Alex , Reid Mary , Repasky Elizabeth , Nwogu Chukwumere 
Published: June 2012

Abstract
Background. Xenograft models of non-small cell lung carcinoma (NSCLC) in immunodeficient mice have played an important role in the study of new chemotherapeutic regimens, including targeted agents. We hypothesize that the success of human tumor implantation in severe combined immune-deficient (SCID) mice will correlate with the observed clinical outcomes in patients with resected NSCLC. Such growth in mice may reflect the aggressiveness of human tumors.
Methods. 196 lung cancer specimens from 193 patients who underwent surgical resection of NSCLC from June 1995 to June 2010 were implanted subcutaneously in (SCID) mice. Mice were observed for a period of six months to assess the success of tumor implantation. This was determined by the growth of tumors from 2-3 mm to 10 mm in diameter. Overall and disease free survival in patients were reviewed and were correlated with tumor growth in SCID mice.
Results. Median overall and disease free survival in patients with successful tumor implantation in SCID mice was 16.3 months and 4.2 months vs. 38.6 and 20.6 months for patients whose tumor did not grow (logrank p = 0.0039 and 0.0024 respectively.) Half of all patients whose tumor successfully grew in SCID mice recurred or died within twelve months.
Conclusions. Success of tumor implantation in SCID correlates with worse clinical outcome in patients with NSCLC. This model can be expanded to evaluate the predicted response of specific tumors to novel chemotherapeutic or molecularly targeted agents.
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 1610. doi:10.1158/1538-7445.AM2011-1610
Abstract 1616: The OPCML tumor suppressor negatively regulates a specific repertoire of 5 receptor tyrosine kinases via a novel proteasomal mechanism, and its recombinant derivative is a potent in-vivo anticancer protein therapy
Authors: McKie Arthur B. , Vaughan Sebastian , Okon Imoh , Wong Joshua L.C. , Zanini Elisa , Lam Eric W-F , Chayen Naomi E. , Gabra Hani 
Published: June 2012

Abstract
OPCML, a GPI anchored tumor suppressor gene is inactivated by somatic methylation in multiple cancers. We previously identified this gene by LOH mapping and demonstrated that it was inactivated by somatic methylation in 80% of ovarian cancers. Restoring OPCML expression by stable transfection suppressed in-vitro growth and in-vivo tumorigenicity. We hypothesized that OPCML might abrogate growth signaling pathways. In SKOV-3 and PEO1, ovarian cancer cell lines with no expression of OPCML, we demonstrated that OPCML negatively regulates a specific repertoire of receptor tyrosine kinases (RTKs) EPHA2, FGFR1, FGFR3, HER2 and HER4, and reciprocally, OPCML siRNA knockdown in normal ovarian surface epithelial cells up-regulates these same RTKs, with no effect on RTKs EPHA10, FGFR2, FGFR4, EGFR, HER3, VEGFR1 and VEGFR3. Example immunoprecipitation experiments revealed that OPCML binds to EphA2, FGFR1 and HER2 extracellular domains with no such interaction to EGFR, thus OPCML binds directly to RTKS that it negatively regulates. We demonstrate that OPCML is located exclusively in the raft membrane fraction and sequesters RTKs that it binds to the raft fraction, leading to polyubiquitination and proteosomal degradation via a cav-1 endosomal mechanism resulting in systems depletion of this specific RTK repertoire, that does not occur with RTKs that OPCML does not bind. We demonstrate that OPCML abrogates EGF mediated phosphorylation of FGFR1, HER2 and EGFR and the downstream phosphosignaling of pErk and pAKT. A recombinant modified OPCML-like protein without a GPI anchor, signal peptide or glycosylation was constructed and expressed in E.Coli. This rOPCML tumor suppressor protein therapeutic caused growth inhibition by apoptosis in 6/7 ovarian cancer cell lines tested with no effect on OPCML expressing normal ovarian surface epithelium by an identical mechanism to the transfected normal protein. rOPCML was then injected intraperitoneally twice weekly in two murine intraperitoneal models of ovarian cancer (nude mouse A2780 and SKOV3) and demonstrated profound inhibition of tumour weight, ascites volume and peritoneal dissemination compared with BSA control. In Summary, the OPCML tumour suppressor mediates its suppressor function by systems level negative regulation of at least 5 RTKs and a recombinant modified derivative is a potent tumor suppressor protein therapeutic in-vitro and in-vivo.
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 1616. doi:10.1158/1538-7445.AM2011-1616
Abstract 1621: The proprotein convertase PCSK1 is a novel drug target in alveolar soft part sarcoma (ASPS)
Authors: Vistica David T. , Kenney Susan , Scudiero Dominic A. , Reinhart Russell A. , Selby Michael H. , Butcher Donna O. , Shoemaker Robert H. 
Published: June 2012

Abstract
Proprotein convertases (PCs) are a family of calcium-dependent serine endoproteases which mediate the proteolytic cleavage, at pairs of dibasic amino acids, of many precursor proteins, including growth factors and pro-hormones, into their functionally active forms. One family member, PCSK1, was identified as a potential therapeutic target in ASPS. This was based on gene expression profiling of 4 primary and 3 metastatic ASPS tumors (BMC Cancer 9:22, 2009). Affymetrix 133 Plus 2 arrays revealed that PCSK1, but not PCSK2 or furin, was significantly up-regulated (range 18.6 to 131 fold) relative to universal RNA, a multi-organ pool of non-tumor RNA's. PCSK1 expression was confirmed by immunohistochemistry and Western Blot analysis in patient tumors, in an ASPS xenograft model, and in a cell line developed from the xenograft tumor (ASPS-1; J Pediatr. Hematol. Oncol., in press 2010) as well as in tumors produced by ASPS-1 in immunocompromised mice. ASPS-1 was utilized, in-vitro, to evaluate a panel of PCSK1 siRNA's, the most potent of these produced a 75% reduction in the PCSK1 RNA transcript, reduced expression of PCSK1 protein and produced a 50% reduction in ASPS-1 growth. As part of an effort to develop new therapeutic approaches toward the treatment of ASPS we have implemented a high-throughput screening effort to identify small molecule inhibitors of PCSK1. Utilizing recombinant PCSK1 and the fluorescent substrate (Pyr-Arg-Thr-Lys-Arg-MCA) a high-throughput screen of a small molecule library (∼15 K compounds) was initiated. Results of a pilot screen of ∼2400 compounds at concentrations ranging from 0.1 to 100 uM yielded several inhibitors of PCSK1 which were retested in a 20 concentration assay to confirm activity. Preliminary analysis of structure-activity relationships identified several active inhibitor chemotypes, comparable in potency to the known peptide PCSK1 inhibitor, Ac-Leu-Leu-Arg-Val-Lys-Arg-NH2, containing aryl groups linked by aliphatic chains containing peptide bonds. Such compounds may act as substrate mimetic inhibitors and will be further evaluated for inhibition of growth of ASPS-1.
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 1621. doi:10.1158/1538-7445.AM2011-1621
Abstract 1627: Proteome-wide analysis of echinoderm microtubule associated protein like 4 – anaplastic lymphoma kinase (EML4-ALK) network in lung cancer
Authors: Zhang Guolin , Chen Ann , Song Lanxi , Fu Jianing , Kinose Fumi , Bai Yun , Fang Bin , Li Jiannong , Eschrich Steven , Koomen John , Haura Eric 
Published: June 2012

Abstract
The translocation of echinoderm microtubule associated protein like 4 – anaplastic lymphoma kinase (EML4-ALK) defines a unique, new subset of patients with non small cell lung cancer (NSCLC). It represents a novel diagnostic biomarker and therapeutic target for NSCLC. PF 02341066 is a ALK small tyrosine kinase inhibitor that has demonstrated high clinical activity in EML4-ALK- positive NSCLC patients. We sought to characterize the signaling network used by EML4-ALK and reveal potential new therapeutic targets. We used tandem affinity purification (TAP) and liquid chromatography-mass spectrometry (LC-MS/MS) to map protein-protein interactions and anti-phosphotyrosine immunoprecipitation coupled with LC-MS/MS to map tyrosine phosphorylation. We selected the human NSCLC H3122 cell line for our studies as it is sensitive to PF 02341066 and harbors ELM4-ALK. Quantitative western blotting results show that activities of MET, ALK, AKT, ERK and STAT3 were inhibited by treatment with PF 02341066. Proteome-wide analysis of tyrosine phosphorylation of the ALK signaling pathway were examined. In total, 311 tyrosine phosphorylated proteins (487 unique phosphorylated sites) were identified. Of those, 73 pTyr sites (62proteins) were upregulated and 78 pTyr sites (58 proteins) were downregulated by 1uM PF02341066. Using TAP, we identified 13 proteints interacting with EML4-ALK including GRB2 and SHC1. Core interactions were verified by coupling of immunoprecipitation to Western blot and mass spectrometry. A comprehensive physical ALK network was generated by integrating both phosphoproteomic data and interactional partners using pathway analysis algorithms. Two adaptors, SHC1and GAB2, are suggested as the first outlets of signaling propagation from ALK. Other sublevels directly connected with ALK may allow further understanding the mechanism of ‘ALK addiction’. A sub-network composed of 35 cell death associated proteins was created. An ongoing functional analysis including siRNA and small inhibitor screen on this small network should validate druggable targets. This network approach has potential translational applications to identify novel approaches to treatment of ALK addicted lung cancers and could be useful in patients with acquired resistance to ALK inhibitors.
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 1627. doi:10.1158/1538-7445.AM2011-1627