bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4931: Inhibitor of DNA binding 4 (Id4) suppresses MMP2 mediated invasion of glioblastoma-derived cells by direct inactivation of twist-1 function.
Authors: Rahme Gilbert J. , Israel Mark A. 
Published: August 2014

Abstract
Invasion of normal tissues by high grade glioma is a key aspect of increased morbidity and mortality associated with these tumors. Malignant glioma comprise over 70% of primary brain tumors with a median survival ranging from 12 to 15 months for patients with glioblastoma multiforme (GBM), the highest grade of glial tumors. Inhibitor of DNA binding (Id) genes are highly expressed in development and tumorigenesis and some members (Id1, Id2 and Id3) have been linked to increased tumor invasion. In sharp contrast to these members of the Id gene family, we found that Id4 expression in GBM-derived cells decreased invasion in in vitro assays. Results of gain-of-function and loss-of-function experiments indicated that Id4 expression decreased GBM invasion and suppressed a gene, matrix metallo-protease 2 (MMP-2), which encodes a proteolytic enzyme key for the destruction of glial tumor extracellular matrix. Western blot and zymography analysis demonstrated that conditioned media from Id4 expressing cells had low levels of pro-MMP2 and cleaved MMP2. An antibody that is known to inactivate MMP-2 was used to demonstrate that MMP2 accumulated in media conditioned by Id4 deficient cells was sufficient to rescue the invasive activity lost in cells expressing high levels of Id4. These findings confirmed that MMP2 suppression by Id4 is responsible for the decrease in invasion observed in Id4 expressing glioma cells.
Twist-1 is a well described mediator of invasion. Co-IP and co-localization studies demonstrated an interaction suggesting a direct inhibition of Twist-1 by Id4. Other data indicate that Id4 also blocks Twist-1 induced transcription of MMP2. Importantly, Twist-1 overexpression can rescue the invasion defect induced by Id4 expression, providing further support that the Id4/Twist-1 interaction mediates the function of Id4 in suppressing GBM invasion. Analysis of The Cancer Genome Atlas (TCGA) data indicated a significantly better survival and prognosis for GBM patients with high Id4 expression (Z&gt;1) suggesting that Id4 could have an important role in the survival of GBM patients. Our data provide strong evidence demonstrating that Id4 suppresses GBM invasion by inhibiting Twist-1 induced expression of MMP2. To our knowledge, this is the first report of an Id protein acting as an inhibitor of invasion rather than mediating the pro-invasive functions of the other Id-gene family members.
Citation Format: Gilbert J. Rahme, Mark A. Israel. Inhibitor of DNA binding 4 (Id4) suppresses MMP2 mediated invasion of glioblastoma-derived cells by direct inactivation of twist-1 function. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4931. doi:10.1158/1538-7445.AM2013-4931
Abstract 4933: Functional properties of PPFIA1, located at the 11q13 amplification region, in epithelial cancer cells.
Authors: Pehkonen Henna , Lepikhova Tatiana , Louhimo Riku , Peitsaro Nina , Imai Misa , Martinez Rafael , Kleftsröm Juha , Hautaniemi Sampsa , Monni Outi 
Published: August 2014

Abstract
PPFIA1 (liprin α1) is a member of the liprin (LAR protein-tyrosine phosphatase-interacting protein) family and is located at the 11q13 amplification region, which is one of the most common amplicons in multiple epithelial cancers. In squamous cell carcinoma of head and neck (HNSCC), this amplification occurs in 30-50% of the cases. In epithelial cancers, the size and structure of 11q13 amplicon is complex and consists of multiple amplicon cores that differ between different tumor types. In HNSCC, the amplicon core contains 10 genes that are amplified in cases with 11q13 amplification. This region contains well-established oncogenes, such as CCND1 and CTTN (cortactin), yet the role of several genes in this region is unknown. Our aim is to study the role of PPFIA1, which has recently been found to be involved in cell motility, modeling of the cell edge dynamics and axon guidance. PPFIA1 is amplified and overexpressed in several epithelial cancers, but the role of it is controversial. PPFIA1 is required for breast and cervical cancer cell invasion, but in contrast depletion of it results in increased invasion of HNSCC cells. We have overexpressed liprin α1 and cortactin in HNSCC cells with no 11q13 amplification and related phenotypes have been analysed in in vitro assays. Migration assays using matrigel coated inserts have shown that overexpression of cortactin increases invasive properties of the HNSCC cells with no 11q13 amplicon whereas liprin α1 has an opposite effect. We have also shown that liprin α1 localizes with cortactin in same vesicular structures, but they do not show physical interaction. Our aim is now to explore the molecular mechanisms behind these findings to assess the role of liprin α1 in vesicular transport and cell motility. We are also carrying out immunoprecipitation and mass spectrometry analyses to identify novel interaction partners for this protein. Our study will provide novel information on the potential specialized functions of liprin α1 in different epithelial cancers, which is likely to improve our understanding on the functional role of 11q13 amplification in malignant potential of cancer cells.
Citation Format: Henna Pehkonen, Tatiana Lepikhova, Riku Louhimo, Nina Peitsaro, Misa Imai, Rafael Martinez, Juha Kleftsröm, Sampsa Hautaniemi, Outi Monni. Functional properties of PPFIA1, located at the 11q13 amplification region, in epithelial cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4933. doi:10.1158/1538-7445.AM2013-4933
Abstract 4934: The role of Aurora A kinase-dependent phosphorylation of cortactin in invadopodia formation.
Authors: Kozyreva Varvara K. , Kelley Laura , McLaughlin Sarah L. , Pugacheva Elena N. 
Published: August 2014

Abstract
Aurora A kinase (AURKA) is a serine/threonine kinase known for its critical role in regulation of cell cycle progression. Overexpression and activation of AURKA is implicated in development of multiple types of human cancer. AURKA upregulation is considered as independent prognostic marker for breast cancer patients and associated with poor survival outcome. Recent work by our laboratory and others suggests a new role for AURKA in promotion of tumor cells migration and invasion through regulation of actin dynamics. However, the specific manner in which AURKA regulates actin-based machinery of migrating cancer cells is unknown. In our current work we show that phosphorylation of cortactin (CTTN) by AURKA directly regulates actin dynamics in breast cancer cells. CTTN is known to be regulated by oncogenic Src kinase. This phosphorylation is pivotal for formation of free barbed ends and further actin polymerization. Dynamic polymerization/depolimerization is required for invasion of cancer cells. Thus inhibition of Src-dependant phosphorylation of CTTN is critical for invadopodia maturation. In our current work we identify the phosphorylation site on CTTN targeted by AURKA and show that phosphorylation of CTTN by AURKA could potentially inhibit further phosphorylation of CTTN by Src leading to stabilization of invadopodia. Inhibition of AURKA activity or depletion of AURKA in cancer cells led to decrease in invasion and invadopodia maturation. In addition, we showed that adaptor protein NEDD9 which is known to bind both AURKA and Src also binds to CTTN and therefore potentially can mediate Src-CTTN-AURKA complex formation that regulates the sequential phosphorylation events necessary for invadopodia genesis. It is our expectation that AURKA-phosphorylated CTTN will inhibit Src-driven tyrosine-phosphorylation of CTTN, regulating a mechanistic switch between complementary actin polymerization and actin stabilization programs.
Citation Format: Varvara K. Kozyreva, Laura Kelley, Sarah L. McLaughlin, Elena N. Pugacheva. The role of Aurora A kinase-dependent phosphorylation of cortactin in invadopodia formation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4934. doi:10.1158/1538-7445.AM2013-4934
Abstract 4947: Inhibition of Rapamycin induced AKT activation elicits differential anti-tumor response in head and neck cancers.
Authors: Radhakrishnan Padhma , Baraneedharan Ulaganathan , Dhandapani Muthu , Thyakumar Allen , Pinto Dency , Prasath Arun , Velu Ayyappan , Kamal A , Brijwani Nilesh , Nair Rohini , Basavaraja R , Jain Misti , Thiyagarajan Saravanan , Majumder Biswanath , Sundaram Mallik , Narayanan Prasad , Kekatpure Vikram D. , Majumder Pradip K. 
Published: August 2014

Abstract
The PI3K/AKT/mTOR pathway is an important signaling axis that is perturbed in majority of cancers. Biomarkers such as pS6RP, GLUT1 and tumor FDG uptake are being evaluated in patient stratification for mTOR pathway inhibitors. In the absence of a clear understanding of the underlying mechanisms in tumor signaling, the biomarker strategy for patient stratification is of limited use. Here, we show that no discernible correlation exists between FDG uptake and the corresponding Ki67, GLUT1, pS6RP expression in tumor biopsies from Head and Neck Cancer (HNC) patients. Correlation between GLUT1 and pS6RP levels in tumors was observed but elevated pS6RP was noticed even in the absence of concomitant AKT activation, suggesting other downstream molecules of PI3K/AKT and/or other pathways upstream of mTOR, are active in these tumors. Using an ex-vivo platform, we identified putative responders to Rapamycin, an mTOR inhibitor in these tumors. However, Rapamycin did not induce anti-tumor effect in the majority of tumors with activated mTOR, potentially attributable to the observation that Rapamycin induces feedback activation of AKT. Accordingly, treatment of these tumors with an AKT inhibitor and Rapamycin uniformly resulted in abrogation of mTOR inhibition induced AKT activation in all tumors but failed to induce anti-tumor response in a subset. Phosphoproteomic profiling of tumors resistant to dual AKT/mTOR inhibitors revealed differential activation of multiple pathways involved in proliferation and survival. Collectively, our data suggest that in addition to biomarker based segregation, functional assessment of patient tumor prior to treatment with mTOR/AKT inhibitors might be useful for patient stratification.
Citation Format: Padhma Radhakrishnan, Ulaganathan Baraneedharan, Muthu Dhandapani, Allen Thyakumar, Dency Pinto, Arun Prasath, Ayyappan Velu, A Kamal, Nilesh Brijwani, Rohini Nair, R Basavaraja, Misti Jain, Saravanan Thiyagarajan, Biswanath Majumder, Mallik Sundaram, Prasad Narayanan, Vikram D. Kekatpure, Pradip K. Majumder. Inhibition of Rapamycin induced AKT activation elicits differential anti-tumor response in head and neck cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4947. doi:10.1158/1538-7445.AM2013-4947
Abstract 4951: The role of endothelin axis signaling pathway in astrocyte mediated chemoprotection of tumor cells.
Authors: Kim Seung Wook , Kim Sun Jin , Choi Hyun Jin , Lee Ho-Jeong , He Junqin , Wu Qiuyu , Lawson Erica J. , Fidler Isaiah J. 
Published: August 2014

Abstract
Purpose: More than 40% of patients with the breast cancer develop brain metastasis that are resistant to conventional chemotherapeutic agents. We have reported that reactive astrocytes establish gap junction communication channels with adjacent tumor cells and protect tumor cells from chemotherapy by up-regulation of survival genes in the tumor cells. We now report on the mechanism by which astrocytes up-regulate expression of the survival genes in tumor cells.
Materials and Methods: Human breast cancer cells, MDA-MB-231 cultured with murine astrocytes produce endothelin 1 (ET-1) leading to expression and activation of endothelin receptors (ETRs). Using small interfering RNA (siRNA) of ETAR and ETBR, and ETRs specific antagonists (BQ123, BQ788, and PD145065) demonstrated the correlation between the activation of the endothelin axis in tumor cells and the induction of survival genes (BCL2L1, GSTA5, and TWIST1) leading to chemoresistance.
Results: Co-culture of MDA-MB-231 cells and murine astrocytes induced up-regulation of ETRs (ETAR and ETBR) and activation of endothelin receptors axis in tumor cells as well as increased production of ET-1 by murine astrocytes. Activation of the ETRs by exogenous ET-1 up-regulated the expression of survival genes, such as BCL2L1, GSTA5 and TWIST1 via activation of phosphorylated AKT/MAPKinase signal transduction pathways, leading to resistance of tumor cells to several chemotherapeutic agents. Knockdown of both ETAR and ETBR by siRNAs or treatment of tumor cells with dual ETR inhibitor abolished the chemoprotection induced by astrocytes.
Conclusion: ET axis signaling pathway plays an essential role in astrocytes-mediated induction of chemoresistance of tumor cells by up-regulation of survival genes in tumor cells. Simultaneous blockade of both ETR can prevent tumor cells from developing resistance to chemotherapeutic agents.
Citation Format: Seung Wook Kim, Sun Jin Kim, Hyun Jin Choi, Ho-Jeong Lee, Junqin He, Qiuyu Wu, Erica J. Lawson, Isaiah J. Fidler. The role of endothelin axis signaling pathway in astrocyte mediated chemoprotection of tumor cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4951. doi:10.1158/1538-7445.AM2013-4951
Abstract 4952: A novel smoothened antagonist, TAK-441, delays castration-resistant progression in prostate cancer by disrupting paracrine hedgehog signaling.
Authors: Ghaffari Mazyar , Ibuki Naokazu , Iu Irene , Pandey Mitali , Fazli Ladan , Kashiwagi Masahide , Tojo Hideaki , Nakanishi Osamu , Gleave Martin E. , Cox Michael E. 
Published: August 2014

Abstract
Hedgehog (Hh) signaling is a highly conserved inter- and intracellular communication mechanism that governs organogenesis and is dysregulated in cancers of numerous tissues, including prostate. Up-regulated expression of the Hh ligands, Sonic (Shh) and Desert (Dhh), has been reported in androgen-deprived and castration-resistant prostate cancer (CRPC). In a cohort of therapy naive, short- and long-term neoadjuvant hormone therapy-treated (NHT), and CRPC specimens, we observed elevated Dhh expression predominantly in long-term NHT specimens and elevated Shh expression predominantly in CRPC specimens. Together with previously demonstrated reciprocal signaling between Shh-producing prostate cancer (PCa) cells and urogenital mesenchymal fibroblasts, these results suggest that castration-induced Hh expression promotes CRPC progression through reciprocal paracrine signaling within the tumor microenvironment. We tested whether the orally available Smoothened (Smo) antagonist, TAK-441, could impair castration-resistant progression of LNCaP PCa xenografts by disrupting paracrine Hh signaling. While TAK-441 or cyclopamine did not affect androgen withdrawal-induced Shh up-regulation or viability of LNCaP cells, castration-resistant progression of LNCaP xenografts was significantly delayed in animals treated with TAK-441. In TAK-441-treated xenografts, expression of murine orthologues of the Hh-activated genes, Gli1, Gli2, and Ptch1, was substantially suppressed, while expression of the corresponding human orthologues was unaffected. Since androgen-deprived LNCaP cells up-regulate Shh expression, but are not sensitive to Smo antagonists, these studies indicate that TAK-441 leads to delayed castration-resistant progression of LNCaP xenografts by disrupting paracrine Hh signaling with the tumor stroma. Thus, paracrine Hh signaling may offer unique opportunities for prognostic biomarker development, drug targeting and therapeutic response monitoring of PCa progression.
Citation Format: Mazyar Ghaffari, Naokazu Ibuki, Irene Iu, Mitali Pandey, Ladan Fazli, Masahide Kashiwagi, Hideaki Tojo, Osamu Nakanishi, Martin E. Gleave, Michael E. Cox. A novel smoothened antagonist, TAK-441, delays castration-resistant progression in prostate cancer by disrupting paracrine hedgehog signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4952. doi:10.1158/1538-7445.AM2013-4952
Abstract 4956: Pharmacological inhibition of Bruton's Tyrosine Kinase (BTK) as a therapy for insulinoma and pancreatic ductal adenocarcinoma.
Authors: Massó-Vallés Daniel , Serrano Erika , Whitfield Jonathan R. , Buggy Joseph J. , Sodir Nicole M. , Affara Nesrine I. , Brown Swigart Lamorna , Evan Gerard I. , Soucek Laura 
Published: August 2014

Abstract
Myc, a pleiotropic transcription factor that is deregulated and/or over-expressed in most human cancers, instructs multiple extracellular programs that are required to sustain the complex microenvironment needed for tumor maintenance, including remodeling of tumor stroma, angiogenesis and inflammation. We previously showed in a model of pancreatic [[Unsupported Character - Symbol Font β]] cell tumorigenesis that acute Myc activation in vivo triggers rapid recruitment of mast cells to the tumor site and that this is absolutely required for angiogenesis and macroscopic tumor expansion. Moreover, systemic inhibition of mast cell degranulation with sodium cromoglycate induced death of tumor and endothelial cells in established tumors. Hence, mast cells are required both to establish and to maintain the tumors. While this intimates that selective inhibition of mast cell function could be therapeutically efficacious, cromoglycate is not a practical drug for systemic delivery in humans and no other systemic inhibitor of mast cell degranulation has hitherto been available.
Ibrutinib is a novel inhibitor of Bruton's tyrosine kinase (Btk) that blocks mast cell degranulation and is currently in clinical trials as a therapy for B cell non-Hodgkin's lymphoma. Here, we show that systemic treatment of insulinoma-bearing mice with Ibrutinib efficiently inhibits Btk, blocks mast cell degranulation and triggers collapse of tumor vasculature and tumor regression. We also show that pancreatic ductal adenocarcinoma (PDAC)-bearing mice treated with Ibrutinib survive longer and present reduced tumor stroma, suggesting that combinatorial therapy with Ibrutinib and standard of care is a feasible therapeutic approach. Conclusions: our data reinforce the notion that mast cell function is required for maintenance of certain tumor types and indicate that the Btk inhibitor Ibrutinib may be useful in treating pancreatic cancer.
Citation Format: Daniel Massó-Vallés, Erika Serrano, Jonathan R. Whitfield, Joseph J. Buggy, Nicole M. Sodir, Nesrine I. Affara, Lamorna Brown Swigart, Gerard I. Evan, Laura Soucek. Pharmacological inhibition of Bruton's Tyrosine Kinase (BTK) as a therapy for insulinoma and pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4956. doi:10.1158/1538-7445.AM2013-4956
Abstract 4960: COX-2 inhibition with celecoxib delays the progression of invasive mammary carcinoma in a murine model of collagen dense stroma.
Authors: Esbona Karla , Inman David R. , Eliceiri Kevin W. , Wilke Lee G. , Keely Patricia J. 
Published: August 2014

Abstract
Breast cancer is the most common invasive cancer in women causing over 40,000 deaths yearly in the United States. Increased mammographic density correlates with over four-fold greater risk for breast cancer, making it one of the most important risk factors known for this disease. High breast density is correlated to increased collagen in the breast tissue, and we have found that increased collagen in the Col1a1tm1jae mouse model promotes mammary tumor formation and progression. Elevated collagen density in vitro increases expression of PTGS2 (prostaglandin-endoperoxide synthase 2), the gene for COX-2, by over four fold. COX-2 over-expression is observed in 40% of invasive breast carcinoma cases and correlates with poor prognosis. Based on these findings, we hypothesized that inhibition of COX-2 may be an effective therapy in the context of mammary tumors arising in dense tissue. Celecoxib is a selective non-steroidal anti-inflammatory drug (NSAID) that specifically inhibits COX-2. To understand the mechanism by which COX-2 affects cell signaling and response to collagen matrix density, we utilized our previously characterized model of MMTV-PyVT tumors on a wild type (wt) or Col1a1tm1jae background. Col1a1tm1jae heterozygote and wt littermates were randomly assigned at 11 weeks of age to treatment with placebo or celecoxib at 400mg per kilogram body weight. Oral treatment was given daily for 21 days. We found that MMTV-PyVT tumors responded to celecoxib in a manner that is regulated by matrix density (p-value &lt;.0001). Tumors that arose on the dense Col1a1tm1jae background were larger and more invasive (p-value &lt;.0001). Endpoint tumor size was diminished in mice treated with a daily dose of celecoxib, which delayed the development of tumors and changed the structure of the dense matrix. The effect of celecoxib was not as prominent for masses which developed on the low density wt background. Immunohistochemistry of relevant markers in these tissues is ongoing and will further our understanding of the effects of COX-2 inhibition in dense matrices. These findings suggest that COX-2 has a direct role in modulating the configuration of dense matrices which promote a more invasive cancer effect. Moreover, these findings suggest that COX-2 may be an effective therapeutic target for women with dense breast tissue.
Citation Format: Karla Esbona, David R. Inman, Kevin W. Eliceiri, Lee G. Wilke, Patricia J. Keely. COX-2 inhibition with celecoxib delays the progression of invasive mammary carcinoma in a murine model of collagen dense stroma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4960. doi:10.1158/1538-7445.AM2013-4960