bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B35: The effect of extracellular matrix proteins from lung on the migration of breast cancer cells
Authors: Carpenter Philip M. , Xiao Cally , Ngo Tuan , Gershon Paul D. 
Published: August 2014

Abstract
The lung is a frequent site of breast carcinoma metastasis, yet little is known about the mechanism of breast carcinoma metastasis to lung. The purpose of this study was to determine if extracellular matrix components from the pulmonary microenvironment had the potential to encourage metastasis by inducing motility in breast carcinoma cells. Previous studies provided evidence that products of conditioned media of pulmonary epithelial cell co-cultures were able to induce dose-dependent motility in breast carcinoma cells. The deposited material was analyzed by mass spectrometry, revealing extracellular matrix proteins, including thrombospondin 1 (TSP), tenascin C, transforming growth factor-beta-induced protein ig-h3 (βig-h3), and the α3 and β3 chains of laminin 332 (LN332). Motility assays using either recombinant preparations of TSP, βig-h3 or tenascin C, or purified LN332 revealed that LN332 induced greater motility at almost all concentrations of each protein tested.
Since pulmonary cells grown on membranes at a liquid air interface more closely resemble the structure of lung tissue in vivo, cells grown in this manner were tested for their ability to produce LN332 and induce motility. After 7-8 days in culture, pulmonary epithelial cells provided a monolayer at the liquid air interface. Membranes with cells on the surface exposed to air were fixed in formalin, paraffin embedded and sectioned for hematoxylin and eosin staining and immunohistochemistry. Immunohistochemistry revealed that the cells produced LN332, which was both cytoplasmic and in a layer on the membrane surface beneath the cells. Lung cells growing at the liquid air interface were removed from the membrane, and MCF-7 cells were added to the same membrane from which lung cells had been removed, or to membranes which had been incubated with pulmonary cell growth media but no lung cells. Whereas MCF-7 cells placed on membranes without prior lung cells grew in tight clusters, MCF-7 cells added to membranes on which lung cells had been removed showed scattering and pseudopodia formation. This response was blocked by antibodies to α3 and β1 integrins, which are receptors of LN332. Finally, western blots of human lung tissue revealed the presence of LN332. These experiments together showed that pulmonary LN332 is a likely motility factor for breast carcinoma cells. These findings provide a mechanism for the migration of metastatic tumor cells from their arrest in the pulmonary vasculature into the surrounding tissue, allowing their establishment as a metastatic colony.
Citation Format: Philip M. Carpenter, Cally Xiao, Tuan Ngo, Paul D. Gershon. The effect of extracellular matrix proteins from lung on the migration of breast cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B35.
Abstract B36: Understanding the mechanisms underlying recurrence of malignant gliomas after antiangiogenesis treatment
Authors: Santiago Nahir Cortes , Gabrusiewicz Konrad , Liu Dan , Hossain Mohammed B. , Conrad Charles , Fueyo Juan , Gomez-Manzano Candelaria 
Published: August 2014

Abstract
Anti-angiogenesis therapies, in particular bevacizumab, are currently offered to patients with malignant gliomas given strong preclinical and clinical data supporting its effectiveness. However, evidence gathered in the literature shows that upon bevacizumab treatment patients will invariably recur with highly invasive tumors resistant to all available therapies. The purpose of the study we have undertaken is to understand the underlying mechanisms involved in this enhanced malignancy with the aim to uncover new combined therapeutic strategies for these patients. Using tissue obtained from glioma bearing mice treated with bevacizumab or control treatment, we have obtained evidence that upon anti-VEGF treatment, a population of Tie2-expressing cells is recruited to the tumor particularly around areas of invasion. Further characterization of this population demonstrated that a significant proportion of these cells are of myeloid origin, Tie2-expressing monocytes or TEMs. Through the use of an M2 polarized culture as well as TEMs obtained from blood of healthy donors we have gathered data supporting that this myeloid cell population has high expression of several transcripts of molecules associated with invasion as well as a much higher secretion of MMP2 and MMP9 than their Tie2 negative counterparts. In an attempt to understand the changes within the tumor microenvironment after anti-VEGF therapy, immunohistochemical analysis for expression of several molecules associated with angiogenesis was performed. Results obtained identified angiopoietin 2 (Ang2), a Tie2 ligand, as being dramatically increased after therapy. Interestingly, our in vitro and in vivo data show that Ang2 serves as a chemo-attractant molecule to TEMs and therefore could be the main molecule responsible for their recruitment into the tumors following anti-VEGF treatment. We gathered preliminary data on the enhanced presence of TEMs as well as higher levels of MMP9 in human surgical samples after bevacizumab treatment. Our data strongly supports a strong influence of TEMs and Ang2 in the recurrent phenotype of gliomas after anti-VEGF therapy. Further studies aim to understand the extent to which targeting Ang2 specifically and the Ang/Tie2 pathway in general, in combination with anti-VEGF therapy, will lead to improved outcomes.
Citation Format: Nahir Cortes Santiago, Konrad Gabrusiewicz, Dan Liu, Mohammed B. Hossain, Charles Conrad, Juan Fueyo, Candelaria Gomez-Manzano. Understanding the mechanisms underlying recurrence of malignant gliomas after antiangiogenesis treatment. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B36.
Abstract B38: Unveiling the mechanisms of melanoma metastasis using a chick embryo neural crest model system
Authors: Bailey Caleb M. , Kulesa Paul M. 
Published: August 2014

Abstract
In an attempt to elucidate the mechanisms of melanoma metastasis, our laboratory has recently performed a molecular comparison between melanoma and the embryonic neural crest. The neural crest is a multi-potent and highly invasive cell population, and represents the ancestral cell type of melanocytes. We report that melanoma cells exploit portions of the embryonic neural crest development program to facilitate invasion. In particular, Eph receptor tyrosine kinases and their cognate ligands, the ephrins, are dynamically regulated by C8161 melanoma cells to facilitate migration. We noted that the purported metastasis suppressor EphB6 was significantly reduced in invasive melanoma cells compared to poorly invasive melanoma cells and primary human melanocytes. In the current study, we have utilized the chick embryo transplant model system to examine the effects of EphB6 re-expression in C8161 melanoma cells. EphB6 over-expression significantly alters cell directionality of migrating melanoma cells within the embryo. We confirmed the anti-metastatic effect of EphB6 in melanoma cells using a chick CAM metastasis assay, which demonstrated a significant decrease in metastatic potential. Importantly, tumor formation appeared unaffected. These results suggest that EphB6 acts specifically as a metastasis suppressor, likely at the metastatic step of intravasation. Our studies also demonstrate the chick embryo as a powerful tool with which to compare and dissect the complex mechanisms of metastasis in vivo that are similar or distinct from normal developmental processes.
Citation Format: Caleb M. Bailey, Paul M. Kulesa. Unveiling the mechanisms of melanoma metastasis using a chick embryo neural crest model system. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B38.
Abstract B39: Inhibiting endothelial FAK activity blocks tumor cell extravasation
Authors: Jean Chris , Nam Ju-Ock , Chen Xiao-Lei , Uryu Sean , Tancioni Isabelle , Lawson Christine , Ward Kristy K. , Walsh Colin T. , Ghassemian Majid , Turowski Patric , Dejana Elisabetta , Weis Sara M. , Cheresh David A. , Schlaepfer David D. 
Published: August 2014

Abstract
Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that modulates signaling from growth factor, integrin, and cadherin receptors in both tumor and stromal cells. Pharmacological FAK inhibition prevents tumor growth and metastasis, but the target cell action associated with this remains unclear. Recent studies using an inducible endothelial cell (EC) specific FAK kinase-inactive knock-in mouse model revealed that vascular endothelial growth factor (VEGF) increased cell permeability was dependent upon FAK activity. VEGF triggers conformational FAK activation, binding of FAK to the cytoplasmic tail of VE-cadherin, and FAK-dependent phosphorylation of adherens junction proteins regulating vascular integrity. Here we provide genetic and pharmacological support for the importance for FAK activity in mediating direct VE-cadherin tyrosine (Y) 658 phosphorylation in tumor-associated ECs in vivo. In cell culture, VEGF-induced transmigration of tumor cells through an EC barrier is prevented by genetic EC-specific FAK inhibition or reconstitution of Y658F VE-cadherin within null ECs. In mice, VEGF enhances circulating tumor cell extravasation within the lungs and this is prevented by inducible knockin of kinase-dead FAK within ECs. These studies provide a mechanistic foundation for the importance of FAK and VE-cadherin interactions in the regulation of adherens junction stability and support future evaluation of FAK inhibitors in the treatment of metastatic cancer.
Citation Format: Chris Jean, Ju-Ock Nam, Xiao-Lei Chen, Sean Uryu, Isabelle Tancioni, Christine Lawson, Kristy K. Ward, Colin T. Walsh, Majid Ghassemian, Patric Turowski, Elisabetta Dejana, Sara M. Weis, David A. Cheresh, David D. Schlaepfer. Inhibiting endothelial FAK activity blocks tumor cell extravasation. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B39.
Abstract B4: Development of a short peptide with antitumor activity
Authors: Wang Suming , Catena Raul , Mittal Vivek , Watnick Randolph S. 
Published: August 2014

Abstract
It has been demonstrated that metastatic tumors establish bone marrow (BM)-derived pre-metastatic niches in distant organs that serve as permissive hubs for supporting future metastases. It is not known, conversely, whether tumors that lack metastatic potential fail to establish such niches, or generate niches which inhibit metastasis. Here, we show that metastasis-incompetent tumors are also capable of generating BM-derived niches at distant sites. However, by secreting prosaposin (psap) these tumors systemically stimulate expression of an antiangiogenic factor thrombospondin1 (Tsp-1) in myeloid progenitor cells in the niche, converting them into metastasis-inhibitory cells. We found that Tsp-1-inducing activity of psap was contained in a short (&lt;10 amino acid) peptide. Importantly this peptide suppressed metastatic outgrowth, which was rescued by genetic ablation of Tsp-1 in the BM. These results provide mechanistic insights into why certain tumors are deficient in metastatic potential, and unexpectedly implicate recruited Gr1+ myeloid progenitor cells as the main source of Tsp-1 in the metastatic lung. Clinically, psap expression was significantly decreased in skeletal metastases in prostate cancer patients, suggesting that the psap peptide may be a potential therapeutic agent against metastatic cancer.
Citation Format: Suming Wang, Raul Catena, Vivek Mittal, Randolph S. Watnick. Development of a short peptide with antitumor activity. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B4.
Abstract B43: A novel breast cancer metastasis suppressor upstream of Hippo signaling
Authors: Ma Li 
Published: August 2014

Abstract
There is a pressing need to identify prognostic markers of metastatic diseases and targets for treatment. Combining high-throughput RNA sequencing, functional characterization, mechanistic studies, and clinical validation, we identify leukemia inhibitory factor receptor (LIFR) as a breast cancer metastasis suppressor downstream of the miR-9 microRNA and upstream of Hippo signaling. Restoring LIFR expression in highly malignant tumor cells suppresses metastasis by triggering a Hippo kinase cascade that leads to phosphorylation, cytoplasmic retention, and functional inactivation of the transcriptional co-activator YAP. Conversely, loss of LIFR in non-metastatic breast cancer cells induces migration, invasion, and metastatic colonization through activation of YAP. LIFR is downregulated in human breast carcinomas and inversely correlates with metastasis. Notably, loss of LIFR in non-metastatic Stage I-III breast tumors is highly associated with poor metastasis-free, recurrence-free and overall survival outcomes in approximately 1,000 patients. These findings identify LIFR as a metastasis suppressor that functions through the Hippo-YAP pathway and has significant prognostic power. As the next step, we will dissect the role of LIFR in spontaneous breast tumorigenesis and metastasis using genetically engineered mouse models, elucidate the mechanisms by which LIFR activates Hippo signaling using biochemical approaches, and develop methods to restore LIFR expression or function as new anti-metastatic therapeutic strategies.
Citation Format: Li Ma. A novel breast cancer metastasis suppressor upstream of Hippo signaling. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B43.
Abstract B54: Coordinate RB/PTEN tumor suppressor loss: Drives aggressive invasive behavior and is strongly associated with the progression of ductal carcinoma to invasive breast cancer
Authors: Witkiewcz Agnieszka , Pajak Thomas , Schwartz Gordon , Knudsen Erik 
Published: August 2014

Abstract
Background: A subset of patients with ductal carcinoma in situ (DCIS) treated by surgery will progress to invasive breast cancer. However, there is a limited understanding of the pathways driving such invasive progression and no accepted markers to differentiate lesions at high risk from those at lower risk of developing invasive disease.
Methods: The association of two tumor suppressor genes, retinoblastoma (RB) and phosphatase and tensin homolog (PTEN), with risk of any ipsilateral breast event (IBE) or progression to invasive breast cancer (IBC) was analyzed using data from 236 DCIS patients treated with breast conserving surgery with long-term follow up. RB and PTEN expression was assessed with immunohistochemistry. The functional effects of RB and/or PTEN loss were evaluated in preclinical models.
Results: Modeling of RB and PTEN loss as observed in DCIS, revealed that the tumor suppressors coordinate complementary processes with respect to proliferation, motility, and invasiveness. Correspondingly, pharmaceutical interventions that mimic activation of RB or PTEN limit the invasive properties of such models. Gene expression profiling demonstrated unique transcriptional programs regulated by each tumor suppressor that are associated with epithelial mesenchymal transition and invasive disease progression. Loss of RB immunoreactivity in DCIS was strongly associated with risk of IBE occurrence (HR=2.64, 95% CI = 1.64 to 4.25) and IBC recurrence (HR=4.66, 95% CI = 2.19 to 9.93). The prognostic power of RB loss alone remained statistically significant in multivariable analyses, although PTEN loss alone did not. However, patients with DCIS lesions that were both RB and PTEN deficient were at higher risk for IBE (HR=3.39, 95% CI = 1.92 to 5.99) and IBC recurrence (HR=6.1, 95% CI = 2.5 to 14.76).
Conclusions: These studies indicate that RB and PTEN have independent functions that modulate the invasive potetntial of breast cancer, and together have prognostic utility that could be used to improve the management of DCIS.
Citation Format: Agnieszka Witkiewcz, Thomas Pajak, Gordon Schwartz, Erik Knudsen. Coordinate RB/PTEN tumor suppressor loss: Drives aggressive invasive behavior and is strongly associated with the progression of ductal carcinoma to invasive breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B54.
Abstract B59: The dual effect of therapy-induced IL-1β expression on tumor progression: Role of tumor-associated macrophages
Authors: Voloshin Tali , Alishekevitz Dror , Miller Valeria , Isakov Lika , Bril Rotem , Benhar Moran , Apte Roney , Shaked Yuval 
Published: August 2014

Abstract
A major obstacle in clinical oncology is that tumors eventually acquire resistance to therapy. The mechanism by which resistance arises is usually associated with changes made in tumor cells in response to the therapy, however, little is known about the effect of the host which may also contribute to tumor resistance. Previous studies from our lab suggest that the induction of host cellular and molecular events following therapy may promote tumor re-growth, angiogenesis and metastasis. In this study we uncovered the possible role IL-1β - a proinflammatory cytokine - has on the growth of primary tumor and its impact on metastasis following paclitaxel (PTX) chemotherapy. We found that plasma and spleen from PTX-treated mice exhibited elevated expression of IL-1β. Furthermore, plasma from PTX-treated mice induced tumor cell invasion, an effect which was abrogated in plasma from mice treated with PTX and Anakinra, an IL-1 receptor antagonist. Consequently, mice inoculated with Lewis lung carcinoma (LLC) cells pre-exposed to plasma from mice treated with the combined therapy survived longer than mice inoculated with tumor cells pre-exposed to plasma from mice treated with PTX or Anakinra monotherapy. We next determined whether treatment efficacy of PTX is enhanced by the combination of PTX and Anakinra using 4T1 metastatic breast cancer model in mice. Tumors treated with the combined therapy were significantly smaller than tumors treated with PTX or Anakinra monotherapy. Surprisingly, although the primary tumors were smaller, such mice succumb to metastasis earlier than mice in any of the other treated groups. Furthermore, an increased number of M2 macrophages colonizing 4T1 primary tumors treated with the combined therapy was observed when compared to their number in PTX treated tumors, indicating a possible pro-metastatic role of M2 macrophages in post treatment IL-1β deprived microenvironment. Parallel results were observed when LLC bearing IL-1β deficient mice, were treated with PTX. Taken together, these findings demonstrate that although treatment outcome is enhanced following the blockade of host-induced IL1β at the primary tumor level, at the metastatic level it may serve as a double-edge sward and can lead to metastatic spread.
Citation Format: Tali Voloshin, Dror Alishekevitz, Valeria Miller, Lika Isakov, Rotem Bril, Moran Benhar, Roney Apte, Yuval Shaked. The dual effect of therapy-induced IL-1β expression on tumor progression: Role of tumor-associated macrophages. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B59.
Abstract B63: Cancer cell invasion determined by cell density-dependent, cytokine-mediated crosstalk
Authors: Sharif Ghada M. , Schmidt Marcel O. , Hu Zhang-Zhi , Glasgow Eric , Riegel Anna T. , Wellstein Anton 
Published: August 2014

Abstract
Metastatic spread of cancer cells from their primary site requires invasion into the vasculature, evasion at the distant organ site and colonization of the distant organ. Here we studied mechanisms of attachment and invasion into endothelial monolayers by cancer cells to identify driver molecules and signaling pathways that are crucial for the invasive and metastatic phenotype. In vitro studies were complemented by studies in zebrafish embryos and mouse models of cancer cell invasion and metastasis. In one approach we compared gene expression profiles across isogenic cell lines with distinct invasive behavior to identify candidate drivers and pathways. These were then subjected to functional validation. This comparison of gene expression profiles of isogenic cancer cell lines showed an upregulation of immune response cytokines associated with an endothelial invasive phenotype in human breast cancer cells. The role of the respective cytokine pathways was validated by blocking the respective receptors in in vitro assays and in a zebrafish metastasis model.
Citation Format: Ghada M. Sharif, Marcel O. Schmidt, Zhang-Zhi Hu, Eric Glasgow, Anna T. Riegel, Anton Wellstein. Cancer cell invasion determined by cell density-dependent, cytokine-mediated crosstalk. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B63.