bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A13: Interleukin-1β promotes brain metastasis of breast cancer by activating Notch signaling through reactive astrocytes
Authors: Xing Fei , Kobayashi Aya , Okuda Hiroshi , Watabe Misako , Pandey Puspa R. , Pai Sudha K. , Liu Yin , Wu Kerui , Watabe Kounosuke 
Published: August 2014

Abstract
Metastatic diseases are responsible for the majority of the deaths in breast cancer patients, and brain is one of the most common metastatic sites. The metastatic tumor in the brain profoundly affects the cognitive and sensory functions as well as morbidity of patients, and the one year survival rate among these patients remains less than 20%. However, little is known about the pathogenesis of brain metastasis, and therefore, it is of paramount importance to elucidate the molecular mechanism of metastatic process in order to define a specific therapeutic target. Our analysis of existing microarray database indicate that interleukin-1β (IL-1β) is highly expressed in MDA-MB231BrM2a (231BrM) cell line which is capable of preferentially metastasizing to the brain. IL-1β is known to have an ability of “activating” astrocytes that are often found in the metastatic niche, and therefore, it is speculated that the reactive astrocytes can promote growth and invasion of metastasized cells in the brain. To explore this possibility, we examined the effect of IL-1β and the conditioned medium of 231BrM cells on rat primary astrocytes in vitro. Our results of qRT-PCR and Western blot analysis indicate that IL-1β and the conditioned medium significantly up-regulated the Notch ligand, JAG1, in astrocytes, and that this up-regulation was abrogated by the NF-kB inhibitors, PDTC and RO 106-9920. We also found that the interaction between CSCs and astrocytes significantly enhances the self-renewal ability of CSCs. To further examine the interaction of astrocytes and tumor cells in the brain, we intracardially injected 231BrM cells in nude mice, and tumor growth was monitored by Xenogen bioimager. After 4 weeks, metastatic tumor growth was observed at multiple sites of the brain, and the results of immunohistochemical analysis indicated that astrocytes adjacent to the metastatic lesions strongly expressed JAG1 and the reactive astrocyte marker, GFAP (Glial fibrillary acidic protein). Finally, we found that a BBB-permeable Notch inhibitor was able to significantly suppress metastatic growth of breast cancer in the brain in our animal model. These results represent a novel paradigm for the understanding of how metastatic breast CSCs re-establish their niche for their self-renewal in a totally different microenvironment, which opens a new avenue to identify a novel and specific target for the brain metastatic disease.
Citation Format: Fei Xing, Aya Kobayashi, Hiroshi Okuda, Misako Watabe, Puspa R. Pandey, Sudha K. Pai, Yin Liu, Kerui Wu, Kounosuke Watabe. Interleukin-1β promotes brain metastasis of breast cancer by activating Notch signaling through reactive astrocytes. [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 A13.
Abstract A19: Ecrg4 downregulation in glioma enables transformed cells to escape immunosurveillance by tumor-associated macrophages/microglia
Authors: Lee Jisook , Dang Xitong , Borboa Alexandra , Coimbra Raul , Baird Andrew , Eliceiri Brian 
Published: August 2014

Abstract
Tumor-associated microglia generally promote tumor invasion, adopting an immunosuppressive phenotype that is distinct from their pro-inflammatory functions. Based on bioinformatic mining of novel sentinel genes encoding biologically active peptides, we have recently identified Ecrg4, as a novel secreted pro-inflammatory mediator of macrophage activation. While downregulation of Ecrg4 expression occurs in various tumor cells, in this study, we demonstrate that the biological activity of Ecrg4 in cancer functions through a paracrine mechanism, where tumor cell-exposed Ecrg4 acts upon tumor-associated microglia. In orthotopic glioma models, tumor cells expressing Ecrg4 induce proliferation and morphological changes in tumor-associated microglia. These Ecrg4-mediated effects on microglia correlate with a reduction in tumor burden and prolonged survival. Together, these results identify Ecrg4 as a novel mediator of glioma progression functioning through a paracrine mechanism that regulates the inflammatory state of tumor-associated microglia/macrophages.
Citation Format: Jisook Lee, Xitong Dang, Alexandra Borboa, Raul Coimbra, Andrew Baird, Brian Eliceiri. Ecrg4 downregulation in glioma enables transformed cells to escape immunosurveillance by tumor-associated macrophages/microglia. [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 A19.
Abstract A21: Human breast-to-brain metastases display GABAergic properties in the neural niche
Authors: Neman Josh , Termini John , Kowolik Claudia M. , Hambrecht Amanda C. , Jandial Rahul , Roberts Eugene 
Published: August 2014

Abstract
The high frequency and poor prognosis of breast-to-brain metastasis (BBM) indicates the need for detailed studies of metastatic breast cancer cells, the brain microenvironment, and the interactions between the two that lead to breast cancer colonization and proliferation. Because neurotransmitters are a major component of the brain microenvironment, we examined fresh tissue and cells from recent surgical specimens of BBM to determine if they expressed CNS-specific neurotransmitter characteristics. We found that BBM cells expressed higher levels of the classical neurotransmitter receptors relative to primary breast cancer, and that, overall, they had a GABAergic phenotype similar to that of neuronal cells. Specifically, GABAAR, GAD67, GABA transporter, and GABA transaminase were highly expressed in BBM cells indicating that they utilize GABA. Moreover, we determined BBM cells exploit the GABA shunt in order to enhance energy production and proliferative potential in vitro. BBM cells also expressed the GABAergic interneuron-specific proteins, parvalbumin and reelin. Parvalbumin is a calcium binding protein that is involved in regulating the local inhibitory effects that GABAergic interneurons exert on pyramidal neurons, and reelin is an extracellular matrix glycoprotein that is involved in the migration and positioning of neurons. These data suggest that metastases of mesenchymal origin can assume neural characteristics when exposed to the brain micronenvironment to facilitate colonization.
Citation Format: Josh Neman, John Termini, Claudia M. Kowolik, Amanda C. Hambrecht, Rahul Jandial, Eugene Roberts. Human breast-to-brain metastases display GABAergic properties in the neural niche. [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 A21.
Abstract A29: Cooption of the reactive stroma by brain metastasis relies on protease inhibitors
Authors: Valiente Manuel , Lee Derek J. , Obenauf Anna , Huse Jason T. , Chaft Jamie E. , Kris Mark G. , Brogi Edi , Massagué Joan 
Published: August 2014

Abstract
Metastatic cancer cells are known to get benefit from the interaction with their microenvironment. The presence of metastatic cells in a target organ induces changes in the stroma. This reactive stroma is very evident in the brain, where cancer cells are ubiquitously associated with reactive glia. Since reactive astrocytes are known sources not only of trophic factors but also deleterious signals, we hypothesized that the ability of metastatic cells to develop in a target organ requires the ability to neutralize these deleterious signals.
We detected reactive astrocytes in the proximity of brain metastasis producing plasminogen activators (tPA and uPA), which activate Plasmin, one of the main proteases in the brain. Plasmin activity in the brain acts as a deleterious factor to metastatic cells in this organ. Cancer cells selected in vivo for their ability to metastasize in the brain overexpress Serine Protease Inhibitors (SERPINs) that block Plasmin activation. Moreover, a significant cohort of human brain metastasis samples from both lung and breast adenocarcinoma scored positive for specific members of the SERPIN family. When the cancer cells were depleted of SERPINs their brain metastatic activity was significantly reduced in all experimental models, including breast and lung adenocarcinoma xenografts and syngeneic mouse models. Brain metastatic cells are sensitive to Plasmin activated killer cytokines (sFASL), and their ability to survive and to grow in the brain depends on genes whose products are inactivated by Plasmin cleavage (VEGFA and L1CAM).
The cooption of SERPINs by brain metastatic cells is required to avoid the deleterious consequences of the reactive stroma and subsequently benefit from the interaction with the microenvironment.
Citation Format: Manuel Valiente, Derek J. Lee, Anna Obenauf, Jason T. Huse, Jamie E. Chaft, Mark G. Kris, Edi Brogi, Joan Massagué. Cooption of the reactive stroma by brain metastasis relies on protease inhibitors. [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 A29.
Abstract A32: Colorectal cancer stroma: Tumor cells in disguise
Authors: Celesti Giuseppe , Caro Giuseppe Di , Bianchi Paolo , Grizzi Fabio , Basso Gianluca , Doni Andrea , Marchesi Federica , Marra Giancarlo , Roncalli Massimo , Mantovani Alberto , Malesci Alberto , Laghi Luigi 
Published: August 2014

Abstract
Background: Epithelial-to-mesenchymal transition (EMT) is thought to mediate cancer cell dissemination and metastasis. However, the role of EMT in the initial progression of human cancer remains unproven, since delaminating neoplastic cells have never been identified in the peritumoral stroma.
Aim: To demonstrate the existence of EMT-neoplastic cells in mesenchymal disguise in the stroma of human colorectal cancer (CRC).
Methods and Materials / Patients: In vitro, gene expression profile analysis of 18 CRC cells by microarray. Transfection/silencing of TWIST1 in CRC cells and invasion and migration assay. Immunohistochemistry for TWIST1 of 11 adenomas and of 201 CRC specimens. Combined TWIST1 immunofluorescence and in situ hybridization (iFISH) for CEP7 and 20 of 20 CRC specimens. In vivo, orthotopic graft of murine CRC cells CT26 in the rectal sub-mucosa of Balb/c mice.
Results: TWIST1 was necessary to maintain mesenchymal phenotype and invasiveness of microsatellite-stable (MSS) cellular models of EMT, either spontaneous (CoLo741) or induced by transfection (SW480). TWIST1 mRNA was not translated in MSI CRC cells (HCT116). In an orthotopic mouse model of CRC, syngenic TWIST1-positive cells (CT26) acquired a mesenchymal phenotype when invading the peritumoral tissues. In human CRC tissues, the presence of TWIST1-positive cells within the stroma correlated with tumor MSS status (p=0.05), stage IV (p=0.02), and patient prognosis (DSS, p&lt;0.01). Trisomies of chromosome 7 and/or chromosome 20 were detected within the tumor compartment of 17/20 CRC specimens. In each of these 17 tumors, TWIST1-positive cells with matching chromosomal gains were traceable in the peritumoral stroma (86 of 776 counted cells, 11.1%), whereas no trisomy was recognized in TWIST1-negative stromal cells (0 of 1249 cells; p&lt;0.001).
Conclusion: TWIST1 plays a crucial role in maintaining EMT in human CRC. By using TWIST1 as marker of EMT cells, we demonstrated that stromal cells, disguised as fibroblasts, are actually neoplastic. Targeting TWIST1+ stromal cells might open new scenarios for interfering with the metastatic cascade of CRC.
Note: This abstract was not presented at the conference.
Citation Format: Giuseppe Celesti, Giuseppe Di Caro, Paolo Bianchi, Fabio Grizzi, Gianluca Basso, Andrea Doni, Federica Marchesi, Giancarlo Marra, Massimo Roncalli, Alberto Mantovani, Alberto Malesci, Luigi Laghi. Colorectal cancer stroma: Tumor cells in disguise. [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 A32.
Abstract A53: CXCR4 drives the metastatic phenotype in breast cancer through induction of CXCR2, transactivation of HER2/EGFR, and activation of MEK and PI3K pathways
Authors: Sobolik Tammy , Su Yingjun , Wells Sam , Richmond Ann 
Published: August 2014

Abstract
Introduction: Aberrant expression of CXCR4 in human breast cancer correlates with metastasis and poor prognosis. Expression of a carboxyl-truncated CXCR4 (CXCR4ΔCTD) is associated with constitutive CXCR4 activity in MCF-7 breast cancer cells, increased motility, loss of E-cadherin, enhanced estrogen independent growth and lung metastasis in vivo. Here, we characterize the mechanism by which CXCR4 induces a mesenchymal phenotype with metastatic properties.
Methods: MCF-7 cells expressing wild-type CXCR4 (CXCR4WT) or CXCR4ΔCTD were evaluated in two-dimensional (2D) and three-dimensional reconstituted basement membrane (3D rBM) cultures for cell morphology and expression of factors that regulate the epithelial to mesenchymal transition (EMT) and cell migration. Effects of inhibition of key cytokine/chemokine signaling pathways activated by CXCR4 were examined. Tumor cell migration within the tumor microenvironment was followed using intravital imaging.
Results: In 2D culture, MCF-7 CXCR4ΔCTD but not CXCR4WT cells, exhibited EMT characterized by up-regulation of ZEB-1 and cadherin 11, loss of E-cadherin, p120 isoform switching, and activation of ERK1/2, and MMP-2. The up-regulation of ZEB-1 was coincident with down-regulation of miR-200b and miR200c. In contrast to the 2D environment, 3D rBM MCF-7 CXCR4WT cultures exhibited the same stellate morphology of CXCR4ΔCTD cells, while MCF-7 control cells formed round acinar clusters. Expression of CXCR4 resulted in induction of expression of CXCR2, CXCR7, CXCL1, CXCL8, CCL2, IL-6 and GM-CSF by MCF-7 cells in 3DrBM, but not 2D culture. CXCR4 expression also induced transactivation of HER2 and EGFR. CXCL1, CXCL8 and CXCR2 appear to signal through a CXCR2 autocrine loop. In 3D rBM culture combined inhibition of CXCR4 and MEK1, or PI3K and MEK1/2 resulted in a change in morphology of CXCR4 expressing cells from stellate to round acinar clusters resembling controls. Combined inhibition of CXCR2 with MEK1, PI3K, or CXCR4 inhibitors also resulted in reversion of the stellate phenotype in 3D rBM. In vivo studies revealed that MCF-7 CXCR4WT and MCF-7CXCR4ΔCTD tumor cells migrate in a collective manner capable of lymphatic spread in athymic nude mice.
Conclusions: Elevated expression or constitutive activation of CXCR4 results in EMT that is accompanied by up-regulation of receptors and cytokines important in collective cell migration leading to lymphatic invasion and tumor metastasis.
Citation Format: Tammy Sobolik, Yingjun Su, Sam Wells, Ann Richmond. CXCR4 drives the metastatic phenotype in breast cancer through induction of CXCR2, transactivation of HER2/EGFR, and activation of MEK and PI3K pathways. [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 A53.
Abstract A61: Lysophosphatidic acid induces ovarian cancer cell invasion through EGFR phosphorylation and proteolytic enzyme expression
Authors: Jeong Kang Jin , Cho Kyung Hwa , Kim Jeong Jin , Choi Moon Jung , Lee Hoi Young 
Published: August 2014

Abstract
Lysophosphatidic acid (LPA) is a biolipid that augments proliferation and metastasis of various cancer cells. LPA was first implicated in human oncogenesis, as higher levels of LPA was observed in the ascitic fluid of ovarian cancer patient than healthy subjects. In the present study, we elucidate the underlying mechanisms by which LPA induces proteolytic enzyme expression and ovarian cancer progression. LPA induced MMP-9 expression in CAOV-3 and PA-1 cells and uPA expression in SKOV-3 cells. LPA-induced proteolytic enzyme expression was required for the invasion of ovarian cancer cells expressing corresponding enzymes. Further we observed that both Gi and G13 contribute to LPA-induced EGFR activation. The activated EGFR in turn initiates a Ras/Rho/ROCK signaling cascade, leading to proteolytic enzyme secretion. Moreover, we provide evidence that resveratrol inhibits EGFR phosphorylation and subsequent activation of a Ras/Rho/ROCK signaling. Therefore, we demonstrate a mechanistic cascade of LPA activating EGFR through Gi and G13 thus inducing a Ras/Rho/ROCK signaling for proteolytic enzyme expression and ovarian cancer cell invasion, as well as interference of the cascade by resveratrol through blocking EGFR phosphorylation. [Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2011-0015761 and 2010-0022216)]
Citation Format: Kang Jin Jeong, Kyung Hwa Cho, Jeong Jin Kim, Moon Jung Choi, Hoi Young Lee. Lysophosphatidic acid induces ovarian cancer cell invasion through EGFR phosphorylation and proteolytic enzyme expression. [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 A61.
Abstract A8: Fibulin-5 (FBLN5) initiates EMT and induces MMPs expression via β1 integrin/EGFR/ERK pathway
Authors: Lee Yonghun , Schiemann William P. 
Published: August 2014

Abstract
Epithelial-mesenchymal transition (EMT) is a normal physiological process that regulates tissue development, remodeling and repair; however, aberrant EMT also elicits disease development in humans, including lung fibrosis, rheumatoid arthritis and cancer cell metastasis. Transforming growth factor-β (TGF-β) is a master regulator of EMT in normal mammary epithelial cells (MECs), wherein this pleiotropic cytokine also functions as a potent suppressor of mammary tumorigenesis. In contrast, malignant MECs typically become resistance to TGF-β-mediated cytostasis and develop the ability to proliferate, invade and metastasize when stimulated by TGF-beta. Therefore, the understanding of how TGF-β promotes EMT may offer new insights into targeting the oncogenic activities of TGF-β in human breast cancers. Previously, we showed that the TGF-β gene target, FBLN5, initiates EMT and enhances that induced by TGF-β. FBLN5 stimulated matrix metalloproteinase (MMP 2,3, and 9) expression and activity, leading to MEC invasion and EMT. While WT FBLN5 induces EMT and MMP expression, RGE mutant (loss of integrin binding activity) of FBLN5 fails to induce EMT and MMP expression. We show here that FBLN5 induces EGFR expression, and the inhibition of EGFR and ERK1/2 MAPK with AG 1478 β3 integrin suppresses FBLN5 induced MMP expression, the expression of D119A mutant β3 integrin fails to suppress FBLN5-induced MMP expression. In addition, knock-down of β1 integrin reverses FBLN5-induced EMT and suppress FBLN5-induced MMPs expression. These results suggest FBLN5 induces EMT and MMP expression in β1 integrin-dependent β1 integrin/EGFR/ERK signaling pathway in MECs. These findings identify a novel EMT and tumor-promoting function for FBLN5 in developing and progressing breast cancers.
Citation Format: Yonghun Lee, William P. Schiemann. Fibulin-5 (FBLN5) initiates EMT and induces MMPs expression via β1 integrin/EGFR/ERK pathway. [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 A8.
Abstract A92: Killing quiescent cancer cells in vitro and in vivo with tumor targeting Salmonella typhimurium A1-R
Authors: Yano Shuya , Zhang Yong , Uehara Fuminari , Hiroshima Yukihiko , Miwa Shinji , Hoffman Robert M. , Zhao Ming 
Published: August 2014

Abstract
Quiescent cancer cells are resistant to cytotoxic agents which target only proliferating cancer cells. Cancer cells were imaged to indicate the cell-cycle phase of each cancer cell in real time in solid tumors growing in vivo as well for cancer cells as in vitro using a fluorescence ubiquitination cell cycle indicator (FUCCI). With FUCCI, quiescent cancer cells express mKusabira-Orange fluorescent protein (red) and proliferating cells express mAzami-Green fluorescent protein (green). FUCCI-labeled cancer cells in monolayer culture and tumor spheres were treated with Salmonella typhimurium A1-R. Time-lapse confocal imaging showed that A1-R encircled and invaded quiescent cancer cells in monlayer culture, thereby eliminating them. Cancer cells in tumor spheres in serum-free culture become and remain quiescent. A1-R infected and killed quiescent cancer cells in tumor spheres. In contrast, cytotoxic agents did not kill quiescent cancer cells in tumor spheres. A1-R infection of FUCCI-expressing subcutaneous tumors growing in nude mice resulted in killing quiescent cancer cells resistant to cytotoxic agents. This study demonstrates that A1-R can kill quiescent cancer cells and suggest a new therapeutic paradigm potentially more effective than current therapy of cancer.
Citation Format: Shuya Yano, Yong Zhang, Fuminari Uehara, Yukihiko Hiroshima, Shinji Miwa, Robert M. Hoffman, Ming Zhao. Killing quiescent cancer cells in vitro and in vivo with tumor targeting Salmonella typhimurium A1-R. [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 A92.
Abstract A95: Therapeutic effects of standardized Wedelia chinensis extract on prostate cancer in vivo
Authors: Hsiao Pei-Wen Hsiao , Tsai Chin-Hsien , Yang Yu-Chih Hsiao , Lee Ming-Ting 
Published: August 2014

Abstract
Globally, prostate cancer is the sixth leading cause of cancer-related death in men with higher prevalence in Western countries. Signaling pathway of androgen receptor plays a central role in the prostate cancer progression. Accordingly, approaches and molecular mechanisms to ablate the androgen receptor function in prostate cancer have been actively studied to improve the disease treatment. However, the disease inevitably develops resistance to all forms of hormonal therapies. To mimic the clinical progression of human prostate cancer in mouse model, we implant human prostate cancer cell lines that were tagged with Luc2 reporter by lentivirus-mediated infection in the prostate gland of nude mouse. After tumor established, the orthotopic xenograft were treated with castration and progressed to castration-resistant prostate cancer (CRPC). While chemotherapy of the CRPC with intravenous docetaxel induced initial tumor regression, the tumors inevitably recurred with subsequent metastasis. We prepared a standardized herbal medicine from Wedelia chinensis plant with compounds that attenuate prostate cancer growth in vivo. Here, we investigated the combinational effect of the herbal remedy and docetaxel in the treatment of CRPC. In contrast to the docetaxel monotherapy, the docetaxel plus herbal remedy significantly delayed the tumor recurrence at primary site and distant sites, among which the CRPC in 27% mice was cured. The promising therapeutic effects of candidate herbal medicine against locally advanced tumor and subsequent metastases warrant further analyses for the underlying cellular and molecular mechanisms. (Supported by Academia Sinica, Career Development Award)
Citation Format: Pei-Wen Hsiao Hsiao, Chin-Hsien Tsai, Yu-Chih Hsiao Yang, Ming-Ting Lee. Therapeutic effects of standardized Wedelia chinensis extract on prostate cancer in vivo. [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 A95.