bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B71: Syndecan-1 promotes breast cancer metastasis by modulating tissue stiffness
Authors: Chute Colleen L. , Keely Patricia , Alexander Caroline , Friedl Andreas 
Published: August 2014

Abstract
Tumor-stroma interactions are integral to breast cancer progression and metastasis. It has been well established that women with dense breast tissue have increased risk of developing breast cancer as compared to women with less dense breast tissue; it has also been documented that a stiffer extracellular matrix (ECM) can promote tumor cell invasion both in vitro and in vivo. Our lab has previously shown that Syndecan-1 (Sdc1), a cell surface heparan sulfate proteoglycan, regulates the in vitro organization of a fibroblast-constructed ECM that thus creates an invasion-permissive microenvironment. Therefore, we sought to characterize the role of stromal Sdc1 in cancer progression in vivo. Using the 4T1 model of late stage metastatic breast cancer in both Sdc1 wild-type (WT) and Sdc1 knock-out (KO) mice, we assayed for tumor metastasis from orthotopic tumor cell implants. Sdc1 deficiency in the host did not influence the primary tumor weight or growth rate, but significantly reduced the incidence and the number of metastatic lesions (p&lt;0.001, p&lt;0.0001, respectively). In an effort to dissect out the mechanism by which loss of stromal Sdc1 is inhibiting metastasis, we analyzed the tumor microenvironment for the presence of specific cell types and structural differences. There was no difference in the recruitment of macrophages, the activation of fibroblasts, angiogenesis, or the structure or deposition of collagen between 4T1-induced tumors in the Sdc1 WT and Sdc1 KO mice. Interestingly, preliminary data suggest the tumors from the Sdc1 WT mice are significantly stiffer than the tumors from Sdc1 KO mice, as measured by atomic force microscopy. To determine whether Sdc1 was influencing later stages of metastasis we injected tumor cells via tail vein to specifically assay extravasation and metastatic outgrowth. After 2 weeks, all mice assayed had metastatic lesions but the Sdc1 WT mice had significantly more numerous and larger lesions (p&lt;0.004, p&lt;0.05, respectively). These data indicate that the presence of stromal Sdc1 promotes tumor cell outgrowth in the metastatic target organ, but may not play as large a role in tumor cell extravasation based on the finding that all mice assayed had metastatic lesions. These results further suggest that Sdc1 influences breast cancer metastasis by promoting increased tissue stiffness, which promotes tumor cell invasion and tumor outgrowth at secondary metastatic target organs, and ultimately promotes formation of metastatic lesions.
Citation Format: Colleen L. Chute, Patricia Keely, Caroline Alexander, Andreas Friedl. Syndecan-1 promotes breast cancer metastasis by modulating tissue stiffness. [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 B71.
Abstract B73: Unraveling the role of a novel endoplasmic reticulum protein in cancer cell migration
Authors: Evensen Nikki Ann , Kuscu Cem , Dufour Antoine , Zucker Stanley , Cao Jian 
Published: August 2014

Abstract
Although considerable progress has been made in our understanding of cancer cell invasion, much of this complex cellular process remains a mystery, ultimately hindering advancements in treatment strategies targeting metastasis. Here we report, for the first time, the vital role of a novel endoplasmic reticulum (ER) resident protein identified by a PCR-subtraction hybridization technique, designated Cancer ER Invasion Gene (CERIG), in cancer cell migration and invasion. Clinical relevance of CERIG is highlighted by upregulation of CERIG in human invasive breast cancer specimens examined by immunohistochemistry and real-time RT-PCR, as well as increased expression in various other forms of human cancer as determined by data mining. This up-regulation of CERIG correlates with poor prognosis of patients with breast cancer assessed by a DNA microarray data-mining approach from three publicly available cohorts containing a total of 696 breast cancer patients. Silencing of CERIG in metastatic MDA-MB-435 cancer cells disrupted mesenchymal morphogenesis in vitro, resulting in a mesenchymal-to-epithelial transition, and interfered with cancer metastasis in vivo. Employing both gain- and loss-of-function approaches, CERIG was found to induce cancer cell migration and invasion. Enhanced cell migration required retention of CERIG within the ER, where this protein forms a stable complex with the ER chaperone protein, GRP78/BiP. Mutagenesis studies identified a novel ER retention motif within CERIG required for its ER localization, BiP interaction, and enhanced migration. Furthermore, fusion of the ER-retention domain to a soluble matrix metalloproteinase (MMP) prevents the secretion of the MMP by retaining it in the ER. Mechanistically, overexpression of CERIG results in ER calcium leakage via the inositol trisphosphate receptor (IP3R) and a subsequent increase in cytosolic calcium, ultimately resulting in activation of PKCα and cell migration. Moreover, chelating intracellular calcium abrogates CERIG induced PKCα activation and cell migration. Taken together, our data indicate that CERIG, as a novel ER resident protein, plays an important role in cancer progression, serving as a novel cell migration-promoting gene.
Citation Format: Nikki Ann Evensen, Cem Kuscu, Antoine Dufour, Stanley Zucker, Jian Cao. Unraveling the role of a novel endoplasmic reticulum protein in cancer cell migration. [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 B73.
Abstract B77: Curcumin deteriorates trabecular and cortical bone in mice bearing metastatic Lewis lung carcinoma
Authors: Yan Lin 
Published: August 2014

Abstract
Bone is a major target of metastasis for many malignancies; curcumin has been studied for its role in cancer prevention including early phase clinical trials for its efficacy and safe use with cancer patients. The present study investigated the effects of dietary supplementation with curcumin (2% and 4%) on (1) pulmonary metastasis of Lewis lung carcinoma and (2) bone microstructural changes in female C57BL/6 mice. Curcumin significantly increased the size of lung metastases, which was accompanied with significant increases in plasma concentrations of angiogenic factors (e.g. angiogenin, VEGF) and inflammatory cytokines (e.g. IL-1β, MCP-1). Morphometric analysis showed that curcumin at 2% and 4% dietary levels significantly reduced bone volume to total volume ratio (BV/TV), connective density (Conn.D.) and trabecular number (Tb.N.) and significantly increased structure model index (SMI, an indicator of the plate- and rod-like geometry of trabecular structure) and trabecular separation (Tb.Sp.) in vertebral bodies, and at the 4% level curcumin significantly reduced BV/TV and Tb.N. and at either level it significantly reduced trabecular thickness (Tb.Th.) in distal femurs compared with the controls. In the mid-shaft of femur, curcumin at the 4% level significantly reduced cortical bone area to total area ratio (Ct.Ar/Tt.Ar.) and cortical thickness (Ct.Th.) compared with the controls. Furthermore, curcumin feeding resulted in dose-dependent decreases in plasma concentrations of osteocalcin (a marker of bone formation) and increases plasma tartrate-resistant acid phosphate 5b (a marker of bone resorption) compared with the controls, indicating that curcumin may deteriorate trabecular and cortical bone by disrupting the balance of bone remodeling. As skeleton is a favored site of metastasis for many cancers, our results that curcumin (1) enhances metastatic growth and (2) results in osteolytic deterioration of bone suggest the need of assessment of bone structural changes for curcumin cancer prevention studies, particularly for human trials with cancer patients who are the risk of malignant spread, to determine the curcumin effects and its interaction with malignancy on skeleton health.
Citation Format: Lin Yan. Curcumin deteriorates trabecular and cortical bone in mice bearing metastatic Lewis lung carcinoma. [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 B77.
Abstract B81: Angiomodulin (AGM/IGFBP-rP1) is overexpressed in tumor vasculature and regulates adhesion of vascular endothelial cells via integrin αvβ3: Possible roles in tumor angiogenesis
Authors: Miyazaki Kaoru , Komiya Eriko , Sato Hiroki , Miyagi Yohei , Higashi Shouichi 
Published: August 2014

Abstract
Angiomodulin (AGM) is a member of insulin-like growth factor binding protein (IGFBP) superfamily and often called IGFBP-rP1. Our past studies identified this protein as a tumor-derived cell adhesion factor (TAF) that is highly accumulated in blood vessels of human cancer tissues (PNAS 93:8384, 1996). Recently we found that AGM is overexpressed in not only vasculature but also stromal fibroblasts in some human cancers (Cancer Sci 4:691, 2012). AGM stimulates the growth of fibroblasts and their expression of fibronectin and α-smooth muscle actin, inducing their morphological change to a myofibroblast-like shape. It is supposed that AGM activates cancer-associated fibroblasts (CAFs) and increases cancer stroma. In contrast to these findings, tumor-suppressing activity of AGM has been reported by other studies. To clarify the roles of AGM in tumor progression, we here investigated the distribution of AGM in benign and invasive breast cancers and its regulatory factors and biological activities. Immunohistochemical analysis showed that AGM was greatly expressed in tumor vasculature even in ductal carcinoma in situ (DCIS) as compared to normal vasculature, while its expression in CAFs was more prominent in invasive carcinomas than DCIS. In vitro analyses showed that AGM was markedly induced by VEGF in vascular endothelial cells but by TGF-β in fibroblasts. Although AGM did not significantly affect the growth of endothelial cells, it potently promoted the adhesion of endothelial cells through integrins. Experiments with neutral anti-integrin antibodies revealed that the cell adhesion activity was mediated mainly by integrin αvβ3 and weakly by integrin α2β1. AGM induced cytoskeletal change in endothelial cells. Furthermore, AGM and integrin αvβ3 were colocalized at high levels in tumor vasculature. These results suggest that AGM regulates angiogenesis and other vascular functions as a ligand of integrin αvβ3 in cancer tissues. The data also indicate that AGM is induced by different mechanisms and plays different roles in tumor progression between CAFs and vasculature.
Citation Format: Kaoru Miyazaki, Eriko Komiya, Hiroki Sato, Yohei Miyagi, Shouichi Higashi. Angiomodulin (AGM/IGFBP-rP1) is overexpressed in tumor vasculature and regulates adhesion of vascular endothelial cells via integrin αvβ3: Possible roles in tumor angiogenesis. [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 B81.
Abstract B87: Antiangiogenic and antimetastatic activities of cat's whiskers tea (Orthosiphon stamineus) extract against colon cancer cell line
Authors: Alsuede Fouad Saleih , Majid Aman Shah Abdul , B Khadeer Ahamed Mohamed , Ismail Z , Kadir M.O , Majid Amin Malik Shah Abdul 
Published: August 2014

Abstract
Orthosiphon stamineus is a popular medicinal herbal tea that is traditionally used for inflammatory joint condition, diabetes and hypertension. In this study we found that the 50% ethanolic extract of O. stamineus strongly suppressed angiogenesis in isolated rat aortic tissues and prevented the formation of chorionic plexus in chick embryo. The extract also inhibited the formation of blood vessels in matrigel plug implanted in mice. A significant inhibition of important stages of HCT-116 colon cancer cells metastasis, invasion, and migration was also observed with significant inhibitory effect of on the growth of the neoplastic cells. However, the extract displayed low cytotoxicity towards human tumor cell lines such as K562, HL-60, Skno-1, MCF-7, HCT-116 and Hep G2, and normal human colonic fibroblast CCD-18Co. HPLC analysis reveals that the extract is abundant with rosmarinic acid, eupatorin, sinensetin, etc. This work highlights usefulness of O. stamineus in treating colon cancer.
Note: This abstract was not presented at the conference.
Citation Format: Fouad Saleih Alsuede, Aman Shah Abdul Majid, Khadeer Ahamed Mohamed B, Z Ismail, M.O Kadir, Amin Malik Shah Abdul Majid. Antiangiogenic and antimetastatic activities of cat's whiskers tea (Orthosiphon stamineus) extract against colon cancer cell line. [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 B87.
Abstract C13: The role of cancer heterogeneity in metastasis
Authors: Shin Yoojin , Jeong Hyo Eun , Han Sewoon , Won Jihee , Chung Seok 
Published: August 2014

Abstract
Breast cancer doesn't contain only one colony of tumor cells. It appears to have heterogeneous cell composition of characteristically different subtypes with distinct molecular and gene expression signatures. Due to the tumor heterogeneity, which determines the risk of metastatic progression and drug resistance, it is difficult to predict progression patterns of cancer and provide the most suitable treatment to patients.
Most research has focused on molecular definition and genetic association for the cancer heterogeneity studies. However, lack of in vitro models to precisely mimic the heterogeneous conditions of tumors has made it difficult to understand the role of heterogeneity in metastasis, especially invasion.
So, to precisely regulate heterogeneous microenvironment of tumors and evaluate the role of the heterogeneity on invasion & metastasis, we developed a microfluidic in vitro assay incorporating 3D ECM scaffolds that emulate in vivo tumor microenvironment in 3D. We cultured highly invasive breast cancer cell, MDA-MB-231, and non-invasive breast cancer cell, MCF-7, together in a mixed population and let the cells interact with other cells and ECMs.
As a result, we found that heterogeneity in cancer cell population promotes metastatic potential. Highly invasive breast cancer cells, MDA-MB-231, made microtracks in ECM and leaded collective migration of non-invasive breast cancer cells, MCF-7, into the microtracks. When MCF-7 were cultured alone, MCF-7 cells didn't invade into ECM. It has been widely announced that only stromal cells such as fibroblast remodel ECM and enhance the invasion potential of cancer cells. However, from the result of our experiment, cancer cells that have different characteristics in single tumor can promote the metastatic potential, result from that ECM remodeling (generating microtracks) by highly invasive cancer cells. It was precisely investigated by IF, rt-PCR and TEM analysis in microfluidic environments. Understanding about not only genetic and molecular definition of cancer heterogeneity, but also the role of heterogeneous cancer cell population in metastatic dissemination, could help new drugs and therapeutic strategies development.
Citation Format: Yoojin Shin, Hyo Eun Jeong, Sewoon Han, Jihee Won, Seok Chung. The role of cancer heterogeneity in metastasis. [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 C13.
Abstract C18: Matrix metalloproteinase-1 (MMP-1) facilitates intravasation and vascular dissemination of human carcinoma cells by regulating the microarchitecture and permeability of intratumoral vasculature
Authors: Juncker-Jensen Anna , Casar Berta , Rimann Ivo , Zajac Ewa , Kupriyanova Tatyana A. , Deryugina Elena I. , Quigley James P. 
Published: August 2014

Abstract
Patients with squamous cell carcinomas (SCCs) often present with advanced stage disease and face one of the lowest 5-year post-therapeutic survival rates. Among 25 signature genes, Mmp1 has been found to be third best SCC tumor predictor, suggesting a critical role of MMP-1 in SCC progression. Functional role of MMP-1 in SCCs was analyzed in this study by employing a highly-disseminating variant of human epidermoid HEp-3 carcinoma, HEp3-hi/diss. The dissemination capacity of HEp3-hi/diss cells in chick embryo spontaneous metastasis models positively correlated with their high levels of MMP-1 expression. MMP-1-deficiency induced by RNA interference resulted in 70-95% inhibition of HEp3-hi/diss intravasation, concomitant with collapse of the intravasation-sustaining microarchitecture of intratumoral vasculature. Furthermore, we have demonstrated the mechanism whereby HEp3-hi/diss-produced MMP-1 contributes to tumor cell intravasation by proteolytically inducing vascular endothelial permeability and increasing rates of carcinoma cells crossing over vascular barriers during the intravasation step of the metastatic cascade.
Citation Format: Anna Juncker-Jensen, Berta Casar, Ivo Rimann, Ewa Zajac, Tatyana A. Kupriyanova, Elena I. Deryugina, James P. Quigley. Matrix metalloproteinase-1 (MMP-1) facilitates intravasation and vascular dissemination of human carcinoma cells by regulating the microarchitecture and permeability of intratumoral vasculature. [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 C18.
Abstract C20: CXCR4 antagonist inhibits perineural invasion of adenoid cystic carcinoma in preclinical murine model
Authors: Jeong Woo-Jin , Choi Ik Joon , Park Min-Woo , An Soo-Youn , Jeon Eun-Hui , Paik Jin Ho , Sung Myung-Whun , Ahn Soon-Hyun 
Published: August 2014

Abstract
Background. Perineural invasion is a characteristic feature of salivary adenoid cystic carcinoma (ACC). Expression of CXCR4 is also a characteristic feature of ACC which distinguishes it from other non-neurotropic head and neck cancers. Therefore, CXCR4 may play a role in the perineural invasion of ACC. In this study, we aimed to demonstrate CXCR4 expression in ACC, to identify its association with perineural invasion, and to investigate the impact of CXCR4 inhibitor in vitro and in a murine perineural invasion model.
Materials & Methods. Expression of CXCR4 was assessed in ACC cell lines and in human tissue. The effect of gene knockdown using siRNA and a specific blocker of CXCR4 (AMD3100) were evaluated in vitro. A preclinical perineural invasion model was developed using BALB/c nude mouse. The effect of AMD3100 was evaluated in vivo.
Results. CXCR4 was highly expressed in aggressive strains of ACC in vitro, in the tumor in the animal model, and in the tumor of human tissue. SDF-1 expression was also demonstrated in the nerve of murine and human tissue. Gene knockdown by siRNA and inhibition by a CXCR4 specific inhibitor AMD3100 effectively abrogated invasion but not proliferation of ACC in vitro. The rate of perineural invasion was significantly decreased with AMD3100 treatment in the animal model (71.4% vs 18.8%, P=.009).
Conclusions. CXCR4 is highly expressed in ACC and is associated with perineural invasion. AMD3100, which can effectively diminish perineural invasion of ACC in vitro and in vivo, may have an adjuvant role in the management of ACC.
Citation Format: Woo-Jin Jeong, Ik Joon Choi, Min-Woo Park, Soo-Youn An, Eun-Hui Jeon, Jin Ho Paik, Myung-Whun Sung, Soon-Hyun Ahn. CXCR4 antagonist inhibits perineural invasion of adenoid cystic carcinoma in preclinical murine model. [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 C20.
Abstract C28: N-Myc interactor: A gatekeeper of malignant progression
Authors: Samant Rajeev S. , Devine Daniel J. , Rostas Jack W. , Metge Brandon J. , Shevde Lalita A. 
Published: August 2014

Abstract
Metastasis is the most lethal attribute of cancer progression. It is becoming increasingly evident that epithelial-mesenchymal transition (EMT) is one of the critical events in the metastatic process of solid tumors. Thus, understanding the molecular signaling that negatively influences EMT is of high importance. Here, we present interesting findings about the novel involvement of N-Myc Interactor (NMI) in restricting EMT.
We observed that NMI expression is significantly compromised in advanced breast malignancies. Restoring its expression restricts malignant activities of breast cancer cell lines in vivo and in vitro. Specifically, exogenous expression reduces invasive and migratory potential of tumor cells along with remarkable morphologic transition towards an epithelial appearance. In addition, several key EMT markers such as TWIST, MMP2, SNAI2 and ZEB2 were reduced along with a concomitant gain of epithelial markers such as E-cadherin and Keratin 18. Conversely, silencing NMI from an immortalized breast epithelial line rendered the cells more mesenchymal. Studies using a variety of additional epithelial cell lines consistently revealed that silencing NMI expression coincided with increased expression of both ZEB2 and SNAI2, while NMI overexpression resulted in decreased expression. These expression profile changes were accompanied with significant changes in cell morphology in both 2-dimensional and 3D culture systems. Thus expression of NMI appears to be necessary and sufficient for maintaining the epithelial phenotype.
TGF-β signaling is one of the key signaling pathways that influence EMT. We observed that NMI negatively regulates SMAD driven transcription. We noticed that NMI is able to contribute to this regulation by positively regulating the expression of the inhibitory SMAD, SMAD7. Overall, our data strongly suggests that loss of NMI may be one of the pivotal events in deregulation of TGF-β/SMAD signaling in invasive breast cancers. This loss leads to increased expression of EMT-inducing transcription factors that drive tumor growth and EMT-dependent malignant progression.
Citation Format: Rajeev S. Samant, Daniel J. Devine, Jack W. Rostas, Brandon J. Metge, Lalita A. Shevde. N-Myc interactor: A gatekeeper of malignant progression. [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 C28.