bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C54: Pdgfrb is an essential mediator of p53(mut)-driven metastasis in pancreatic cancer
Authors: Weissmueller Susann , Saborowski Michael , Manchado Eusebio , Thapar Vishal , Lowe Scott W. 
Published: August 2014

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer due to its high metastatic potential and resistance to existing treatments. Recent advances in cancer genomics have identified mutations and copy number changes that are linked to pancreatic cancer but which of these influence metastatic behavior remain poorly understood. 50-80% of PDACs carry a mutation in the TP53 tumor suppressor gene (p53(mut)), which possibly results in a gain-of-function that contributes to, amongst others, tumor cell invasiveness. Therefore the aim of this study was to explore the underlying molecular pathways of invasive PDAC that are mediated by TP53(mut). To this end, we combined cell lines, murine models, and RNA interference to confirm that p53(mut)-expressing tumors acquire a higher invasive capability, which is dependent on the continued expression of the mutant allele. In-depth transcriptional profiling of p53(mut) versus knockdown cells identified downstream mediators responsible for the gain-of-function phenotype. Specifically, we conducted a follow-up invasion screen to analyse the top 40 deregulated genes for their potential to induce invasiveness and we identified Platelet-derived growth factor receptors isoform b (Pdgfrb) as a p53(mut) downstream mediator. Moreover, we found that the expression of Pdgfrb is transcriptionally regulated by p73. In the presence of p53(mut) proteins, a direct p73-p53(mut) interaction alleviates the inhibitory effect that p73 exerts on the Pdgfrb promoter, thereby inducing Pdgfrb expression and, hence, invasiveness. Attenuating Pdgfrb levels by RNAi or a small molecule inhibitor reduced cellular invasion in a p53(mut) background, thereby mimicking the effects of p53-null cells. We confirmed these findings in several human pancreatic cancer cells. More importantly, we found that elevated Pdgfrb expression in human colorectal and ovarian cancers predicts poor metastasis-free survival, thereby confirming our hypothesis that high Pdgfrb levels drive metastases development.
Citation Format: Susann Weissmueller, Michael Saborowski, Eusebio Manchado, Vishal Thapar, Scott W. Lowe. Pdgfrb is an essential mediator of p53(mut)-driven metastasis in pancreatic cancer. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C54.
Abstract A100: Fibrillar human serum albumin suppresses ovarian cancer metastasis by targeting β1 integrin and its downstream FAK signaling pathways
Authors: Chen Tai-An , Hung Shao-Wen , Chang Yu-Ching , Chen Chih-Yuan , Hsieh Hsin-Ying , Liang Chi-Ming , Liang Shu-Mei 
Published: August 2014

Abstract
Due to the high mortality caused by frequent relapse and metastasis in patients with ovarian cancer, advances in treatment remain necessary. In this study, we developed a chromatographical process which converted native protein human serum albumin (HSA) into a water-soluble nano-fibrillar protein structure and aimed to explore the potential inhibitory effect of fibrillar HSA (F-HSA) on ovarian tumor metastasis. Transwell migration assay, western blotting and gelatin zymography were used to investigate the effects of F-HSA in vitro. Its effects in vivo were evaluated in orthotopic and metastatic xenograft mouse models established using an SKOV3 ovarian cancer cell line that stably expressed green fluorescent protein and luciferase. The fibrillar structure of converted HSA was verified by transmission electron microscopy and Thioflavin T (ThT) fluorescence assay. Treatment with F-HSA decreased the viability, migration and invasion of several ovarian cancer cell lines in vitro. F-HSA bound to β1 integrin receptor to increase PTEN phosphorylation and decrease phosphorylation of FAK and Akt. The inhibitory effect of F-HSA on invasive ability of SKOV3 cells was associated with decreases in phosphorylation of Raf and Erk as well as changes in Crk phosphorylation leading to down-regulation of Rac and MMP2 activities. Orthotopic and metastatic xenograft mouse models showed that F-HSA treatment suppressed tumor growth and metastasis and prolonged survival of SKOV3-bearing mice. These results suggest that F-HSA may have great potential for development as a novel therapeutic agent for metastatic and drug-resistant ovarian cancer.
Citation Format: Tai-An Chen, Shao-Wen Hung, Yu-Ching Chang, Chih-Yuan Chen, Hsin-Ying Hsieh, Chi-Ming Liang, Shu-Mei Liang. Fibrillar human serum albumin suppresses ovarian cancer metastasis by targeting β1 integrin and its downstream FAK signaling 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 A100.
Abstract A17: Regulation of EGFR: Stat3 signaling by Mig6 is required for metastatic outgrowth in triple-negative breast cancer
Authors: Wendt Mike K. , Balanis Nikolas , Schiemann Barbara , Carlin Cathleen , Schiemann William 
Published: August 2014

Abstract
Stat3 is an oncogene that enriches for tumor initiating breast cancer cells. Stat3 activity is driven by numerous signaling inputs, including those initiated by EGFR. Herein we shown that Stat3 is critically involved in EGFR-driven tumorigenesis as EGFR molecules harboring a mutation in the juxtamembrane domain that specifically prevents activation of Stat3 fail to transform mammary epithelial cells. Using this model of EGFR transformation, we previously established that the induction of epithelial-mesenchymal transition (EMT) enhances pulmonary tumor formation. Surprisingly, EMT drastically diminishes the capacity of EGFR to signal to Stat3. Indeed, using the MCF-10A progression series, we show that constitutive activation of Stat3 is consistent with the acquisition of a mesenchymal phenotype but independent of EGFR activity. As a compensatory mechanism, we find that EMT increases the expression and ability of fibronectin to directly activate Stat3 in an EGFR-independent, Jak2-dependent manor. Indeed, human triple-negative breast cancer (TNBC) cells that fail to activate Stat3 in response to EGF robustly activate Stat3 upon fibronectin adhesion. Consistent with these results, TNBC outgrowth in pulmonary 3D-organotypic cultures is enhanced by the addition of fibronectin, a process that is absolutely dependent on β1-integrin, Jak2 and Stat3, but independent of EGFR. Underscoring the importance of this switch from EGFR-mediated to fibronectin-mediated Stat3 activation in metastatic TNBC cells, we demonstrate that shRNA-mediated diminution of the EGFR inhibitory molecule MIG6 results in increased apoptosis and consequently, decreased pulmonary tumor formation by TNBC cells. Our data clearly demonstrate that matrix-initiated signaling is sufficient to drive Stat3 activation, a reaction that likely contributes to the resistance of metastatic TNBCs to molecular therapies, particularly those that target EGFR.
Citation Format: Mike K. Wendt, Nikolas Balanis, Barbara Schiemann, Cathleen Carlin, William Schiemann. Regulation of EGFR: Stat3 signaling by Mig6 is required for metastatic outgrowth in triple-negative 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 A17.
Abstract A43: Direct visualization of changes of lymphatic function and drainage pathways in lymph node metastasis of B16F10 melanoma using near-infrared fluorescence imaging
Authors: Kwon Sunkuk , Agollah Germaine , Wu Grace , Sevick-Muraca Sevick 
Published: August 2014

Abstract
The lymphatic system provides an initial route for cancer cell dissemination in many cancers including melanoma. However, it is largely unknown how the lymphatic system changes during tumor progression, due in part to the lack of imaging techniques available. In this study, we non-invasively imaged changes of lymphatic function and drainage patterns using dynamic near-infrared fluorescence (NIRF) imaging.
Dynamic NIRF imaging following intradermal injection of indocyanine green (ICG) was conducted in C57BL/6 mice prior to inoculation of B16F10 murine melanoma cells to the dorsal foot for baseline data and until 21 days post-implant (p.i.). A series of acquired fluorescent images were quantified to measure lymphatic contractile function. Computed tomography (CT) was also performed to measure the volume of tumor-draining lymph nodes (LNs). In addition, intravital color images using a stereomicroscope were acquired after a skin incision. Then, the PLNs and inguinal LNs (ILNs) were harvested for ex vivo NIRF and intravital color imaging.
We observed significant reduction of lymphatic contractility from 7 days p.i. until 21 days p.i.. Altered lymphatic drainage patterns were detected at 21 days p.i., due to lymphatic obstruction of normal lymphatic drainages caused by extensive tumor invasion of draining LNs. Magnified fluorescent images of tumor-draining lymphatic vessels showed numerous fluorescent lymphatic vessels at day 21 p.i. as compared to well-defined fluorescent vessels from a baseline image. Our CT data showed enlarged tumor-draining PLNs at 21 days p.i. and intravital images confirmed the PLN harbored melanoma cells. Overlay of white light and fluorescent images of dissected LNs showed strong ICG fluorescence in the ILN and to less extent in the PLN on the tumor bearing side, indicating significantly reduced lymph flow to the PLN due to blockage of normal lymph flow by tumor in the PLN.
Since lymphatic function and architecture were progressively altered during tumor growth and metastasis, non-invasive NIRF imaging may provide a new method to stage disease. In addition, this novel technique can be used as a diagnostic method to non-invasively assess lymphatic response as mechanism of therapeutic action.
Citation Format: Sunkuk Kwon, Germaine Agollah, Grace Wu, Sevick Sevick-Muraca. Direct visualization of changes of lymphatic function and drainage pathways in lymph node metastasis of B16F10 melanoma using near-infrared fluorescence imaging. [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 A43.
Abstract A47: Microfluidic in vitro platform for imaging metastasis: Perfusable microvascular networks and cancer cells on a microfluidic chip
Authors: Jeon Noo Li , Kim Sudong , Hyunjae Lee , Minhwan Chung 
Published: August 2014

Abstract
In vivo imaging has provided significant insights to different mechanisms involved in cancer metastasis. An in vitro experimental platform that reproduce cancer microenvironment with blood vessels, tumors, immune cells and others would allow more detailed experiments with more experimental conditions can complement the animal studies.
We describe a reproducible, in vitro approach to grow perfusable 3D microvascular networks on a microfluidic chip. These engineered blood vessels exhibit morphological and biochemical markers of tight junctions, apical-basal polarity, basement membrane deposition, and upregulated markers in response to inflammatory cues.
A novel microfluidic device was designed and tested for real-time imaging of various steps of cancer metastasis. Perfusable microvascular networks formed within the microfluidic device reproduce the 3D cellular niche, facilitating high-resolution live imaging of cancer cell extravasation. This approach provides a platform for developing physiologically complex but experimentally straightforward human disease models and holds potential for medical and pharmaceutical applications in drug screening and basic cancer biology.
Citation Format: Noo Li Jeon, Sudong Kim, Lee Hyunjae, Chung Minhwan. Microfluidic in vitro platform for imaging metastasis: Perfusable microvascular networks and cancer cells on a microfluidic chip. [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 A47.
Abstract A5: Functional role of SOX2 in hypoxia-mediated metastasis-associated functions in prostate cancer
Authors: Dai Yao , Bae Kyung-Mi , Vieweg Johannes , Siemann Dietmar W. 
Published: August 2014

Abstract
Purpose: SOX2 is a typical embryonic stem cell marker that is involved in not only tumorigenesis but also metastasis in several human malignancies including prostate cancer. Hypoxia has been demonstrated as a common feature of prostate cancer that is associated with disease progression and poor prognosis. Although SOX2 has been shown to be activated by oxygen depletion in other cancer types, its functional role under hypoxic microenvironment in prostate cancer setting and its association with hypoxia inducible factors (HIFs) have not been reported. In the present study, we evaluate the role of SOX2 in hypoxia-mediated cellular behaviors associated with metastasis, including invasion and sphere formation, in prostate cancer cells.
Experimental Design: A tissue microarray containing samples from 80 prostate cancer patients was employed to examine the expression of HIF-1α and its correlation with SOX2 by immunohistochemical analysis. Expression of stem cell markers and HIFs was detected by Western blot. The role of SOX2 and HIF-1/2α in the regulation of cell invasion and sphere formation with various hypoxic exposures was investigated by short hairpin RNA (shRNA) - mediated knockdown in PC-3, DU145 and LNCaP cells.
Results: HIF-1α expression was significantly elevated in prostate cancer compared to non-malignant prostate tissues, and in tumors HIF-1α was strongly correlated with SOX2. In all three prostate cancer cells, while HIF-1α and HIF-2α were mainly induced under short term (acute) and long term (chronic) hypoxic conditions, respectively, SOX2 was the only one among five stem cell markers that was stimulated by both hypoxic exposures. Genetic depletion of SOX2 attenuated capacities of tumor cells to invade under acute hypoxia and form spheroids under chronic hypoxia. In addition, knockdown of HIF-1α but not HIF-2α decreased acute hypoxia-mediated cell invasion, whereas only HIF-2α gene silencing resulted in reduced sphere formation capacity mediated by long term oxygen deprivation.
Conclusions: SOX2 is suggested to be correlated with hypoxia in prostate cancer. SOX2 plays an important role in acute hypoxia-induced invasiveness and chronic hypoxia-induced stemness that is associated with HIF-1α and HIF-2α activation, respectively. These results indicate that SOX2 may be a key mediator for hypoxia-induced metastasis-associated functions hence may serve as a potential target for therapeutic interventions for advanced prostate cancer.
Citation Format: Yao Dai, Kyung-Mi Bae, Johannes Vieweg, Dietmar W. Siemann. Functional role of SOX2 in hypoxia-mediated metastasis-associated functions in prostate 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 A5.
Abstract A74: Tumor secreted Hsp90 initiates tumor growth and the epithelial to mesenchymal transition (EMT) in prostate cancer
Authors: Hance Michael W. , Nolan Krystal , Gopal Udhayakumar , Bohonowych Jessica E. , Jezierska-Drutel Agnieszka , Neumann Carola A. , Liu Haibo , Isla Garraway P. , Franco Omar E. , Hayward Simon W. , Isaacs Jennifer S. 
Published: August 2014

Abstract
Prostate cancer (PCa) is the most frequently diagnosed malignancy and second most common cause of cancer related lethality in men. Disease mortality is due primarily to metastatic spread, highlighting the urgent need to identify factors involved in this progression. Increased secretion of heat shock protein 90 (Hsp90) has been reported in diverse cancer cells, and secreted, or extracellular Hsp90 (eHsp90) is also found in patient plasma. Although eHsp90 promotes cancer cell motility and invasion and facilitates tumor metastasis, the mechanistic basis for its activity has remained unknown. The goal of this study was to explore whether extracellular Hsp90 (eHsp90) may play a role in PCa progression. To explore this, 3 sets of lineage-related differentially metastatic cell pairs were utilized to evaluate eHsp90 expression and activity. We found that eHsp90 secretion correlated with PCa aggressiveness. To evaluate the functional role of eHsp90, we modulated its expression and activity. Upregulation of eHsp90 was accomplished by exposure of prostate epithelial cells to exogenous Hsp90 protein, or alternatively, cells were transduced with a lentivirus directing the secretion of Hsp90. Blockade of eHsp90 function was accomplished by exposure of cells to anti-Hsp90 antibodies or to a cell-impermeant specific inhibitor of Hsp90. We demonstrate that eHsp90 is a critical factor required for PCa cell motility and for initiation of the epithelial to mesenchymal transition (EMT) genetic program. Moreover, modest increases in eHsp90 were sufficient to induce tumor growth and localized invasion in a subrenal capsule xenograft model of PCa. Finally, eHsp90 was detected in human cancer specimens and its expression was correlated with upregulated expression of pro-invasive genes. Our findings offer insights into the mechanistic basis of eHsp90 in PCa, and further support a putative clinical role for eHsp90 as a potential driver of PCa progression.
Citation Format: Michael W. Hance, Krystal Nolan, Udhayakumar Gopal, Jessica E. Bohonowych, Agnieszka Jezierska-Drutel, Carola A. Neumann, Haibo Liu, Garraway P. Isla, Omar E. Franco, Simon W. Hayward, Jennifer S. Isaacs. Tumor secreted Hsp90 initiates tumor growth and the epithelial to mesenchymal transition (EMT) in prostate 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 A74.
Abstract A75: Circulating tumor cells in human breast cancer exhibit dynamic changes in epithelial and mesenchymal composition
Authors: Yu Min , Bardia Aditya , Wittner Ben , Stott Shannon , Smas Malgorzata , Ting David , Isakoff Steven , Ciciliano Jordan , Wells Marissa , Shah Ajay , Concannon Kyle , Donaldson Maria , Sequist Lecia , Brachtel Elena , Sgroi Dennis , Baselga Jose , Ramaswamy Sridhar , Toner Mehmet , Haber Daniel , Maheswaran Shyamala 
Published: August 2014

Abstract
Epithelial mesenchymal transition (EMT) has been postulated to contribute to the dissemination of cancer cells, but supporting histopathological evidence is limited. We used a microfluidic device to isolate circulating tumor cells (CTCs), combined with multiplex RNA-in-situ hybridization (ISH) and RNA sequencing, to quantify and characterize EMT in breast CTCs. Whereas only rare cells in the primary tumor expressed both mesenchymal and epithelial markers, such biphenotypic as well as purely mesenchymal cells were enriched among CTCs, across all histological subtypes of breast cancer. Analysis of treatment responses in 10 patients suggested an association of mesenchymal CTCs with disease progression. In an index patient followed longitudinally, fluctuation in epithelial and mesenchymal states was observed as a function of initial response and subsequent resistance to therapy. Mesenchymal markers were predominant in clusters of tumor cells, many of which had adherent platelets. Finally, RNA sequencing of CTC clusters identified EMT-related signatures, including FOXC1, a known transcriptional regulator of EMT. Together, these data support a role for EMT in the blood-borne dissemination of breast cancer and point to the dynamic nature of this cell fate change.
Citation Format: Min Yu, Aditya Bardia, Ben Wittner, Shannon Stott, Malgorzata Smas, David Ting, Steven Isakoff, Jordan Ciciliano, Marissa Wells, Ajay Shah, Kyle Concannon, Maria Donaldson, Lecia Sequist, Elena Brachtel, Dennis Sgroi, Jose Baselga, Sridhar Ramaswamy, Mehmet Toner, Daniel Haber, Shyamala Maheswaran. Circulating tumor cells in human breast cancer exhibit dynamic changes in epithelial and mesenchymal composition. [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 A75.
Abstract A85: Novel mouse models to investigate the molecular pathogenesis of metastatic osteosarcoma
Authors: Zhao Shuying , Kurenbekova Lyazat , Donehower Lawrence A. , Yustein Jason T. 
Published: August 2014

Abstract
Background: Osteosarcoma (OS) is the primary bone tumor in the pediatric population with the main determinant for patient prognosis being the presence of metastatic disease. Approximately 25-30% of patients will present with metastatic osteosarcoma. Patients with metastatic disease have long-term survival rates often &lt;20%.
Objectives: We hypothesize that the molecular pathogenesis of metastatic osteosarcoma is different from localized disease. We intend this work to provide a relevant, endogenous model of metastatic OS that can be utilized to advance our understanding of the molecular pathogenesis of the disease, insights into novel therapeutic targets and as a pre-clinical model for investigating the efficacy of novel therapies.
Design: We have developed a tissue-specific alteration of the p53 status by using osteoblast specific Cre-recombinase expressing mice to generate progeny that spontaneously form endogenous osteosarcomas. Through the use of a mutated, gain of function form of p53, shown previously to be associated with metastatic disease, we have developed a novel immunocompetent model that significantly enhances the endogenous development of metastatic OS.
Results: Tumor analysis has revealed genetic insights in the metastatic progression of osteosarcoma. These include the significant downregulation of Wnt-signaling inhibitors, such as NKD2, APCDD1 and Wnt5a in the metastatic tumors. Functional studies have determined that overexpression of NKD2, also downregulated in several human OS metastatic cell lines, in metastatic mouse OS cell lines leads to a significant decrease in metastatic lung lesions upon transplantation into immunodeficient mice. Possible NKD2-dependent functions include regulation of not only the Wnt signaling pathway, but also blood vessel formation, regulation of cell migration and cell adhesion.
We have also noted the dysregulation of several critical microRNAs in metastatic OS, including the upregulation of mir-130b in the metastatic lesions. This particular microRNA has recently been shown to have clinical correlation in Ewing's sarcoma, with higher levels of tumor mir-130b having a significantly poorer outcome. We are actively pursuing the role of this (and other) microRNA(s) in the molecular pathogenesis of metastatic osteosarcoma.
Conclusion: This novel model has enabled valuable molecular insights into the development and progression of metastatic OS that can lead to the identification of novel therapeutic targets.
Citation Format: Shuying Zhao, Lyazat Kurenbekova, Lawrence A. Donehower, Jason T. Yustein. Novel mouse models to investigate the molecular pathogenesis of metastatic osteosarcoma. [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 A85.