bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A97: Antitumor effect of metformin in breast cancer is associated with AMPK and FOXO3a activation
Authors: Fonseca Eveline A I , Oliveira Maria Aparecida , Eichler Rosangela , Akamine Eliana H. , Carvalho Maria Helena C. , Barbosa Aneli M. , Dekker Robert F. H. , Khaper Neelam , Fortes Zuleica B. 
Published: August 2014

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR15) of the Conference Proceedings.
Citation Format: Eveline A I Fonseca, Maria Aparecida Oliveira, Rosangela Eichler, Eliana H. Akamine, Maria Helena C. Carvalho, Aneli M. Barbosa, Robert F. H. Dekker, Neelam Khaper, Zuleica B. Fortes. Antitumor effect of metformin in breast cancer is associated with AMPK and FOXO3a activation. [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 A97.
Abstract B102: Fibroblast-dependent modulation of drug sensitivity, stemcellness, and tumor cell dormancy
Authors: Paulsson Janna , Strell Carina , Roswall Pernilla , Rannikmae Helena , Weiland Anne , Rydén Lisa , Östman Arne 
Published: August 2014

Abstract
Solid tumors are composed of tumor cells and different cell types making up the tumor stroma — endothelial cell, pericytes, immune cells and cancer associated fibroblasts. We focus on the impact of cancer associated fibroblasts on the stem cell properties of tumor cells, including drug sensitivity, anchorage independent growth and tumor initiating capacities. Previous work in our group showed that expression of platelet derived growth factor receptor β (PFGFRβ) in the tumor stroma is associated with worse prognosis in breast cancer. Furthermore, two experimental approaches were used to explore PDGFR-dependent paracrine signaling: (1) primary human breast fibroblasts isolated from normal as well as cancer tissue co-cultured with human breast cancer cell lines and (2) tumor cells, cancer associated fibroblasts and normal breast tissue fibroblasts derived from a genetic breast cancer mouse model.
When looking at PFGFRβ expression in tumors from a randomized tamoxifen study we found that tumors with high expression in the tumor stroma did not seem to respond to the treatment. Ongoing in vitro studies are analyzing the impact of co-cultured fibroblasts on breast cancer cell tamoxifen sensitivity in vitro. Specifically we want to investigate how PDGF receptors, expressed by the tumor stroma, play a role in the sensitivity to tamoxifen by the tumor cells.
We have also investigated the impact of fibroblasts on stemness properties of tumor cells derived from tumors of the MMTV polyoma middle T antigen driven mouse breast cancer model. Conditioned medium of tumor associated fibroblasts but also from normal mouse breast tissue fibroblasts increased the anchorage independent sphere forming capacity of the tumor cells in vitro. Conditioned media from the tumor cells themselves had similar effects. Tumor-supporting effects of fibroblasts were confirmed after orthotopic coinjection of tumor cells together with fibroblasts in syngeneic mice. The presence of fibroblasts resulted in a significant increase in the tumor take rate.
Together these studies identify fibroblast-mediated modulation of “stemness” of breast cancer cells and a PDGFR-dependent modulation by fibroblasts of tamoxifen-sensitivity.
Citation Format: Janna Paulsson, Carina Strell, Pernilla Roswall, Helena Rannikmae, Anne Weiland, Lisa Rydén, Arne Östman. Fibroblast-dependent modulation of drug sensitivity, stemcellness, and tumor cell dormancy. [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 B102.
Abstract B2: Oligodendritic precursor mediates vascular remodeling within glioma microenvironment in PDGF-C dependent manner
Authors: Huang Yujie , Lyden David , Greenfield Jeffrey 
Published: August 2014

Abstract
The platelet derived growth factor (PDGF) signaling pathway is upregulated in many glioma subtypes, plays a role in gliomagenesis and promotes brain tumor progression. In this study, we demonstrate a role for PDGF signaling in the maintenance of brain tumor microenvironment homeostasis. We detected PDGFRa-expressing stromal cells potentially derived from oligodendritic precursor cells in both human and mouse high-grade gliomas. PDGFRa+ cells are predominately located at the invasive front of gliomas, and have a unique perivascular distribution. We suggest that these stromal cells play an important role in both initiating angiogenesis and supporting tumor progression. In an orthotopic model of glioma in PDGFRa deficient mice, tumor growth was significantly inhibited and gadolinium enhancement was decreased shown by bioluminescence and MRI, respectively. Glioma-associated blood vessels in PDGFRa knockout mice have smaller lumens and relatively normal vascular morphology. Glioma-associated oligodendritic precursor cells promoted endothelial sprouting and tubule formation by abrogating the inhibitory effect of astrocytes. We also demonstrated stromal-derived PDGF-CC as a key factor in the recruitment and activation of PDGFRa+ stromal cells. Utilizing PDGF-CC deficient mice, we recapitulate the glioma phenotype demonstrated in PDGFRa; knockout mice, suggesting their joint contribution to this pathway's integrity. In conclusion, the PDGF-CC/PDGFRa signaling axis in glioma stroma appears to contribute to the remodeling of the vascular architecture in the brain and influences subsequent angiogenesis.
Citation Format: Yujie Huang, David Lyden, Jeffrey Greenfield. Oligodendritic precursor mediates vascular remodeling within glioma microenvironment in PDGF-C dependent manner. [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 B2.
Abstract B24: Hepatocyte growth factor activator inhibitor type 1 (HAI-1) suppresses tumor growth and metastasis of pancreatic adenocarcinoma cells
Authors: Ye Jing-Jia , Kawaguchi Makiko , Haruyama Yukihiro , Kanemaru Ai , Fukushima Tsuyoshi , Kataoka Hiroaki 
Published: August 2014

Abstract
Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is a membrane-bound serine proteinase inhibitor expressed on epithelial and carcinoma cell surface. HAI-1 regulates hepatocyte growth factor activator, kallikrein 1-related peptidase 4 and 5 and several membrane-anchored serine proteinases such as matriptase, prostasin, hepsin, TMPRSS13 and human airway trypsin-like protease. These proteases are reported to be involved in tumor progression, and among them, matriptase and prostasin are known to activate protease-activated receptor-2 (PAR-2). Previously, we reported that S2-CP8 cells, a metastatic variant of SUIT-2 pancreatic adenocarcinoma cells, showed decreased HAI-1 expression compared to SUIT-2 and acquired EMT phenotype. To assess the HAI-1 function in metastasis of S2-CP8 cells, we established a stable S2-CP8 subline that expressed HAI-1 under control of tetracycline-regulated promoter and analyzed in a nude mouse orthotopic xenograft model.
S2-CP8 cells expressed matriptase, TMPRSS13, TMPRSS4, prostasin and PAR-2. Matrigel invasion assay revealed that S2-CP8 cells showed enhanced invasion compared to SUIT-2 cells. The enhanced invasiveness was significantly suppressed by forced HAI-1 expression. Moreover, the HAI-1 loss-induced invasiveness was partly alleviated by knockdown of matriptase or PAR-2. Then, we examined the effect of HAI-1 expression on metastasis in vivo using an orthotopic xenograft model. Four weeks after the transplantation, mice were sacrificed and prepared for histological evaluation. We found that 50% of control mice developed distant metastasis. However, mice treated with tetracycline to express HAI-1 did not develop the metastasis. Though there was no difference in cell proliferation rates in vitro, tumor size was decreased by the expression of HAI-1. These results suggested that, in SUIT-2 pancreatic adenocarcinoma cell line, loss of HAI-1 enhances cell invasiveness, at least in part, through PAR-2/matriptase system in vitro, and HAI-1 plays a suppressive role in metastasis of the cells in vivo.
Citation Format: Jing-Jia Ye, Makiko Kawaguchi, Yukihiro Haruyama, Ai Kanemaru, Tsuyoshi Fukushima, Hiroaki Kataoka. Hepatocyte growth factor activator inhibitor type 1 (HAI-1) suppresses tumor growth and metastasis of pancreatic adenocarcinoma 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 B24.
Abstract B3: CD24 affects tumor cell properties and cytokine secretion in a STAT3-dependent fashion
Authors: Bretz Niko P. , Salnikov Alexei V. , Moldenhauer Gerhard , Altevogt Peter 
Published: August 2014

Abstract
CD24 is a glycosyl-phosphatidylinositol (GPI)-anchored membrane protein frequently over-expressed in human carcinomas and associated with metastasis and poor prognosis. Previous work has shown that CD24 expression affects various cellular properties such as invasion, adhesion, proliferation and apoptosis in vitro as well as tumor growth in vivo.
By analyzing underlying mechanisms of CD24-dependent tumor cell behaviour we discovered the influence of CD24 on STAT3 signaling and gene regulation via the tyrosine kinase c-Src.
Altered activity of c-Src mediated by CD24 knock-down was responsible for reduced levels of phosphorylated STAT3 (Y705). Diminished activity of STAT3 was confirmed by luciferase-reporter assays. Silencing of c-Src, similar to CD24, reduced the expression of prototype STAT3-regulated genes. Likewise, the over-expression of CD24 augmented c-Src activity, the recruitment of c-Src into lipid rafts, levels of p-STAT3 and the expression of STAT3-dependent target genes. Functionally, depletion of CD24 reduced cell proliferation and increased apoptosis, suggesting a pivotal role of regulated target genes for these functional effects.
Even more profoundly, CD24 expression was accompanied with the secretion of the STAT3 target IL-6. We could show a strong correlation between IL-6 secretion and CD24 expression in tumor cell lines. Furthermore, treatment with conditioned cell culture medium from CD24 over-expressing- or CD24 knock-down tumor cells initiated paracrine STAT3 signaling and gene regulation in the monocytic precursor cell line THP-1. This suggested a regulative role of CD24 on the tumor microenvironment. We propose that CD24 is capable of influencing not only tumor cellular properties but also has impact on the cytokine milieu of the tumor microenvironment.
Citation Format: Niko P. Bretz, Alexei V. Salnikov, Gerhard Moldenhauer, Peter Altevogt. CD24 affects tumor cell properties and cytokine secretion in a STAT3-dependent fashion. [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 B3.
Abstract B44: Loss of the keratin cytoskeleton is not sufficient to induce epithelial mesenchymal transition in a novel KRAS-driven sporadic lung cancer mouse model
Authors: Koenig Katharina , Meder Lydia , Kroeger Cornelia , Diehl Linda , Florin Alexandra , Rommerscheidt-Fuss Ursula , Kahl Philip , Wardelmann Eva , Magin Thomas M. , Buettner Reinhard , Heukamp Lukas C. 
Published: August 2014

Abstract
Epithelial-to-mesenchymal transition (EMT), the phenotypical change of cells from an epithelial to a mesenchymal type, is thought to be a key event in invasion and metastasis of adenocarcinomas. These changes involve loss of keratin expression as well as loss of cell polarity and adhesion. We here aimed to determine whether the loss of keratin expression itself drives increased invasion and metastasis in adenocarcinomas and whether keratin loss leads to the phenotypic changes associated with EMT. Therefore, we employed a recently described murine model in which conditional deletion by Cre-recombinase leads to loss of the entire keratin
multiprotein family. These mice were crossed into a newly generated Cre-recombinase inducible KRAS-driven murine lung cancer model to examine the effect of keratin loss on morphology, invasion and metastasis as well as expression of EMT related genes in the resulting tumors.
We here clearly show that loss of a functional keratin cytoskeleton did not significantly alter tumor morphology or biology in terms of invasion, metastasis, proliferation or tumor burden and did not lead to induction of EMT. Further, tumor cells did not induce synchronously expression of vimentin, which is often seen in EMT, to compensate for keratin loss. In summary, our data suggest that changes in cell shape and migration that underlie EMT, are dependent on changes in signaling pathways that cause secondary changes in keratin expression and organization. Thus, we conclude that that loss of the keratin cytoskeleton per se is not sufficient to causally drive EMT in this tumor model.
Citation Format: Katharina Koenig, Lydia Meder, Cornelia Kroeger, Linda Diehl, Alexandra Florin, Ursula Rommerscheidt-Fuss, Philip Kahl, Eva Wardelmann, Thomas M. Magin, Reinhard Buettner, Lukas C. Heukamp. Loss of the keratin cytoskeleton is not sufficient to induce epithelial mesenchymal transition in a novel KRAS-driven sporadic lung cancer mouse 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 B44.
Abstract B46: The role of integrin switching and Deptor in metastatic breast cancer
Authors: Parvani Jenny G. , Taylor Molly A. , Schiemann William P. 
Published: August 2014

Abstract
Mammary tumorigenesis converts TGF-β; from a tumor suppressor in normal mammary epithelial cells (MECs) to a tumor promoter in cancerous MECs, likely via Epithelial-Mesenchymal Transiton (EMT). Integrin signaling plays a critical role in this conversion, although the underlying molecular mechanisms remain elusive. Previously, both β1 and β3 integrins have been associated with TGF-β; mediated EMT and metastasis in breast cancer, making both integrins attractive therapeutic targets. Importantly, the interplay and requirement for β1 and β3 integrins in mediating metastatic disease and the downstream effectors that effectuate the malignancy associated with these intergrins have not been fully evaluated. Here, we describe an integrin switching mechanism where functional disruption of β1 integrin mediates compensatory upregulation of β3 integrin expression, which augments TGF-β; signaling and mediates 3D outgrowth of metastatic breast cancer cells. We demonstrate that sole targeting of β1 integrin is insufficient in reducing tumor burden, while sole targeting of β3 integrin significantly alleviates the disease. Furthermore, we identify Deptor, the endogenous inhibitor of mTOR, to be downregulated in β3 integrin expressing cells, suggesting that attenuated Deptor expression may engender the malignancy associated with β3 integrin. Importantly, functional disruption of Deptor in systemically invasive 4T07 cells induces their acquisition of mesenchymal characteristics, while attenuating their ability to proliferate. Collectively, we demonstrate that targeting β1 integrin alone is insufficient in alleviating metastatic breast cancer, while sole targeting of β3 integrin significantly attenuates the disease. Furthermore, our data identifies Deptor as a potential downstream effector in β3 integrin-dependent malignancies.
Citation Format: Jenny G. Parvani, Molly A. Taylor, William P. Schiemann. The role of integrin switching and Deptor in metastatic 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 B46.
Abstract B49: Integrin alpha2beta1 (α2β1) promotes prostate cancer skeletal metastasis
Authors: Sottnik Joseph L. , Daignault-Newton Stephanie , Zhang Xiaotun , Colm Morrissey , Hussain Maha H. , Keller Evan T. , Hall Christopher L. 
Published: August 2014

Abstract
Men who die of prostate cancer (PCa) do so because of systemic metastases, the most frequent of which are within the skeleton. Recent data suggest that the colonization of the skeleton is mediated in part by collagen type I, the most abundant protein within the bone. We have shown that enhanced collagen I binding through increased expression of integrin α2β1 stimulated in vitro invasion and promoted the growth of PCa cells within the bone. Accordingly, we tested whether α2β1 integrin is both a mediator and a predictive marker of skeletal metastasis. To directly test whether α2β1 integrin expression mediates PCa cell metastasis, α2 integrin was over-expressed in low-tumorigenic LNCaP PCa cells or selectively knocked-down in highly metastatic LNCaPcol PCa cells. The over-expression of full-length cDNA to α2 integrin stimulated whereas shRNA-mediated knock-down of α2 integrin abolished the ability of transduced cells to bind to or migrate towards collagen I. Correspondingly, α2 integrin knock-down reduced both the tumor volume of intra-osseous lesions and the formation of experimental metastases in the liver and skeleton compared to control-transduced cells demonstrating that α2β1 promotes the establishment of distant metastases. To investigate the clinical significance of α2β1 expression in PCa, α2β1 protein was measured in prostatic tissues and in soft tissue and bone metastases. The data demonstrate that α2β1 protein was elevated in PCa skeletal metastases compared to either PCa primary lesions or soft tissue metastases suggesting that α2β1 mediates the selective metastasis of PCa cells to the bone. Taken together, these data support that α2β1 integrin promotes the systemic metastasis of PCa cells and provide evidence that α2β1 integrin activity may promote skeletal metastasis in PCa patients. These studies provide a strong rationale for the development of α2β1 as a therapeutic target for the treatment of PCa skeletal metastases and thus have the potential to reduce both the incidence and mortality associated with metastatic PCa.
Citation Format: Joseph L. Sottnik, Stephanie Daignault-Newton, Xiaotun Zhang, Morrissey Colm, Maha H. Hussain, Evan T. Keller, Christopher L. Hall. Integrin alpha2beta1 (α2β1) promotes prostate cancer skeletal 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 B49.
Abstract B55: The regulation of matriptase activation through PDGF D-mediated extracellular acidosis
Authors: Najy Abdo J. , Kim Hyeong-Reh C. 
Published: August 2014

Abstract
Prostate cancer (PCa) is the second most diagnosed and sixth leading cause of cancer-related death in men worldwide. Activation of β-PDGFR (platelet-derived growth factor receptor) has been demonstrated in 50% of PCa cases and it is part of a 5-gene signature predicting PCa recurrence after prostatectomy. Analysis of the β-PDGFR ligands in PCa revealed association between PDGF D expression and Gleason score as well as tumor stage. When we examined the functional consequences of PDGF ligand-specific β-PDGFR signaling in PCa, we discovered a novel PDGF D-specific autocrine pathway, resulting in activation/shedding of the serine protease matriptase leading to PCa cell invasion, migration, and tumorigenesis. The present study showed that PDGF D, not PDGF B, induces extracellular acidification which correlates with increased matriptase activation. Furthermore, exposure of control or PDGF B expressing cells to an acidic buffer resulted in increased matriptase activation, indicating the functional significance of the acidic milieu in matriptase activation. A cDNA microarray analysis showed that PDGF D/β-PDGFR signaling upregulates expression of the acidosis regulator carbonic anhydrase IX (CA IX), a classic target of the transcriptional factor HIF-1. Interestingly, cellular fractionation displayed a strong HIF-1 nuclear localization in PDGF D expressing cells. Treatment of vector control or PDGF B expressing cells with the HIF-1 activator, CoCl2, specifically led to increased CA IX expression accompanied by extracellular acidosis and matriptase activation. Taken together, these novel findings reveal a new paradigm in matritpase activation involving PDGF D-specific signal transduction leading to extracellular acidosis. Considering the fact that intratumoral acidosis leads to chemo- and radiation resistance, understanding the role PDGF signaling plays in this process will enhance the efficacy of current clinical therapeutics.
Citation Format: Abdo J. Najy, Hyeong-Reh C. Kim. The regulation of matriptase activation through PDGF D-mediated extracellular acidosis. [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 B55.
Abstract C24: Identification and characterization of serum biomarkers associated with metastatic progression of breast cancer
Authors: Za'abi Adhari Abdullah Al , Graves Steven , Hansen Marc 
Published: August 2014

Abstract
Breast cancer is the most prevalent form of cancer among women in the United States. Treatment is greatly complicated by metastasis of cells from the primary tumor site, which increases mortality; about 40 percent of breast cancer patients will relapse and develop metastatic disease. Eighty percent of breast cancer patients are treated with adjuvant chemotherapy to decrease their risk of getting metastasis, while as indicated previously only 40% of them will eventually relapse and develop metastatic disease. Despite this precautionary measure, adjuvant chemotherapy is shown to increase 15-years survival of such patients by only 3-10%. Further, about 40,000 women die of breast cancer every year due to undetected early metastasis. Clearly detection of metastatic disease has major clinical implications. Identifying specific blood serum biomarkers that accurately and reproducibly indicate the presence of metastatic disease could greatly improve treatment, as they could substitute for more invasive procedures that are in current use and be used to monitor remission at higher resolution. Analysis of protein content in serum has been widely used as a method for biomarker identification, but detection, identification, and analysis of short peptide biomarkers faces technical challenges that have prevented widespread application of this approach. We report here results from a proteomics study aimed at identifying and characterizing short peptide biomarkers in serum samples taken from patients with stage I and stage III breast cancer. Serum samples contain over 2500 distinct peaks representing distinct peptides. A preliminary analysis reveals that the abundance of 92 peptides are significantly reduced in samples from patients with stage III disease, while the abundance of 64 peptides show significant increase in stage III sera. A large number of additional peptides show smaller changes in abundance in sera from the two patient groups. Our future work will be to characterize the identity of the serum biomarkers identified and validate their appearance or disappearance in a large cohort of patients.
Citation Format: Adhari Abdullah Al Za'abi, Steven Graves, Marc Hansen. Identification and characterization of serum biomarkers associated with metastatic progression of 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 C24.