bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B02: Oncogene MCT-1 deregulates oxidative metabolism and promotes tumor metastasis via YY1 signaling network
Authors: Tseng Hong-Yu , Chen Yen-An , Chen Yi-Rong , Hsu Hsin-Ling 
Published: October 2016

Abstract
The underlying mechanism of oncogene activation that induces reactive oxygen species (ROS) generation and promotes tumor progression and metastasis is still ambiguous. We now demonstrate that the oncogenic MCT-1 activation protects cells from oxidative damage via increase of YY1 and subsequently enhances EGFR expression and activation. Overexpressing MCT-1 induces cell invasion, intracellular ROS generation and MnSOD expression in mitochondria via YY1 pathway, thus targeting YY1 suppresses cancer cell invasion and blocks EGFR-MnSOD signaling function enhanced by MCT-1. Recapitulating in vitro outcomes, MCT-1 increment promotes tumor angiogenesis, necrosis and metastasis with oxidative metabolism deregulation and malignant microenvironment development in xenograft mice. Clinical data also confirms that MCT-1 enrichment connects to poor survival and prognosis coincident with YY1, EGFR and MnSOD upregulation in patients with lung cancer. Collectively, MCT-1 is a key inducer of YY1-EGFR-MnSOD axis involving the redox mechanism in the process of carcinogenesis.
Citation Format: Hong-Yu Tseng, Yen-An Chen, Yi-Rong Chen, Hsin-Ling Hsu. Oncogene MCT-1 deregulates oxidative metabolism and promotes tumor metastasis via YY1 signaling network. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B02.
Abstract B03: Control of pancreatic cancer metabolism and histone acetylation by the tumor microenvironment
Authors: Sherman Mara H. , Evans Ronald M. 
Published: October 2016

Abstract
Though the significance of reciprocal interactions between genetically altered tumor cells and adjacent stroma is increasingly appreciated, this complex crosstalk remains poorly understood. Pancreatic ductal adenocarcinoma (PDAC) has a particularly prominent stromal compartment, shown to exert both tumor-supportive and tumor-suppressive or homeostatic functions in the context of the wound-like tumor microenvironment. To investigate the paracrine effects of PDAC stromal elements on pancreatic cancer cells, we developed a “stromal” culture system, which incorporates structural and diffusible stroma-derived elements into homotypic PDAC cell cultures amenable to functional genomics and metabolomics. These analyses revealed that microenvironmental cues co-regulate cancer metabolism and gene expression. Stromal inputs broadly influenced histone acetylation in the PDAC epigenome, which coincided with induction of genes implicated in anabolic metabolism and inflammation. The gene expression and metabolic changes induced by stromal factors overlap with those previously identified following oncogenic Kras, suggesting functional complementarity between cell-autonomous and microenvironmental pathways characteristic of PDAC. As epigenome modification results in changes in gene expression through the functions of readers, such as the bromodomain-containing BET proteins, we tested JQ1, a small molecule inhibitor of BET family bromodomain-containing proteins, for the capacity to inhibit gene expression changes downstream of stromal factors. Paracrine induction of pro-growth and inflammatory genes was inhibited by JQ1, suggesting that the BET family serves as a key transducer of stromal inputs to drive alterations in gene expression. Inhibition of acetyl-lysine sensing by the BET family reduced pancreatic tumor growth and associated inflammation in vivo, with significant reduction in expression of genes implicated in macromolecule biosynthesis and tumor-permissive immune regulation. This work suggests paracrine epigenome regulation as a conduit through which stromal signals drive metabolic and immune adaptation to a challenging tumor microenvironment.
Citation Format: Mara H. Sherman, Ronald M. Evans. Control of pancreatic cancer metabolism and histone acetylation by the tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B03.
Abstract B17: Disrupting tumor growth through targeting TEM8
Authors: Høye Anette M. , Tolstrup Sofie , Cox Thomas R. , Mauldin Jeremy P. , Frankel Arthur E. , Erler Janine T. 
Published: October 2016

Abstract
Tumor Endothelial Marker 8 (TEM8) is an integrin-like cell-surface receptor originally identified being specific to tumor endothelial cells in colorectal cancer (CRC) blood vessels. Further investigation showed upregulated TEM8 expression in tumor vessels of various tumor types, as well as in certain tumor cells. We observe an increase in TEM8 expression in metastatic cancer cell lines compared to their non-metastatic counterpart in both colon and breast cancer cell lines.
In order to investigate whether TEM8 is required for tumor growth and metastasis we have developed a humanized anti-TEM8-toxin-conjugated antibody. The antibody shows preclinical effectiveness in a CRC model in vivo. We have also utilized the CRISPR-Cas9 technology to create TEM8 knockout cell lines, which show impaired proliferation and invasion in vitro and reduced tumor growth in vivo compared to control cell lines.
Intriguingly, microarray analysis showed a significant increase in TEM8 mRNA levels in breast cancer cells seeded on collagen modified by the crosslinking enzyme lysyl oxidase (LOX). We have previously shown that LOX plays a role in tumor progression, metastasis, and pre-metastatic niche formation through its ability to modulate matrix stiffness. Importantly, both high TEM8 and LOX expression is correlated with decreased survival in ER- breast cancer patients.
Collagen VI, a TEM8 ligand, and their interaction have been implicated in being important for migration and for stimulating Wnt-signaling in breast cancer stem cells. Using global quantitative mass spectrometry we observe an increase in collagen VI in the extracellular matrix of CRC tumors overexpressing catalytically active, but not catalytically inactive, LOX compared to low-LOX expressing tumors. Furthermore, using publicly available databases TEM8 and collagen VI are found to be co-expressed in CRC patient datasets.
Thus, we speculate that another possible mechanism of LOX mediated tumor and metastasis progression is through TEM8. Further, that combined targeting of TEM8 and LOX may inhibit primary and metastatic tumor growth.
Citation Format: Anette M. Høye, Sofie Tolstrup, Thomas R. Cox, Jeremy P. Mauldin, Arthur E. Frankel, Janine T. Erler. Disrupting tumor growth through targeting TEM8. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B17.
Abstract B18: CXCL10 suppresses tumor angiogenesis and impedes expression of critical angiogenic factors in renal cell carcinoma
Authors: Jin Hyun A , Heo Jun Hyeok , Kang You Hyun , Kim Ki Hong , Han Kyung Suk , Hong Sung Joon 
Published: October 2016

Abstract
Background: Angiogenic progress is complex and several factors are involved as a promoter or inhibitor of angiogenesis. Tumor can use the imbalance of pro- and antiangiogenic factors in progression. The CXC chemokine family are consisted of pro- or antiangiogenic factors. Recent studies revealed CXCL10 as an anti-angiogenic factor in response to angiogenic factors like bFGF or VEGF. However, a role of CXCL10 in cancer and angiogenesis is unclear. Here, we investigated the role of CXCL10 on tumor angiogenesis and its mechanisms in renal cell carcinoma.
Methods: Human vascular endothelial cell (HUVEC) was used to evaluate the effects of CXCL10 on endothelial cells. MTS assay was performed to assess cell proliferation. Cell cycle analysis was performed using flow cytometry with propidium iodide. RT-PCR and western blot were performed to assess the baseline expression of CXCL10 in a panel of renal cell carcinoma cells. Overexpression of CXCL10 was developed by lentiviral transfection. Quantitative RT-PCR for angiogenic factors (VEGF, PDGF, FGF, MMP9) was performed by angiogenesis multigene screening array. Subcutaneous tumor xenografts were developed using Caki-1 cells to evaluate in vivo effects of CXCL10.
Results: CXCL10 inhibited proliferation and tube formation of HUVEC in a dose-dependent manner, while it did not affect in vitro tumor proliferation of renal cell carcinoma cells. Expression of CXCL10 was downregulated in Caki-1, UMRC3 and UMRC6 cells. Overexpression of CXCL10 suppressed expression of angiogenic factors including VEGF-A, PDGF, FGF2 and MMP9 in Caki-1 cells, suggesting that CXCL10 is involved non only as an anti-angiogenic factor but also as a suppressor of critical angiogenic factors in renal cell carcinoma. In vivo Restoration of CXCL10 expression suppresses tumor growth in renal cell carcinoma by suppressing tumor angiogenesis in xenografts.
Conclusions: CXCL10 has a role as an anti-angiogenic factor and also as a suppressor of critical angiogenic factors in renal cell carcinoma. Restoration of CXCL10 expression suppresses tumor growth in renal cell carcinoma by impeding expression of other angiogenic factors including VEGF, PDGF, FGF, MMP9 in renal cell carcinoma as well as inducing anti-angiogenic effect on endothelial cells. Our data suggest that targeting CXCL10 might be a novel therapeutic option for advanced renal cell carcinoma.
Citation Format: Hyun A Jin, Jun Hyeok Heo, You Hyun Kang, Ki Hong Kim, Kyung Suk Han, Sung Joon Hong. CXCL10 suppresses tumor angiogenesis and impedes expression of critical angiogenic factors in renal cell carcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B18.
Abstract B36: Interrogating cellular metabolism to improve therapy for EGFR mutant NSCLC
Authors: Chiang Chun-Te , Chiu Chi-Li , Arnesano Cosimo , Fraser Scott E. , Agus David B. , Ruderman Dan L. , Mumenthaler Shannon M. 
Published: October 2016

Abstract
Tyrosine kinase inhibitors (TKIs) that target the EGFR are the standard of care for patients with EGFR mutant non-small lung cancer (NSCLC). However, TKIs are not curative; most patients with EGFR-mutant NSCLC treated with EGFR TKIs develop resistance within 9 to 14 months. The tumor microenvironment is thought to influence the fitness of cancer cells and drive the evolution of a tumor, but the effect of altered environmental conditions on oncogenic signaling and therapeutic response is not well understood. In the present study, we used the Operetta® High Content Imaging System to track cell dynamics over time and found that microenvironmental stress, specifically nutrient starvation, had a differential effect on growth rates of TKIs sensitive and resistant cells. Furthermore, we discovered that TKIs sensitive and resistant cells have differential metabolic signaling in response to this microenvironmental stress. To further interrogate cellular metabolism in TKIs sensitive and resistant cells, we utilized fluorescence lifetime imaging microscopy (FLIM), a state-of-the-art live-cell imaging technique to measure the autofluorescence lifetime of metabolic coenzyme NADH, the principle electron acceptor in glycolysis and electron donor in oxidative phosphorylation. Taken together, our data suggest that TKIs sensitive and resistant cells have adopted different metabolic strategies to cope with stressful environmental conditions, and interrogating tumor metabolic adaptations would inform the design of new therapeutic strategies to delay or prevent the outgrowth of resistant clones during treatment of EGFR mutant NSCLC.
Citation Format: Chun-Te Chiang, Chi-Li Chiu, Cosimo Arnesano, Scott E. Fraser, David B. Agus, Dan L. Ruderman, Shannon M. Mumenthaler. Interrogating cellular metabolism to improve therapy for EGFR mutant NSCLC. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B36.
Abstract B42: Dysregulation of key microRNAs controlling tumor-host interactions triggers escape from osteosarcoma dormancy
Authors: Tiram Galia , Ofek Paula , Udagawa Taturo , Shomron Noam , Roniger Maayan , Kerem Batsheva , Shaked Yuval , Aviel-Ronen Sarit , Barshack Iris , Calderon Marcelo , Haag Rainer , Satchi-Fainaro Ronit 
Published: October 2016

Abstract
The presence of dormant, microscopic cancerous lesions possesses a major obstacle for the treatment of metastatic and recurrent cancers. While it is well-established that microRNAs play a major role in tumorigenesis, their involvement in tumor dormancy has yet to be fully elucidated. We established and comprehensively characterized a human osteosarcoma dormancy model of a pair of cells originating from the same parental tissue; one that remains avascular and non-palpable a year following inoculation into mice and another that generates vascularized palpable tumors one month following inoculation. Using this model of cell lines generating dormant or fast-growing osteosarcomas, we identified three novel regulators of osteosarcoma dormancy: miR-34a, miR-93 and miR-200c. This is the first report showing that loss of these three microRNAs occurs during the switch from dormant avascular into fast-growing angiogenic phenotype. Furthermore, we validated their downregulation in patients' tumor samples compared to normal bone, making them attractive candidates for osteosarcoma therapy. Reconstitution of these microRNAs into Soas-2 and MG-63 cells, which generate fast-growing osteosarcomas, reduced the levels of their target genes, MET proto-oncogene, hypoxia-inducible factor 1α, and moesin, critical to cancer angiogenesis and cancer cells' migration. We further demonstrate that these miRNAs attenuate the angiogenic capabilities of fast-growing osteosarcoma in vitro and in vivo. Moreover, treatment with each of these microRNAs using our novel polyglycerol dendritic nanocarrier significantly prolonged their dormancy period. Taken together, these findings suggest that miR-34a, miR-93 and miR-200c have a key role in osteosarcoma progression, and provide the rationale for the development of novel diagnostic and therapeutic tools for osteosarcoma and other malignancies.
Citation Format: Galia Tiram, Paula Ofek, Taturo Udagawa, Noam Shomron, Maayan Roniger, Batsheva Kerem, Yuval Shaked, Sarit Aviel-Ronen, Iris Barshack, Marcelo Calderon, Rainer Haag, Ronit Satchi-Fainaro. Dysregulation of key microRNAs controlling tumor-host interactions triggers escape from osteosarcoma dormancy. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B42.
Abstract C04: In vivo upregulation of bone morphogenic protein 4 (BMP4) in esophageal cancer is through tumor-stroma crosstalk
Authors: Calpe Silvia , Read Matthew , Sancho-Serra Maria del Carmen , Straub Danielle , Clemons Nick , Liu David , Phillips Wayne , Krishnadath Kausilia K. 
Published: October 2016

Abstract
Bone morphogenic proteins (BMPs) are multi-functional growth factors that belong to the transforming growth factor-beta (TGFβ;) superfamily. Amongst them, BMP4 is becoming increasingly attractive due to its crucial role in the development of many cancers. Whereas in malignancies such as glioblastoma and myeloma high levels of BMP4 are associated with benign features, in gastrointestinal cancers BMP4 possesses tumorigenic capacities. In these cancers, BMP4 acts on tumor epithelial cells enhancing their pro-metastatic behavior and chemo-resistance. However, whether BMP4 is being secreted by the epithelial cells or by the stroma, has not been well established yet, in part due to a lack of specific anti-BMP4 antibodies.
To elucidate the functional implications of the origin of BMP4 production, we made use of a novel esophageal adenocarcinoma (EAC) tumor xenograft model and a newly generated Llama-derived anti-BMP4 antibody. Using in vivo molecular imaging techniques we find that BMP4 expression in the tumor is increased after engraftment of BMP4 negative human EAC tumor cells into immunodeficient mice. Immunohistochemical studies of the engrafted tissue reveal both a mouse and a human origin of BMP4 protein, suggesting that both epithelial as well as stromal cells are involved in BMP4 secretion. This implies that whereas the stroma directly secretes BMP4; it also produces molecules that activate autocrine BMP4 production by the cancer epithelial cells. In vitro analysis such as co-cultures with different stromal cells, revealed the functional effects of stroma-derived BMP4 on tumor cells, and how our anti-BMP4 antibodies can inhibit these. Further, these studies also uncovered the stromal components that induce BMP4 secretion by the human epithelial cells.
In sum, these studies suggest a pivotal role of the microenvironment in regulating both directly and indirectly BMP4 expression in a model of esophageal cancer. As BMP4 has also been shown to be responsible for tumor progression in other gastrointestinal cancers, stromal regulation of BMP4 production might not be restricted to EAC, and might be a common feature in gastrointestinal cancers. Finally, as our anti-BMP4 Llama-derived antibodies can inhibit these effects in vitro, they might represent a novel therapy in targeting stromal function and preventing metastasis.
Citation Format: Silvia Calpe, Matthew Read, Maria del Carmen Sancho-Serra, Danielle Straub, Nick Clemons, David Liu, Wayne Phillips, Kausilia K. Krishnadath. In vivo upregulation of bone morphogenic protein 4 (BMP4) in esophageal cancer is through tumor-stroma crosstalk. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C04.
Abstract C15: Neutrophil elastase (NE) induces epithelial-mesenchymal transition (EMT) via upregulation of inhibitor of DNA binding 1 (ID1)
Authors: Kargl Julia , Gregory Alyssa , Yang Hye Youn , Busch Stephanie , Metz Heather , Houghton A. McGarry 
Published: October 2016

Abstract
Neutrophil elastase is a neutrophil-derived serine protease with broad substrate specificity. We have previously shown that NE promotes lung tumor growth in vitro and in vivo and that NE is capable of entering tumor cell endosomes in a clathrin-dependent fashion.
Epithelial-mesenchymal transition (EMT) is a fundamental event for primary tumors to metastasize to distant sites. Altered gene and protein expression causes changes in cell morphology and behavior resulting in the loss of attachment to neighboring cells, intravasation, and migration into distant tissue. However, the entities residing within the tumor microenvironment that drive EMT are poorly understood.
We identified NE, expressed and released by tumor-associated neutrophils, as such an entity. We found that NE induces EMT-like morphology and behavior in several cancer cell lines as well as upregulates genes (Snail and Twist) and proteins (N-cadherin, α-SMA, Fibronectin and Vimentin) associated with EMT. Furthermore, NE provokes tumor cell migration and invasion in vitro and is required for metastasis formation in vivo. Besides known EMT markers we identified significant upregulation of inhibitor of DNA binding 1 (ID1) in tumor cells in the presence of NE. Increased ID1 expression was previously shown to correlate with tumor progression and metastasis. Clathrin-dependent NE internalization is required for both ID1 expression and the EMT-like phenotype. We localized NE in different compartments of tumor cells and found it predominantly in the nuclear fraction; more specifically, NE is located in the chromatin-bound fraction, indicating a potential role in chromatin remodeling and transcriptional regulation. Additionally, the proteolytic activity of NE was measured in the nuclear and chromatin-bound fractions and is required for induction of ID1 expression and EMT-like behavior. Taken together, these data suggest the importance of NE-induced ID1 expression in metastasis formation.
Citation Format: Julia Kargl, Alyssa Gregory, Hye Youn Yang, Stephanie Busch, Heather Metz, A. McGarry Houghton. Neutrophil elastase (NE) induces epithelial-mesenchymal transition (EMT) via upregulation of inhibitor of DNA binding 1 (ID1). [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C15.
Abstract C20: Investigating the role of the tumor microenvironment and its role in radiation therapy in pancreatic cancer
Authors: O'Neill Fiona , Moore Gemma , O'Keeffe Serena , McClean Brendan , McVey Gerard , Moriarty Michael , Breen Laura , Clynes Martin 
Published: October 2016

Abstract
Pancreatic cancer is the 10th most common cancer in Ireland and the 5th most common cause of death. The 5 year survival rate is approximately 6%, due to late diagnosis by which time usually metastasis has occurred. Despite an increase in research on the disease in recent years very little progress has been made and the development of new, more effective therapies is needed.
The role of the tumor microenvironment in the progression of pancreatic cancer is becoming the focus of more and more research. It has been determined that the tumor microenvironment plays a significant role in the progression and invasion of the cancer cells and also plays a role in the resistance of tumor to therapy.
Utilizing established pancreatic cell lines and human derived fibroblasts and stellate cells, an indirect co-culture approach has been utilized to investigate the mechanisms by which the fibroblasts and stellate cells in the tumor influence the behavior of the cancer cells.
Using the same indirect co-culture approach we have sought to evaluate the role in which these stromal components have in the tumor cells response to radiation therapy. We have utilized single and fractionated doses to determine if the different approaches have varying effects on the proliferation, invasion and colony forming ability of the cancer cells.
It is hoped that this in vitro evaluation could be used to inform a better approach to radiation treatment of pancreatic cancer.
Citation Format: Fiona O'Neill, Gemma Moore, Serena O'Keeffe, Brendan McClean, Gerard McVey, Michael Moriarty, Laura Breen, Martin Clynes. Investigating the role of the tumor microenvironment and its role in radiation therapy in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C20.