bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5067: Preadipocyte exosomes promote early stage breast cancer formation by enhancing cancer stem cell renewal signaling
Authors: Wolfson Benjamin , Gernapudi Ramkishore , Duru Nadire , Zhou Qun 
Published: August 2015

Abstract
The tumor microenvironment plays a critical role in regulating breast cancer progression. Adipocytes differentiate from preadipocytes, which possess mesenchymal stem cell properties. Preadipocytes and adipocytes are essential components of the tumor microenvironment, and signaling between preadipocytes and breast cancer cells has been found to promote breast tumor formation and metastasis. Exosomes secreted from preadipocytes are also important components of the cancer stem cell niche. The primary goal of our studies is to examine how preadipocyte-derived exosomes can regulate early-stage breast cancer formation via regulating stem cell renewal. We use human and mouse preadipocytes and early-stage breast cancer cells (ductal carcinoma in situ, DCIS), as well as xenografts in immunodeficient mice to determine the role of preadipocyte secreted exosomes in DCIS stem cell behavior and tumor formation. By using protein arrays, we reveal CD81 and FLOT-1 as key exosomal protein markers and SOX2 and SOX9 as exosomal secretion of stem cell renewal regulators. We identify a key miR-140/SOX2/SOX9 axis that regulates differentiation, stemness, and migration in the tumor microenvironment. Next, we find that the natural antitumor compound shikonin can suppress preadipocyte signaling, inhibiting nearby DCIS cells. Through co-culture experiments we show that shikonin treated preadipocytes secrete exosomes containing high levels of miR-140 that can impact nearby DCIS cells through targeting SOX9 signaling. We demonstrate that preadipocyte-derived exosomes promote tumorigenesis in vivo, providing strong support for the importance of exosomal signaling in the tumor microenvironment. Finally, our data also show that targeting the tumor microenvironment may assist in blocking tumor formation.
Citation Format: Benjamin Wolfson, Ramkishore Gernapudi, Nadire Duru, Qun Zhou. Preadipocyte exosomes promote early stage breast cancer formation by enhancing cancer stem cell renewal signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5067. doi:10.1158/1538-7445.AM2015-5067
Abstract 5071: Inhibition of Porcupine reduces Wnt-dependent colony formation and/or proliferation in both autocrine and paracrine cell models
Authors: Thompson Ben A. , Messenger Kate J. , Linnane Emily , Coupland Sarah E. , Calcraft Peter J. 
Published: August 2015

Abstract
Aberrant activation of the pro-survival Wnt signalling pathway is a key determinant in numerous cancers (Nusse and Varmus, 2012) and therefore constituents of this pathway are potentially promising therapeutic targets.
The membrane-bound o-acyltransferase porcupine (PORCN) is required for post-translational modification of all Wnts, and is vital for Wnt secretion (Herr et. al., 2012). Due to the complex and varied oncogenic roles of the known Wnt ligands, prevention of active ligand secretion provides an effective mechanism for inhibiting canonical and non-canonical Wnt signalling in both paracrine and autocrine systems.
Here we show that a novel inhibitor of porcupine potently inhibits both autocrine and paracrine models of Wnt/β-catenin signalling. Treatment of the pancreatic cancer cell line CAPAN-2 with REDX05562 resulted in a significant decrease of axin 2 mRNA expression by qPCR (10.4 fold, 10nM). This reduction in expression was partially reversed by the addition of recombinant human Wnt-3A (100ng.ml−1). The decrease in axin 2 expression was concomitant with an inhibition of CAPAN-2 proliferation (IC50 1.4nM +/- 0.8nM).
Conversely treatment of MCF-7 mammospheres with REDX05562 did not inhibit sphere forming efficiency (SFE). However, when stimulated with recombinant Wnt-3A an increase in anoikis resistance was observed suggesting a potential paracrine influence. In vivo the presence of cancer associated fibroblasts (CAFs) are a likely source of paracrine Wnt (Green et. al., 2013). Indeed, conditioned media taken from primary CAFs (isolated from fresh mastectomies) increased anoikis resistance in MCF-7 cells without any discernible effect on CAF proliferation. This effect was significantly inhibited when MCF-7 cells were incubated with conditioned media taken from primary CAFs treated with REDX05562. Moreover, immunofluorescent labelling of PORCN revealed that PORCN expression is markedly higher in CAFs than in MCF-7s. This is consistent with the hypothesis that different mechanisms underpin Wnt-signalling in breast and pancreatic cancer.
The above data show that the novel PORCN inhibitor REDX05562 effectively reduces the impact of pro-survival Wnt ligand-mediated signalling in both paracrine and autocrine models. This further emphasises the broad therapeutic potential of PORCN inhibition in Wnt-dependent cancers.
Citation Format: Ben A. Thompson, Kate J. Messenger, Emily Linnane, Sarah E. Coupland, Peter J. Calcraft. Inhibition of Porcupine reduces Wnt-dependent colony formation and/or proliferation in both autocrine and paracrine cell models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5071. doi:10.1158/1538-7445.AM2015-5071
Abstract 5076: Tumor cell-derived exosomes educate bone marrow mesenchymal stromal cells toward a protumorigenic function
Authors: Nakata Rie , Borriello Lucia , Fabbri Muller , Shimada Hiroyuki , Declerck Yves A. 
Published: August 2015

Abstract
The bone marrow constitutes a microenvironment for tumor cells that promotes their survival, dormancy and therapeutic resistance. Central to this sanctuary function are mesenchymal stromal cells (MSC) which, like tumor-associated macrophages, can have an anti- or a pro-tumorigenic function in cancer progression. Here, using neuroblastoma, the second most common cancer in children that is highly metastatic to the bone marrow as a model of tumor cell - MSC communication - we have explored the mechanism by which tumor cells “educate” MSC toward a pro-tumorigenic function. We demonstrate that neuroblastoma cells release 30-100 nm size extracellular vesicles rich in tetraspanins (CD63) and chaperone proteins (HSP70), and therefore with characteristics of exosomes, and that they are captured by MSC. As a result, MSC increase their expression of several pro-tumorigenic cytokines and chemokines like interleukin (IL)-4, IL-6, IL-8, vascular endothelial cell growth factor (VEGF) and monocyte-chemotactic protein-1 (MCP-1). Capture of tumor-derived exosomes by MSC activates MEK/ERK1/2 and Akt (but not NF-κB), and whereas MEK/ERK1/2 activation is critical for the production of pro-tumorigenic cytokines/chemokines, Akt activation is not. In addition to the presence of structural, metabolic and chaperone proteins and the absence of inflammatory cytokines, a proteomic analysis of the cargo of these neuroblastoma-derived exosomes revealed an abundance of Galectin-3 binding protein (Gal-3BP), a protein that we had previously reported to increase the transcriptional expression of IL-6 in MSC. Further supporting the role of exosomes in educating MSC, we found that inhibition of exosome release in neuroblastoma cells by knock-down of Rab-27B, a GTPase involved in exosome secretion, was associated with a suppression of cytokine/chemokine production by MSC. We then demonstrated that “educated” MSC stimulate neuroblastoma cell proliferation both in vitro and in vivo and their resistance to chemotherapy in a signal transduction and activation (STAT)3 and MEK-ERK1/2- dependent manner. These data thus indicate that the production of exosomes by tumor cells induces the production of cytokines and chemokines in bone marrow-derived MSC, contributing to the protective microenvironment of the bone marrow niche.
Citation Format: Rie Nakata, Lucia Borriello, Muller Fabbri, Hiroyuki Shimada, Yves A. Declerck. Tumor cell-derived exosomes educate bone marrow mesenchymal stromal cells toward a protumorigenic function. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5076. doi:10.1158/1538-7445.AM2015-5076
Abstract 5084: A multifaceted role of the Hedgehog pathway in modulating pancreatic ductal adenocarcinoma biology
Authors: Thomas Dafydd Huw , Lee Albert , Palermo Carmine , Sastra Stephen , Rabadan Raul , Olive Kenneth 
Published: August 2015

Abstract
The Hedgehog (Hh) developmental pathway is reactivated in pancreatic ductal adenocarcinoma (PDA) and forms a paracrine axis from the tumor cells to the supporting stromal cells. Previous work from this laboratory found that, in established tumors, inhibition of the Hedgehog (Hh) pathway caused a loss of tumor stroma implicating this axis in the development of the profuse desmoplastic stroma observed in PDA. However, the mechanisms by which Hh signaling modulates the stroma in PDA remain unknown.
In this study we have attempted to identify the target genes of the Hh pathway in the stroma of pancreatic tumors. Using a novel tumor biopsy procedure coupled with RNA-SEQ analysis we have identified genes acutely sensitive to Hh pathway inhibition in the KPC mouse model of PDA. The gene signature of down-regulated genes following Hh inhibition implicated the Hh pathway in the proliferation of its target stromal cells as well as a possible indirect effect on the proliferation of tumor cells. Interestingly, a significant number of genes were also up-regulated following inhibition of the Hh pathway. This gene signature was consistent with the migration and infiltration of leukocytes. Taken together these data suggest that the Hh pathway can drive proliferation of both the stromal and epithelial compartments as well as actively suppress leukocyte infiltration into pancreatic tumors.
In addition we have utilized a Gli1-GFP reporter mouse to study the Hh target cells in the stroma of KPC mice. Previous work has suggested that Hh target cells in pancreatic tumors are myofibroblasts and thus α-Smooth muscle actin (α-SMA) positive. However, we observed that while some Gli1 positive stromal cells are α-SMA positive a significant proportion are α-SMA negative. In addition, costaining KPC-Gli1-GFP tumors for other stromal markers, including Fibroblast specific protein-1 (FSP-1), Glial Fibrillary Acidic Protein (GFAP), Desmin, Vimentin and Platelet-derived growth factor receptor β (PDGFRβ) reveals subsets of Hh target cells in the tumor stroma. These data suggest the Hh pathway targets a complex set of stromal fibroblasts to mediate its effects.
Taken together, these data suggest that the Hh pathway regulates multiple facets of pancreatic tumor biology both in negative and positive manner and does so through targeting a complex array of stromal cells.
Citation Format: Dafydd Huw Thomas, Albert Lee, Carmine Palermo, Stephen Sastra, Raul Rabadan, Kenneth Olive. A multifaceted role of the Hedgehog pathway in modulating pancreatic ductal adenocarcinoma biology. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5084. doi:10.1158/1538-7445.AM2015-5084
Abstract 5089: Desmoplastic stroma affects growth and invasion of progressively mutated human pancreatic cancer cells in vitro
Authors: Malik Ruchi , Luong Tiffany , Karamil Seda , Lelkes Peter , Cukierman Edna 
Published: August 2015

Abstract
Desmoplastic (desmo) stroma is a prognostic marker for pancreatic cancer, yet mechanisms behind its tumorigenic effects remain poorly understood. Tumor stroma, known to act permissive to naïve cells, may exacerbate tumor progression in mutated cells, whereas normal stroma acts restrictive to even aggressively mutated cells. The mechanistic details of these responses remain unclear. Previous studies suggested that a 3D microenvironment (i.e. Matrigel) is necessary for the manifestation of the metastatic phenotype in vitro in aggressively K-Ras mutated pancreatic cancer cells. Here we describe a new 3D in vitro model to study how human pancreatic stromal extracellular matrices (ECMs) interact with pancreatic epithelial cells, how these interactions activate specific integrins and downstream signaling pathways such as PI3K and ERK1/2, and how these signaling pathways may synergize with intrinsic mutational cues to enhance progression of pancreatic cancer. Our model is comprised of physiologically relevant desmo and normal 3D cell-derived matrices as well as polyacrylamide gel-based bioengineered ECMs. The influences of cell-derived and bioengineered ECMs were tested using a series of isogenic pancreatic ductal epithelial cells (PDEC) displaying different aggressive behavior.
In preliminary studies, we established that physiological desmo ECMs are tumor permissive (i.e. induce growth and/or invasion) for all PDEC cells (especially kRas mutated cells) when compared with matched restrictive/normal ECMs. In addition, K-Ras cells cultured on stromal activated (i.e. desmo) myofibroblast-derived 3D ECMs resulted in enhanced ERK1/2 activity, similar to what had been previously observed with Matrigel based system. In order to discern distinct cellular and signal responses mediated by cell-derived ECM in the various PDEC cells, we independently modulated microenvironmental cues such as stiffness, topography, and biochemical composition in the bioengineered ECMs. Our initial data suggests that the various PDEC cells differentially respond to alterations in microenvironmental cues. We anticipate that our studies will lead to better understanding of ECM-PDEC interactions in more detail, and help in identification of novel biomarker for early detection or prevention of pancreatic cancer.
Citation Format: Ruchi Malik, Tiffany Luong, Seda Karamil, Peter Lelkes, Edna Cukierman. Desmoplastic stroma affects growth and invasion of progressively mutated human pancreatic cancer cells in vitro. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5089. doi:10.1158/1538-7445.AM2015-5089
Abstract 5122: In vivo imaging models of bone and brain metastases and pleural carcinomatosis developed using a novel human EML4-ALK lung cancer cell line, A925LPE3
Authors: Nanjo Shigeki , Takeuchi Shinji , Kita Kenji , Fukuda Koji , Nakada Mitsutoshi , Nishihara Hiroshi , Yano Seiji 
Published: August 2015

Abstract
Introduction:EML4-ALK lung cancer accounts for approximately 3%-7% of non-small cell lung cancer cases. Crizotinib, an ALK tyrosine kinase inhibitor, shows dramatic clinical efficacy with a response rate of approximately 60%-80% in EML4-ALK NSCLC patients. However, almost all patients who strongly responded to crizotinib acquired resistance over time. Recently, new generation ALK-TKIs such as alectinib and ceritinib have been approved for treatment of ALK-rearranged NSCLC patients, and it is now clear that resistance may also develop against this class of inhibitors. To investigate the molecular mechanism underlying tumor progression and targeted drug sensitivity/resistance in EML4-ALK lung cancer, clinically relevant animal models are indispensable.
Methods: A human lung adenocarcinoma cell line A925L, which expresses an EML4-ALK gene fusion (variant 5a, E2:A20), established from a surgical specimen obtained from a Japanese male patient. We further established highly tumorigenic A925LPE3 cells with luciferase gene transfection, which also have the EML4-ALK gene fusion. A925LPE3 cells were injected into the right thoracic cavity for the pleural carcinomatosis model, into the tibia for the bone metastasis model, and into the right striatum for the brain metastasis model. After inoculation, the quantity of tumors and the quality of bones were tracked in live mice by repeated noninvasive optical imaging of tumor-specific luciferase activity using the IVIS Lumina XR Imaging System.
Results: In this study, we found that A925L and A925LPE3 cell lines are sensitive to the ALK inhibitors crizotinib and alectinib. By using A925LPE3 cells we established in vivo imaging models for pleural carcinomatosis, bone metastasis, and brain metastasis, all of which are significant clinical concerns of advanced EML4-ALK lung cancer. Interestingly, crizotinib caused tumors to shrink in the pleural carcinomatosis model, but not in bone and brain metastasis models, while alectinib showed remarkable efficacy in all three models, indicative of the clinical efficacy of these ALK inhibitors.
Conclusions: Our in vivo imaging models of multiple organ sites may provide useful resources to analyze further the pathogenesis of EML4-ALK lung cancer and its response and resistance to ALK inhibitors in various organ microenvironments.
Citation Format: Shigeki Nanjo, Shinji Takeuchi, Kenji Kita, Koji Fukuda, Mitsutoshi Nakada, Hiroshi Nishihara, Seiji Yano. In vivo imaging models of bone and brain metastases and pleural carcinomatosis developed using a novel human EML4-ALK lung cancer cell line, A925LPE3. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5122. doi:10.1158/1538-7445.AM2015-5122
Abstract 5123: Curative fluorescence-guided surgery of pancreatic cancer in combination with UVC irradiation in orthotopic mouse models
Authors: Hiroshima Yukihiko , Maawy Ali , Zhang Yong , Sato Sho , Murakami Takashi , Yamamoto Mako , Uehara Fuminari , Miwa Shinji , Yano Shuya , Momiyama Masashi , Chishima Takashi , Tanaka Kuniya , Bouvet Michael , Endo Itaru , Hoffman Robert M. 
Published: August 2015

Abstract
Fluorescence-guided surgery (FGS) has shown great promise, but has not been shown to be curative. Human MiaPaCa-2 pancreatic cancer cells, expressing green fluorescent protein (GFP), were implanted orthotopically in nude mice. Brightlight surgery (BLS) was performed on 24 tumor-bearing mice. After BLS, mice were randomized to BLS-only (n = 8) or FGS (n = 8) or FGS-UVC (n = 8) groups. The residual tumors were resected using a portable imaging system. FGS or FGS followed by UVC irradiation with 2700 J/m2 UVC (254 nm) was performed. Residual tumor area after FGS was significantly smaller than after BLS only (p = 0.007). The BLS treated mice had reduced survival compared to FGS- and FGS-UVC-treated mice for both relapse-free survival (RFS) (p,0.001 and p,0.001, respectively) and overall survival (OS) (p,0.001 and p,0.001, respectively). With FGS-UVC, RFS lasted at least 150 days indicating the animals were cured. UVC irradiation in combination with FGS has curative potential in the clinic.
Citation Format: Yukihiko Hiroshima, Ali Maawy, Yong Zhang, Sho Sato, Takashi Murakami, Mako Yamamoto, Fuminari Uehara, Shinji Miwa, Shuya Yano, Masashi Momiyama, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman. Curative fluorescence-guided surgery of pancreatic cancer in combination with UVC irradiation in orthotopic mouse models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5123. doi:10.1158/1538-7445.AM2015-5123
Abstract 515: Cell fate determination factor DACH1 inhibits lung adenocarcinoma invasion and tumor growth through repression of CXCL5 signaling
Authors: Han Na , Yuan Xun , Wu Hua , Xu Hanxiao , Chu Qian , Guo Mingzhou , Yu Shiying , Chen Yuan , Wu Kongming 
Published: August 2015

Abstract
The onset of human lung cancer involves the loss of tumor suppressor genes and activation of tumor inducing genes. Current studies have proved EGFR, RAS, ALK as as key driver genes, however, in about 50% lung cancer samples there are no known genes to explain tumorigenesis, suggesting many novel pathways remain to be elucidated. Recent study on whole-genome and transcriptome sequencing NSCLC identified cell fate determinatiton gene DACH1 as novel alteration in genes involved in NSCLC. However, the role of DACH1 in NSCLC and its downstrem targets are largely unknown. We showed that expression of DACH1 was significantly decreased in human NSCLC tissues andits protein abundance was inversely correlated with the tumor stage and grade. Restoration of DACH1 function in NSCLC cells significantly reduced cellular proliferation, clone formation, migrasion and invasion in vitro, as well as tumor growth in vivo. By unbiased screen of secreting factors, we found out that CXCL5 was dramaticcaly repressed by DACH1. Furthermore, functional study suggested that CXCL5 was contribute to the DACH1-mediated repression of migrative in vitro and tumorigenesis in vivo. Consistingly, there was a inverse relationship between the mRNA level of DACH1 and CXCL5 in both lung cancer cell lines and huamn NSCLC tissues. Moreover, Kaplan-Meier analysis of human NSCLC samples demonstrated that high mRNA abundance of DACH1 was predicted favorate prognosis for both relaspse-free survivl and overall survival; in contrast, high CXCL5 expression predict worse prognosis for survival. To our understanding, this is the first study to demonstrate DACH1 regulated paracrine signaling in lung cancer and DACH1 could predict prognosis. In conclusion, DACH1 acts as a tumor suppressor gene through repression of paracrine signaling and is a potential biomarker for prognosis.
Citation Format: Na Han, Xun Yuan, Hua Wu, Hanxiao Xu, Qian Chu, Mingzhou Guo, Shiying Yu, Yuan Chen, Kongming Wu. Cell fate determination factor DACH1 inhibits lung adenocarcinoma invasion and tumor growth through repression of CXCL5 signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 515. doi:10.1158/1538-7445.AM2015-515