bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 915: Thrombomodulin expression regulates the tumor stroma differentiation of mesenchymal stem cells for controlling tumor growth
Authors: Shih Tsung-Hsien , Li Jhy-Ming , Shi Guey-Yueh , Wu Hua-Lin 
Published: July 2017

Abstract
Introduction: Thrombomodulin (TM), a thrombin receptor on endothelial cell surface, acts as an anti-coagulant factor in thrombin-catalyzed protein C activation and inhibits the pro-coagulant functions of thrombin. Owing to TM’s widely expression patterns on various cell types, our studies have demonstrated that beside anti-coagulation, TM also participates in controlling cell-cell adhesion, tumor growth, inflammation, angiogenesis, and atherosclerosis. However, the significance of TM expression in mesenchymal stem cells (MSCs) has never been investigated. The non-hematopoietic MSCs could specifically home into the developing tumors and becomes the active components of tumor stroma, which affects tumor’s growth, immunity, progression, and therapeutic resistance. Recently, we investigated the role of TM on the tumor microenvironment differentiation of MSCs for establishing the active stroma that assists tumor growth.
Materials & methods: Normal and TM gene-targeting transgenic mice-isolated bone marrow-derived MSCs were used as the research models to investigate the expressing significance of TM on MSC’s biological activities and differentiations during mouse melanoma B16F10 cell’s conditioning in vitro and in vivo.
Results: Our data showed that MSC's TM expression was low in the quiescent state but was up-regulated while treating with B16F10 cell’s conditioned medium in the mechanism of plate-derived growth factor signaling dependence. Accordingly, using conditional gene knockout strategy, under the condition of tumor cell other than normal culture resulted in that TM gene knockout significantly affected MSC’s proliferation, migration, interleukin-6 secretion, angiogenic activity, and tumor-associated fibroblast differentiation in vitro. Furthermore, TM knockout notably reduced the capacity of MSCs on regulating the growth, vasculogenesis, and active stroma establishment of B16F10 melanoma xenograft in vivo.
Conclusion: These results indicate that the secretion of tumor-associated plate-derived growth factor is a critical event for MSC’s TM expression that controls MSC’s stroma differentiation for developing active tumor microenvironment, which promotes tumor progression. This study further suggests that the modulation of TM expression on MSCs has the therapeutic potential via diminishing the establishment of functional tumor stroma that sensitizes tumor for the therapies.
Citation Format: Tsung-Hsien Shih, Jhy-Ming Li, Guey-Yueh Shi, Hua-Lin Wu. Thrombomodulin expression regulates the tumor stroma differentiation of mesenchymal stem cells for controlling tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 915. doi:10.1158/1538-7445.AM2017-915
Abstract 916: Asymmetric cell division regulator prevents hyperproliferation in glioma cell-of-origin
Authors: Daynac Mathieu , Petritsch Claudia K. 
Published: July 2017

Abstract
In the past, we demonstrated that adult oligodendrocyte progenitor cells (OPC) undergo asymmetric cell division (ACD) to self-renew and generate functional cells by unequally distributing active EGFR and the OPC-specific marker NG2. Moreover, premalignant OPC switch from an asymmetric to symmetric, self-renewing division mode at premalignant stages, and exhibit aberrant proliferation and impaired differentiation (Sugiarto S et al Cancer Cell 2011). OPC are the cell-of-origin of glioma in genetically engineered mouse models (Persson A et al Cancer Cell 2010) and OPC-like glioma cells have high tumor-initiating potential in some glioma types. These data contribute to the emerging evidence that asymmetric cell division (ACD) has tumor suppressive activity. Whether the loss of ACD directly promotes tumor initiation is unclear, because the detailed mechanisms of mammalian ACD have not been elucidated (Gomez-Lopez S et al. Cell Mol Life Sci 2014). Lethal giant larvae 1 (Lgl1) was initially identified as a tumor suppressor in Drosophila and has been implicated in the asymmetric localization of cell fate determinants in mammalian neural progenitor cells (Klezovitch et al., Genes Dev, 2004). Others have shown also that human Lgl1 is inhibited by PTEN loss, which is common in glioblastoma, and Lgl1 depletion in human glioblastoma cells increases their invasive properties (Gont et al, Oncotarget, 2013 and 2014). Whether Lgl1 restricts proliferation, promotes differentiation and prevents neoplastic transformation of OPC, by regulating their asymmetric division, is unknown. We developed a flow cytometry method to isolate proliferative and differentiation-committed OPC (COP) and showed that Lgl1 expression is elevated in differentiation. Using a Cre-conditional knock-out allele (Klezovitch et al., Genes Dev, 2004), we show that Lgl1 knockout OPC proliferate more and differentiate less when compared with Lgl1 wildtype OPC. Lgl1 depletion increases symmetric, self-renewing divisions and reduces the frequency of ACD. Lgl1 appears to control the expression of several conserved ACD regulators, as revealed by comparative Taqman expression analyses of Lgl1 knockout versus control OPC. Ongoing studies are aimed to investigate the link of Lgl1 depletion, altered ACD regulator expression and observed OPC phenotypes. Data derived from this work are expected to provide further insights into the extent to which defective ACD contributes to neoplastic transformation in all cancers.
Citation Format: Mathieu Daynac, Claudia K. Petritsch. Asymmetric cell division regulator prevents hyperproliferation in glioma cell-of-origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 916. doi:10.1158/1538-7445.AM2017-916
Abstract 924: Dedifferentiation into polyploid blastomere-like cancer stem cells via formation of polyploid giant cancer cells
Authors: Niu Na , Liu Jinsong 
Published: July 2017

Abstract
We have recently shown that polyploid giant cancer cells (PGCCs) are capable of tumor initiation and acquisition of embryonic-like stemness and thus represent a novel type of cancer stem cells. However, two important questions remain to be answered from this surprising finding: (1) how PGCCs acquire such stemness; (2) on which stage of normal development PGCCs correspond to. Here, we tracked the fate of single PGCCs induced via mitotic failure by paclitaxel. Morphologically, early spheroids derived from PGCCs were indistinguishable from human embryos at the polyploid blastomere, compaction, morula, and blastocyst-like stages by scanning electron microscopy. PGCCs showed time- and space-dependent activation of expression of the embryonic stem cell markers OCT4, NANOG, SOX2, and SSEA-1 and lacked expression of Xist. PGCCs also showed time-dependent activation of expression of the germ layer-specific markers alpha-fetoprotein, smooth muscle actin, and β3-tubulin and were capable of redifferentiation into three germ layers in vitro. PGCCs-derived daughter cells showed attenuated invasive ability and increased resistance to paclitaxel. PGCCs-derived spheroids grew into a wide spectrum of human neoplasms, including malignant dysgerminoma and embryonic carcinoma, poorly differentiated or well-differentiated carcinomas, and benign squamous tissue. We also observed PGCCs in ovarian cancer from patients treated with chemotherapy. Thus, our data demonstrated that PGCCs acquired novel cancer stem cell properties and capability to redifferentiate into different tumors including the germ cell tumors, which are at the topmost developmental hierarchy. Our studies, for the first time, link PGCCs to the polyploid blastomere-like cancer stem cells and thus offer a new paradigm for the origin of cancer.
Citation Format: Na Niu, Jinsong Liu. Dedifferentiation into polyploid blastomere-like cancer stem cells via formation of polyploid giant cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 924. doi:10.1158/1538-7445.AM2017-924
Abstract 941: CXCL1-CXCR2 signaling might recruit the bone marrow-derived mesenchymal cells to the carcinoma-associated fibroblasts of gastric cancer
Authors: Yashiro Masakazu , Okuno Tomohisa , Kasashima Hiroaki , Miki Yuichiro , Nakamae Hirohisa , Kitayama Kisyu , Kawashima Toshiyuki , Hatano Takaharu , Fujikawa Heishiro , Hasegawa Tsuyoshi , Nakane Takahiko , Hino Masayuki , Hirakawa Kosei , Ohira Masaichi 
Published: July 2017

Abstract
Background & Aims: Activated fibroblasts in the tumor stroma, also termed carcinoma-associated fibroblasts (CAFs), play a critical role in the progression of cancer. In our previous studies, we identified CAFs as playing an important role in cancer progression in the development of gastric cancer. However, it remains unclear which factor recruit and promote CAFs. The aim of this study is to clarify from where CAFs originate and which factor recruits them into the gastric cancer microenvironment.
Methods: In vitro study analyzed the chemotaxis-stimulating factor from gastric cancer cells using bone marrow-derived mesenchymal cells (BM-MCs). The nude mice with bone marrow transplantation from CAG-EGFP mice were used for the in vivo gastric cancer experiments. The influences of chemokine (C-X-C motif) receptor 2 (CXCR2) inhibitor on the migration of BM-MCs were examined in vitro and in vivo.
Results: BM-MCs migrated into tumor stroma of in vivo gastric cancer. The number of BM-MCs was much greater in the gastric tumor than in normal tissue from three days after inoculation of cancer cells. C-X-C motif ligand 1 (CXCL1) from gastric cancer cells significantly (p&lt;0.001) stimulated the chemoattractant ability of BM-MCs in vitro. Anti-CXCL1 antibody and CXCR2 inhibitor significantly (p&lt;0.05) decreased the migration-stimulating activity of gastric cancer cells. A CXCR2 inhibitor, SB225002, decreased tumor size and lymph node metastasis of gastric tumor, and significantly (p=0.039) prolonged survival of gastric-tumor bearing mice. The histologic findings indicated that SB225002 decreased the recruitment of BM-MCs into the tumor stroma, resulting in the reduction of CAFs.
Conclusions: BM-MSCs recruit into gastric tumor and differentiate into CAFs. CXCL1 from gastric cancer cells stimulates the recruitment of BM-MCs into gastric cancer locus via CXCR2 signalling. Inhibition of BM-MCs’ recruitment appears a promising therapy for gastric cancer.
Citation Format: Masakazu Yashiro, Tomohisa Okuno, Hiroaki Kasashima, Yuichiro Miki, Hirohisa Nakamae, Kisyu Kitayama, Toshiyuki Kawashima, Takaharu Hatano, Heishiro Fujikawa, Tsuyoshi Hasegawa, Takahiko Nakane, Masayuki Hino, Kosei Hirakawa, Masaichi Ohira. CXCL1-CXCR2 signaling might recruit the bone marrow-derived mesenchymal cells to the carcinoma-associated fibroblasts of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 941. doi:10.1158/1538-7445.AM2017-941
Abstract 952: Modulation of immune cell trafficking into human colorectal cancer by gut microbiota
Authors: Cremonesi Eleonora , Garzón Jesus G. , Governa Valeria , Mele Valentina , Amicarella Francesca , Padovan Elisabetta , Muraro Manuele , Zajac Paul , Oertli Daniel , Borsig Lubor , Iezzi Giandomenica 
Published: July 2017

Abstract
Introduction: Colorectal cancer (CRC) is a leading cause of cancer-related death. CRC infiltration by immune cells, including cytotoxic CD8+ T cells (CTLs), IFN-gamma-producing T-helper 1 cells (Th1), Foxp3+ regulatory T cells (Tregs) and CD16+ MPO+ neutrophils, is associated with favorable prognosis. However, chemokines driving these cell populations into the tumor site, their cellular sources and their microenvironmental triggers remain to be elucidated.
Aim: We investigated the chemokine/chemokine receptor network promoting CRC infiltration by immune cells associated to favorable prognosis.
Results: CRC infiltration by immune cells was associated with defined chemokine gene signatures, including CCL5, CXCL9 and CXCL10 for cytotoxic T lymphocytes and T-helper 1 cells, and CCL17, CCL22 and CXCL12 for T-helper 1 and regulatory T cells. Most of these chemokine genes were expressed by tumor cells upon exposure to gut bacteria in vitro and in vivo. Indeed, chemokine expression levels were significantly higher in orthotopic xenografts than in intraperitoneal tumors, and were drastically reduced by antibiotic treatment of tumor-bearing mice. Importantly, in human CRC samples, extents of chemokine production and immune cell infiltration was significantly associated with bacterial loads.
Conclusion: Gut microbiota stimulates chemokine production by CRC cells, thus favoring T cell recruitment into tumor tissues.
Note: This abstract was not presented at the meeting.
Citation Format: Eleonora Cremonesi, Jesus G. Garzón, Valeria Governa, Valentina Mele, Francesca Amicarella, Elisabetta Padovan, Manuele Muraro, Paul Zajac, Daniel Oertli, Lubor Borsig, Giandomenica Iezzi. Modulation of immune cell trafficking into human colorectal cancer by gut microbiota [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 952. doi:10.1158/1538-7445.AM2017-952
Abstract 956: Novel oral small molecule CXCR4 inhibitor improves activity of immune checkpoint blockade in ovarian cancer mouse model
Authors: Starbuck Kristen , McGray Robert , Masoumi-Moghaddam Samar , Francois Ariel , Odunsi Kunle , Zsiros Emese 
Published: July 2017

Abstract
Ovarian cancer continues to be the most lethal gynecologic malignancy with no real cure for patients presenting with advanced stage disease. Immune check point blockade showed modest clinical response in patient with recurrent ovarian cancer, thus additional therapeutic strategies for combination therapy are needed. As chemokines and their receptors drive both immune cell migration and tumor growth, angiogenesis and metastasis formation, they are an attractive target for combinatorial cancer therapy.
CXCR4 is the most highly expressed chemokine receptor in advanced stage high grade serous ovarian cancer, thus the objective of this study was to evaluate the efficacy of a novel oral small molecule CXCR4 inhibitor (X4-136) alone and in combination with immune checkpoint inhibition and the anti-angiogenic agent bevacizumab, and characterize the changes in circulating immune cells during treatment in murine ovarian cancer model. The ID8 cell line was used in C57BL/6J mice to establish an immune competent murine model and to compare single agent and combination therapy with oral X4-136 CXCR4 inhibitor, bevacizumab, and anti-PD1. During treatment blood sampling was performed and immune cells were analyzed by flow cytometry.
Our results demonstrated that single agent therapies alone with either drug had no significant effect on tumor progression or survival. Combination therapy with the CXCR4 inhibitor and anti-PD1 improved survival compared to control animals and the other combination therapy groups. The addition of bevacizumab to the dual combination did not further prolong survival. Analysis of circulating immune cells revealed elevations in CD11b+Ly6C+ and the ratio of CD11b+Ly6C+ to CD11b+Ly6G+ in groups treated with the CXCR4 inhibitor, indicating an increase in circulating myeloid cells. Bevacizumab had no activity in this mouse model as a single agent, and did not have synergistic effect in combination therapy.
For the first time we demonstrated that novel CXCR4 inhibitor X4-136 in combination therapy with anti-PD1 showed improved survival in murine ovarian cancer model. CXCR4 blockade increased the proportion of circulating myeloid cells during active treatment, thus further investigation into this novel therapeutic approach is warranted.
Citation Format: Kristen Starbuck, Robert McGray, Samar Masoumi-Moghaddam, Ariel Francois, Kunle Odunsi, Emese Zsiros. Novel oral small molecule CXCR4 inhibitor improves activity of immune checkpoint blockade in ovarian cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 956. doi:10.1158/1538-7445.AM2017-956
Abstract 980: BAY-299, a novel chemical probe for in-depth analysis of the function of the bromodomain proteins BRPF2 and TAF1
Authors: Bouche Lea , Christ Clara D. , Siegel Stephan , Tallant Cynthia , Fernández-Montalván Amaury E. , Huber Kilian V. , Pütter Verra , Müller Susanne , Fedorov Oleg , Laak Antonius ter , Sugawara Tatsuo , Stöckigt Detlef , Meier Julia , Holton Simon J. , Hartung Ingo V. , Haendler Bernard 
Published: July 2017

Abstract
With the exception of the bromodomain and extra-terminal domain BET subgroup, little is known about the role of bromodomain (BD) containing proteins in cancer so that there is a dire need for chemical probes addressing other family members. The bromodomain and PHD-finger (BRPF) family encompasses three paralogs, BRPF1, BRPF2 and BRPF3, which are all found in histone acetyltransferase (HAT) complexes. BRPF2 is a scaffold protein and its knock-out leads to embryonic lethality at E15.5, potentially due to its role in embryonic stem cell differentiation. Here we present the structure-activity relationship (SAR) and characterization of the first selective BRPF2 chemical probe BAY-299, with additionnal strong activity at TAF1, a major component of the basal transcription initiation complex TFIID. BAY-299 shows in vitro activity for BRPF2 (IC50 = 67 nM) and TAF1 second bromodomain (BD2; IC50 = 8 nM) in the TR-FRET assay, as well as in the cellular NanoBRET assay [IC50 (BRPF2) = 575 nM; IC50 (TAF1 BD2) = 825 nM]. To the best of our knowledge BAY-299 is the only disclosed inhibitor showing BRPF2 selectivity over its two paralogues BRPF1 and BRPF3. It belongs to the 1,3-benzimidazolone scaffold and bears a novel substitution which is responsible for its high BRPF2 selectivity and also for its inactivity on BET BDs. The dual inhibitory properties of BAY-299 against BRPF2 and TAF1 make it an ideal research tool for further investigation of these two proteins in physiological and pathological processes.
Citation Format: Lea Bouche, Clara D. Christ, Stephan Siegel, Cynthia Tallant, Amaury E. Fernández-Montalván, Kilian V. Huber, Verra Pütter, Susanne Müller, Oleg Fedorov, Antonius ter Laak, Tatsuo Sugawara, Detlef Stöckigt, Julia Meier, Simon J. Holton, Ingo V. Hartung, Bernard Haendler. BAY-299, a novel chemical probe for in-depth analysis of the function of the bromodomain proteins BRPF2 and TAF1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 980. doi:10.1158/1538-7445.AM2017-980
Abstract 992: Patient-derived tumor organoids of neuroendocrine prostate cancer
Authors: Puca Loredana , Bareja Rohan , Shaw Reid , Karthaus Wouter , Gao Dong , Pauli Chantal , Mosquera Juan Miguel , Cyrta Joanna , Rosati Rachele , Rao Rema , Sboner Andrea , Grandori Carla , Inghirami Giorgio , Chen Yu , Rubin Mark A. , Beltran Himisha 
Published: July 2017

Abstract
Background: The development of neuroendocrine prostate cancer (NEPC) is one mechanism of treatment resistance to androgen receptor (AR)-targeted therapies for a subset of patients with advanced prostate cancer. This is associated with transition from a prostate adenocarcinoma to small cell/NEPC histology, low AR signaling signaling, and expression of neuroendocrine markers as Chromogranin A (CGHA), Synaphophysin (SYP) and CD56). Patient derived preclinical models recapitulating the NEPC phenotype may be used to address NEPC pathogenesis and test emerging therapeutic targets.
Methods: Tumor organoids were developed according to protocols previously described (Gao et al, Cell 2015). Briefly the tissue biopsies (liver and bone biopsy) were washed, enzymatically digested and then seeded in Matrigel (BD) droplets. Organoids were characterized at genomic (WES), RNA and protein level (IHC) to confirm the expression of specific markers. Lentiviral infections were performed using shRNAs against EZH2 to knock down EZH2 in organoids. Organoids were also subcutaneously injected in NSG mice to generate patient derived xenografts (PDXs) for drug treatment in vivo.
Results: We developed and characterized two NEPC tumor organoids from tumor biopsies (liver and bone) of two patients both in vitro and in vivo (as PDXs). NEPC tumor organoid models retained the molecular and histological characteristic of their matched patient samples. We successfully manipulated the activity of the histone methyltransferase EZH2 by using a catalytic inhibitor and its expression by infecting organoids with shEZH2. We showed that the absence of EZH2 affects the expression of neuroendocrine-associated programs as stem cell and neuronal pathway. Moreover treatment with EZH2 inhibitor decreased tumor organoids viability and PDXs tumor volume. Drug screening approaches on NEPC organoids were used to discovery novel drug targets and combinations that could potentially benefit NEPC patients. Top single agent hits included previously identified targets such as EZH2, AURKA, as well as novel synergies.
Conclusions NEPC patient tumor organoids are clinically relevant tumor models to study the NEPC phenotype in advanced prostate cancer and may be used to elucidate novel drug targets.
Citation Format: Loredana Puca, Rohan Bareja, Reid Shaw, Wouter Karthaus, Dong Gao, Chantal Pauli, Juan Miguel Mosquera, Joanna Cyrta, Rachele Rosati, Rema Rao, Andrea Sboner, Carla Grandori, Giorgio Inghirami, Yu Chen, Mark A. Rubin, Himisha Beltran. Patient-derived tumor organoids of neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 992. doi:10.1158/1538-7445.AM2017-992