bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1987: Exosome from CAF-ESCC aggravates tumor progression by its containing molecular miR-3656
Authors: Chen Xiaojia , Jin Yuan , Zhang Bihui , LI Xiaocen , Tian Baoqing , Wang Qiang , Hong An 
Published: August 2019

Abstract
Background: Exosome plays an important role in cell communication and cell environment. But the mechanism of how exosome derived from cancer-associated fibroblast (CAF) influent esophageal squamous cell carcinoma (ESCC) progression is not clear. In this work, compared with normal fibroblast-derived exosomes (NDEs), we found that CAF derived exosomes (CDEs) can enhance the growth, migration, and invasion of ESCC cells obviously. Therefore, we would like to clarify the role of CDEs in ESCC progression.
Methods and Results: Using microRNA array to analyze the different miRNAs in the CDEs and NDEs, we got a series of up-regulation miRNAs and two down-regulation miRNAs in CDEs. Among them, miR-3656 shows a significantly highest level. Then, we transfected miR-3656 mimics to the ESCC cells and found the mimics increased the growth, migration, and invasion of ESCC cells in cell proliferation assay. cell scratch tests and chamber invasion experiments. We established recombinant ESCC cells with miR-3656 high expression by the lentiviral system. The cells were injected into mice to form the xenograft tumor. The results showed the miR-3656 can enhance the tumor formation. After that, aided by TargetScan software, we found ACAP2, one of miR3656 targets, was significantly down-regulating in ESCC cells at the high level of miR-3656. When ACAP2 expression was knocked-down by siRNA, the proliferation and migration of ESCC cells was increased, which indicated ACAP2 a potential anti-tumor factor. Furthermore, we detected the different proteins between ESCC cells with high expression miR-3656 and normal ESCC cells through LC_MS; the results were analyzed by Integrate Pathway Analysis (IPA) system and many differential proteins were found to be involved of PI3K/AKT and Wnt pathways.
Conclusions: In this study, we found the CDEs promote the progression of their sounding ESCC cells in vitro and in vivo. The main reason is that CDEs carry some tumor-promoting miRNAs that influent the target ESCC cells. Especially, miR-3656 expresses the highest level of miRNAs in CDEs. It not only decreases the expression of ACAP2 but also impacts the expression of proteins involved PI3K/AKT and Wnt pathways in ESCC cells. The results indicate the CDEs playing a very important role in ESCC progression.
Citation Format: Xiaojia Chen, Yuan Jin, Bihui Zhang, Xiaocen LI, Baoqing Tian, Qiang Wang, An Hong. Exosome from CAF-ESCC aggravates tumor progression by its containing molecular miR-3656 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1987.
Abstract 1989: Breast cancer-derived exosomes modulate the endocytic pathway in brain endothelial cells
Authors: Morad Golnaz , Carman Christopher V. , Moses Marsha A. 
Published: August 2019

Abstract
Breast cancer brain metastasis is associated with high mortality and has shown a rising trend in incidence during the recent years. Given the rapid progression of brain metastasis, elucidation of the early events that lead to brain metastasis will pave the way to identifying potential diagnostic and therapeutic targets for early intervention. To explore the early mechanisms of breast cancer brain metastasis, we focused on the role of breast cancer-derived exosomes in this process. While extensive studies have explored the role of tumor-derived exosomes in tumor progression, the current understanding of the contribution of tumor-derived exosomes to brain metastasis remains limited. Using a mouse model of brain metastasis, we showed that pre-treatment of mice with exosomes derived from the brain-seeking MDA-MB-231 breast cancer cell line (Br-Ex) increases brain metastasis growth. This facilitation of brain metastasis was not observed with exosomes derived from the parental MDA-MB-231 cells (P-Ex). It is widely acknowledged that during early stages of brain metastasis, tumor cells grow along the brain vasculature, the blood brain barrier (BBB). To understand the mechanisms of the exosome-derived facilitation of brain metastasis, we studied the interactions between exosomes and the BBB. Using state-of-the-art models of the BBB and high-resolution microscopy, we have identified, for the first time, the mechanisms by which Br-Ex modulate the endocytic pathway in brain endothelial cells to decrease exosome degradation. Interestingly, our mechanistic studies showed that these effects are induced through the transfer of exosomal miRNAs enriched in Br-EX. Moreover, we have shown that Br-Ex can exclusively change the expression of integrins in brain endothelial cells in a way that it could alter the microenvironment around the BBB in favor of metastatic tumor cells. These findings indicate that exosomes derived from a brain-seeking subpopulation of breast cancer cells can exclusively modify the physiological regulation of the BBB at multiple levels to accelerate metastatic growth in the brain microenvironment. Taken together, these studies increase our understanding of the early events that facilitate brain metastasis and provide multiple potential targets for diagnostic and therapeutic applications in brain metastasis. (This work was supported by the Breast Cancer Research Foundation and NIH R01CA185530.)
Citation Format: Golnaz Morad, Christopher V. Carman, Marsha A. Moses. Breast cancer-derived exosomes modulate the endocytic pathway in brain endothelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1989.
Abstract 199: TGF-β in exosomes facilitates HNSCC progression by accelerating tumor angiogenesis
Authors: Ludwig Nils , Yerneni Saigopalakrishna S. , Hinck Cynthia S. , Pietrowska Monika , Hinck Andrew P. , Whiteside Theresa L. 
Published: August 2019

Abstract
TGF-β is a key regulator for tumor initiation and progression in head and neck squamous cell carcinoma (HNSCC). Tumor-derived exosomes (TEX) contain TGF-β and accumulate in the tumor microenvironment (TME). This study characterizes the TGF-β content of HNSCC-derived exosomes and evaluates in vitro and in vivo TGF-β signaling by exosomes that results in promotion of angiogenesis. TEX were isolated from supernantants of 5 different HNSCC cell lines by mini size exclusion chromatography (mini-SEC) and characterized by electron microscopy, nanoparticle tracking analysis and mass spectrometry (LC-MS/MS). TGF-β content in exosomes was evaluated by immunoblotting. Proliferation and migration of SVEC4-10 lymphendothelial cells in response to TEX were investigated in vitro and results were confirmed in vivo, using a matrigel plug model in mice. In these experiments a novel trivalent TGF-β receptor trap (mRER) was used to inhibit TGF-β signaling. TGF-β levels and activity were similarly measured in exosomes isolated from plasma of 20 HNSCC patients. TEX carried high levels of TGF-β and were found to be potent inducers of angiogenesis in vitro and in vivo through functional reprogramming and phenotypic modulation of endothelial cells. Proliferation (p&lt;0.01) and migration (p&lt;0.01) by SVEC4-10 were stimulated by TEX and effects were inhibited by mRER treatment of SVEC4-10 (p&lt;0.05). TEX promoted formation of defined vascular structures in vivo, and increased (p&lt;0.001) vascularization in matrigel plugs relative to control. Those effects were inhibited by mRER treatment (p&lt;0.05). Exosomes in plasma of HNSCC patients carried varying levels of TGF-β, and patients with nodal metastases had elevated TGF-β levels (p&lt;0.01) relative to patients with no meastasis.The data show that TGF-β signaling by TEX in HNSCC promotes angiogenesis and drives tumor progression. Future efforts should focus on silencing TEX, thereby adding new options to existing anti-angiogenic therapies.
Citation Format: Nils Ludwig, Saigopalakrishna S. Yerneni, Cynthia S. Hinck, Monika Pietrowska, Andrew P. Hinck, Theresa L. Whiteside. TGF-β in exosomes facilitates HNSCC progression by accelerating tumor angiogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 199.
Abstract 2005: Optimized range of osmotic pressure and viscosity for a lymphatic drug delivery system
Authors: Kodama Tetsuya , Mori Shiro 
Published: August 2019

Abstract
The lymphatic drug delivery system (LDDS) is a method that allows the injection of drugs into sentinel lymph nodes (SLNs) to facilitate their delivery to downstream lymph nodes (LNs) via the lymphatic network to treat or prevent cancer cell development in both LNs. A high concentration of drug is effectively maintained in both LNs. Here we show that therapeutic effects in metastatic LNs depend on the osmotic pressure and viscosity of the administered drug in a metastatic mouse (MXH10/Mo-lpr/lpr) model. We found using an in vivo bioluminescence imaging system that indocyanine (ICG) solutions were retained in the proper axillary lymph node (PALN) at an osmotic pressure &gt; 1,700 kPa and 6 mPa·s viscosity, when ICG solution was injected into the SiLN to deliver it to the (PALN). Edematous swelling was detected near the SiLN at &gt; 3,500 kPa osmotic pressure and 400 mPa·s viscosity. Furthermore, we established that the therapeutic effects of drugs on metastatic PALN were observed in the osmotic pressure range 1000 - 2400 kPa and viscosity range 2 - 30 mPa·s, after tumor cells were injected into the SiLN to induce metastasis in the PALN. Cisplatin solution was injected into the accessory axillary lymph node to deliver cisplatin to the metastatic PALN. Our results demonstrate the optimized values of osmotic pressure and viscosity for LDDS. We anticipate our results to be a starting point for more sophisticated drug administration by a LDDS.
Citation Format: Tetsuya Kodama, Shiro Mori. Optimized range of osmotic pressure and viscosity for a lymphatic drug delivery system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2005.
Abstract 2019A: TLR3 facilitate breast cancer metastasis to lymph node
Authors: Torres-Luquis Odalys J. , Mohammed Sulma 
Published: August 2019

Abstract
Tumor cells can only enter the lymphatic circulation at the interface between the invasive edge of the tumor and the adjacent host stroma that contains the lymphatic circulation. The existence of this distance barrier means that it would be unlikely for tumor cells to passively enter the lymph drainage. Instead, Toll-like receptors (TLRs) are important mediators for active migration and chemotaxis for tumor cells entry into the lymphatic drainage from the primary tumor. Here we use a microsurgical technique to collect lymph circulating tumor cells (LCTC) prior to its entry into sentinel lymph node in rat models and determine if the TLR expression induces the migration and tumor progression. In our results, we observed high levels of TLR3 expression in LCTC when cells were treated with Poly (I:C), a synthetic ligand for TLR3 induction. NFkB activation was also observed in LCTCs, after TLR3 activation this pathway can express genes involved in cancer progression. In addition, when looking at the expression of cytokines and chemokines factors present in the lymph or secreted by the tumor cells, CXCL10 had a high expression on induced TLR3 of LCTC and its ligand CXCR3 was also expressed in the lymph. CXCL10 is involved in chemotaxis, induction of apoptosis, and regulation of cell growth. The CXCL10/CXCR3 signaling mediates paracrine interactions between tumor and stromal cells that govern leukocyte trafficking and angiogenesis. Suppression of CXCR3 or receptors signaling limits metastasis suggesting CXCR3 contributes to the metastatic process. TLR3 Knockdown prevented tumor growth and metastasis in rat. Our data suggest that for breast cancer metastasis, TLR3 might play a role in active migration of tumor cells and tumor progression. Activation of TLRs in tumor cells can dampen the anti-tumor functions of infiltrating immune cells, altering the inflammatory response and promoting cancer progression.
Citation Format: Odalys J. Torres-Luquis, Sulma Mohammed. TLR3 facilitate breast cancer metastasis to lymph node [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2019A.
Abstract 2046: Egr-1 promotes bone marrow fibrosis in primary myelofibrosis
Authors: Rao Rekha M. , Kumar Amar , Vekaria Pratikkumar , Yacoub Abdulraheem , Skikne Barry , McGuirk Joseph 
Published: August 2019

Abstract
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by JAK-STAT-activated proliferation of leukemia cells and progressive bone marrow fibrosis. However little is known about the bone marrow stromal cell (BMSC) intrinsic factors that work in concert with leukemia stem cells (LSCs) to promote fibrosis of the bone marrow in PMF. In this study we developed an in vitro model to simulate bone marrow fibrosis in PMF by exposing cultured BMSC, HS-5 cells to PMF-patient plasma. We observed that exposure of BMSCs to PMF plasma but not normal serum increased total cellular and mitochondrial reactive oxygen species (ROS), as well as Early growth response 1 (Egr-1) and its target gene expression in BMSCs. Egr-1 is a transcription factor that upregulates fibrosis-associated genes, and is acutely induced by numerous cytokines (e.g. TGF-β, PDGFα) that are elevated in PMF. Utilizing this model, we performed RNA sequencing of HS-5 cells exposed to PMF plasma. We observed that PMF plasma exposure alters pathways responsible for multiple DNA damage responses, G1/s cell cycle checkpoint regulation and protein homeostasis. Since PMF progression is associated with enhanced oxidative stress which induces both DNA damage and Egr-1 expression, we determined the effect of anti-oxidants on the induction Egr-1 and fibrosis associated genes in BMSCs following treatment with PMF plasma. We report that treatment with N-acetyl-cysteine (a ROS scavenger) and mitotempo (a mitochondrial ROS scavenger) abrogated the up-regulation of PMF plasma-induced fibrosis-associated genes in BMSCs. Additionally, knockdown of Egr-1 in BMSCs resulted in the down-regulation of collagen 1A1 and connective tissue growth factor (CTGF) following exposure to PMF plasma. These findings suggest that PMF plasma induces ROS and promotes the upregulation of pro-fibrotic genes in an Egr-1-dependent manner in PMF. Our studies suggest that inhibition of ROS and Egr-1-induced gene transcription could be used as a strategy to alleviate bone marrow fibrosis; a disease complication in PMF for which there are no approved therapies.
Citation Format: Rekha M. Rao, Amar Kumar, Pratikkumar Vekaria, Abdulraheem Yacoub, Barry Skikne, Joseph McGuirk. Egr-1 promotes bone marrow fibrosis in primary myelofibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2046.
Abstract 2060: Combination of CD20 targeted engineered toxin body, MT-3724, with chemotherapy or IMiDs for the treatment of non Hodgkin's lymphoma
Authors: Higgins Jack P. , Iberg Aimee , Howard Caleigh , Willert Erin 
Published: August 2019

Abstract
MT-3724 is a novel recombinant fusion protein consisting of a CD20 binding variable fragment (scFv) fused to Shiga-like toxin-I A1 (SLTA) ribosome inactivating protein. Engineered Toxin Bodies (ETBs) are unique as they can induce internalization after binding to non- or poorly-internalizing receptors with subsequent enzymatic and permanent ribosome destruction through SLTA, representing a novel mechanism of direct cell-kill in oncology. MT-3724 has demonstrated single agent anti-tumor activity in heavily pre-treated relapsed/refractory (R/R) Non-Hodgkin’s lymphoma NHL patients in a Phase I clinical study. Specifically, in R/R diffuse large B cell lymphoma (DLBCL) patients who had low pre-existing serum levels of rituximab, an objective response rate (ORR) of 30% (3 of 10) and disease control rate of 70% (7 of 10) has been observed thus far (NCT02361346).
Given the unique ribosomal inhibition mechanism of action for MT-3724, we hypothesized that combination of MT-3724 with agents possessing a differentiated mechanism of action could result in additive or synergistic cellular cytotoxicity in CD20 positive NHL cell lines. Preclinical studies were conducted to assess MT-3724 in combination with cytotoxic chemotherapeutic agents (doxorubicin, gemcitabine, bendamustine, and vincristine) or an immunomodulatory (IMiD) agent (lenalidomide) on selected NHL cell lines. The combination of MT-3724 with all agents demonstrated additive or synergistic cytotoxicity of NHL cell lines.
The single agent clinical activity of MT-3724 in heavily pre-treated R/R NHL patients along with this preclinical combinatorial effect of MT-3724 with chemotherapy and IMiDs used in the treatment of R/R NHL have lead the opening of a Phase 2a study of MT-3724 in combination with Gemcitabine and oxaliplatin (GEMOX, NCT03488251) and another planned Phase 2a study of MT-3724 in combination with lenalidomide (NCT03645395).
MT-3724 has demonstrated good tolerability and early signs of clinical activity as monotherapy in patients with R/R NHL along with additive and/or synergistic effects in combination with chemotherapy and IMiDs preclinically. Additional clinical studies to evaluate MT-3724 as single agent and in combination with GEMOX or lenalidomide are underway.
Citation Format: Jack P. Higgins, Aimee Iberg, Caleigh Howard, Erin Willert. Combination of CD20 targeted engineered toxin body, MT-3724, with chemotherapy or IMiDs for the treatment of non Hodgkin's lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2060.
Abstract 208: Transcriptional profiling of the microenvironment in pediatric osteosarcoma
Authors: Sorenson Laurie , McEachron Troy A. 
Published: August 2019

Abstract
Osteosarcoma (OS) is the most common bone tumor in pediatric and adolescent/young adult patients. Over the past three decades, significant improvements in the survival rates or therapeutic approaches for these patients have not been made, especially in the context of metastatic disease. While immune checkpoint blockade has revolutionized the therapeutic landscape in various adult malignancies, its impact in OS has been largely underwhelming. Currently, it is unknown whether the lack of therapeutic benefit of immune checkpoint inhibition observed in patients with OS is truly due to treatment inefficacy rather than a limited understanding of the tumor microenvironment that supports this aggressive disease. To address this knowledge gap, we have performed targeted gene expression profiling of metastatic and non-metastatic osteosarcoma specimens. Our profiling experiments have revealed that metastatic OS specimens are immunologically “colder” than non-metastatic OS specimens. Our data also demonstrates that T cells are largely excluded from the metastatic specimens and that this exclusion significantly correlates with markers of vascular instability. In a pathological setting, such as that of cancer, VEGF and ANG2 signaling promote vascular instability which limits leukocyte extravasation and subsequent tumor infiltration. Our data suggests that vascular destabilization mediated by VEGF/ANG2 signaling impedes T cell infiltration specifically in metastatic OS and identifies these molecules as potential targets for therapeutic intervention.
Citation Format: Laurie Sorenson, Troy A. McEachron. Transcriptional profiling of the microenvironment in pediatric osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 208.
Abstract 2080: Novel molecularly targeted combination for renal cell carcinoma
Authors: Jordan Andre R. , Wang Jiaojiao , Lopez Luis E. , Morera Daley S. , Lokeshwar Vinata B. 
Published: August 2019

Abstract
INTRODUCTION: Despite many available treatments, &gt;90% of metastatic renal cell carcinoma (mRCC) patients die within 5 years. Due to its modest efficacy, Sorafenib (SF) is a second line treatment for mRCC. Molecular basis for SF failure is unknown. Hymecromone (HC) is a non−toxic orally bioavailable agent used in Europe for improving liver health. We examined the molecular basis of SF failure in clinical specimens and provided mechanistic evidence for why SF+HC could be a potent therapeutic combination against mRCC.
METHODS: UGT1A9 (A9) levels and SF glucuronidation were measured in kidney specimens (45 normal; 86 tumor) by qPCR and a glucuronidation assay using tumor microsomes. Response to SF+HC combination in vector-only (EV), A9-overexpressing (A9) and A9-knockdown (A9-KO) 786-0 and Caki-1 transfectants, primary RCC spheroids, and endothelial cells was examined by proliferation, apoptosis, motility and invasion assays. Target analysis was performed by immunoblot. Treatment efficacy was evaluated in Caki−1 s.c. and orthotopic xenograft models, with bioluminescence imaging.
RESULTS: A9 has been shown to glucuronidate and inactivate SF. A9 levels were 8-10-fold elevated in mRCC patients’ tumors compared to non-mRCC patients and normal kidney tissues. A9 levels were an independent predictor of metastasis (P=0.022; efficacy: 73%; sensitivity: 93.8%). Tumor microsomes from mRCC patients’ glucuronidated SF 5-fold higher than from non-mRCC patients. In RCC cells, HC treatment downregulated A9 levels, A9 promoter activity and inhibited SF-glucuronidation. SF (5 µM) and HC (20-40 µg/ml) combination inhibited RCC cell and primary tumor spheroid proliferation (&gt;90%), motility/invasion (&gt;80%), and induced apoptosis (5-fold). While A9 transfectants were resistant to SF+HC treatment, A9-KO cells were sensitive to SF alone. Endothelial cells co-cultured with A9 transfectants were resistant to SF+HC treatment. SF+HC upregulated apoptosis effectors, but downregulated CD44, RHAMM, and phospho-Met levels in EV but not A9 transfectants. HC (100 or 200 mg/kg) and SF (30 mg/kg) oral combination abrogated Caki−1 tumor growth (&gt;80%) without serum/tissue toxicity. HC+SF treatment decreased A9 levels, Ki67 index and microvessel density. A9-overexpressing tumors were resistant to treatment.
CONCLUSION: This is the first study to demonstrate that A9 overexpression in mRCC is likely a mechanism of SF failure and A9 downregulation can re-sensitize cells. HC+SF is an orally bioavailable and non-toxic combination that may be an effective therapeutic strategy for mRCC.
Citation Format: Andre R. Jordan, Jiaojiao Wang, Luis E. Lopez, Daley S. Morera, Vinata B. Lokeshwar. Novel molecularly targeted combination for renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2080.