bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4034: Macrophage-dependent activation of a non-canonical NOTCH-RhoA signaling pathway regulates tumor cell intravasation
Authors: Bravo Cordero Jose Javier , Roh-Johnson Minna , Pignatelli Jeanine , Oktay Maja , Hodgson Louis , Condeelis John 
Published: August 2015

Abstract
Intravital imaging of rodent mammary tumors has shown that direct contacts between a Mena expressing tumor cell, a perivascular macrophage and an endothelial cell forms a microanatomical structure named TMEM (Tumor Microenvironment of Metastasis). Clinical studies have shown that the number of TMEM is correlated with an increased risk of developing distant metastasis in breast cancer patients. While TMEM is an excellent prognostic marker for predicting metastasis the mechanisms of TMEM assembly and function are not understood. Recently, we showed that heterotypic cell contact between tumor cells and macrophages induces the formation of invadopodia in tumor cells, invasive structures necessary for matrix degradation and required for tumor cell intravasation. Using high resolution FRET imaging, we further found that macrophage-induced invadopodium formation is dependent on RhoA activation in the tumor cell. However, what remained to be determined was the signaling pathway that regulated this heterotypic cell contact-mediated phenomenon. We explored the role of NOTCH, a known receptor involved in heterotypic cell contact signaling, in stimulating macrophage-dependent tumor cell invadopodium formation and transendothelial migration. We found that, in the absence of Notch signaling, macrophage-induced invadopodium formation and tumor cell intravasation are abolished. Moreover, RhoA is no longer activated in tumor cells upon macrophage contact when Notch signaling is perturbed. These results show that Notch signaling regulates heterotypic cell contact mediated invadopodium formation through RhoA activation, and reveals a novel non-canonical NOTCH/RhoA pathway as a molecular target to prevent TMEM function and therefore metastasis.
Citation Format: Jose Javier Bravo Cordero, Minna Roh-Johnson, Jeanine Pignatelli, Maja Oktay, Louis Hodgson, John Condeelis. Macrophage-dependent activation of a non-canonical NOTCH-RhoA signaling pathway regulates tumor cell intravasation. [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 4034. doi:10.1158/1538-7445.AM2015-4034
Abstract 4035: Extracellular secreted Ref-1 triggers triple negative breast cancer cells apoptosis
Authors: Lee Yu Ran , Kim Ki Mo , Joo Hee Kyoung , Jeon Byeong Hwa , Choi Sunga 
Published: August 2015

Abstract
Triple-negative breast cancers (TNBCs) are most aggressive type and resistant to standard chemotherapy. There is a high demand for developing approaches to treat TNBCs. Recently, some agents inducing post-translational modification (PTM) were suggested to treat therapeutic-resistant cancer cells. We previously discovered that trichostatin A (TSA), histone deacetylase inhibitor (HDACi), - mediated acetylation induced extracellular secretion of the acetylated apurinic apyrimidinic endonuclease 1/redox factor-1 (Ac-APE1/Ref-1). This is the first report showing that the Ac-APE1/Ref-1 is not merely a secreted protein but also a signal molecule that plays a critical role in the apoptotic cell death pathway in TNBC. To study the functional significance of the secreted Ac-APE1/Ref-1, we induced PTM, hyperacetylation of intracellular proteins with co-treatment of acetylsalicylic acid (ASA) and TSA in MDA-MB-231 cells. In response to hyperacetylation, the secretion of Ac-APE1/Ref-1 in a form of exosome-like vesicles was observed in both electron microscopy and confocal image analysis. Accordingly, it was caused a statistically significant inhibition of cell viability and induction of apoptotic DNA fragmentation, leading activation of p38 mitogen-activated protein kinase and apoptotic cell death. Blockade of Ac-APE1/Ref-1 thoroughly recovered from the cell death effects. The hyperacetylation-mediated apoptotic cell death was comparably efficient in treatment of another TNBC cell lines, BT549, and MDA-MB-468. Keeping in view secreted APE1/Ref-1 following acetylation - causing apoptotic cell death we suggest that PTM qualifies as an excellent candidate to be exploited for therapeutic agents to treat TNBCs. For future clinical investigations of TNBCs, this study offers a novel paradigm, which stimulation of apoptotic pathway by action of PTM-induced auto- or paracrine signaling molecules is prior to treatment of standard chemotherapeutic resistant cancer cells.
Citation Format: Yu Ran Lee, Ki Mo Kim, Hee Kyoung Joo, Byeong Hwa Jeon, Sunga Choi. Extracellular secreted Ref-1 triggers triple negative breast cancer cells apoptosis. [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 4035. doi:10.1158/1538-7445.AM2015-4035
Abstract 404: MK2461 suppress progression of pancreatic cancer disrupting interaction between pancreatic cancer cells and stellate cells
Authors: Inoue Koetsu , Ohtsuka Hideo , Motoi Fuyuhiko , Douchi Daisuke , Kawasaki Shuhei , Kawaguchi Kei , Masuda Kunihiro , Fukase Koji , Ohnuma Shinobu , Naitoh Takeshi , Katayose Yu , Egawa Shinichi , Unno Michiaki 
Published: August 2015

Abstract
Pancreatic cancer is characterized excessive desmoplasia, which occupies 80% of pancreatic cancer tissue and mainly consists of pancreatic stellate cells (PSCs). Desmoplasia has been shown to play an important role in the progression, invasion, and metastasis of pancreatic cancer and has been implicated in the development of resistance to chemotherapy and radiotherapy. Growth factors are one of the components modulating the interactions between pancreatic cancer cells (PCCs) and PSCs. Therefore, blocking growth factor signaling could suppress cancer progression. In this study, we profiled the expression of receptor tyrosine kinases (RTKs) with quantitative targeted absolute proteomics using liquid chromatography tandem mass spectrometry (LC-MS/MS) in PCCs and PSCs. In PCCs, epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (MET) levels were elevated compared with those in PSCs. In PSCs, platelet-derived growth factor receptor beta (PDGFRβ) and MET were upregulated compared with other RTKs. Conditioned medium from PSCs promoted the proliferation of PCCs, and vice versa. In addition, MK2461, a multikinase inhibitor targeting MET and PDGFRβ, suppressed the effects of conditioned medium on PCCs and PSCs. In addition, MK2461 significantly inhibited tumor growth in mice xenograft model. In conclusion, PDGFRβ and MET may play a critical role in the interaction between PCCs and PSCs. Moreover, MK2461 may have therapeutic potential in the treatment of pancreatic cancer by targeting the interaction between PCCs and PSCs.
Citation Format: Koetsu Inoue, Hideo Ohtsuka, Fuyuhiko Motoi, Daisuke Douchi, Shuhei Kawasaki, Kei Kawaguchi, Kunihiro Masuda, Koji Fukase, Shinobu Ohnuma, Takeshi Naitoh, Yu Katayose, Shinichi Egawa, Michiaki Unno. MK2461 suppress progression of pancreatic cancer disrupting interaction between pancreatic cancer cells and stellate cells. [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 404. doi:10.1158/1538-7445.AM2015-404
Abstract 4084: Transient SNAIL1 expression is necessary for metastatic competence in breast cancer
Authors: Tran Hung D. , Kim Michael , Luitel Krishna , Zhang Kun , Longmore Gregory , Tran David D. 
Published: August 2015

Abstract
SNAIL1 has been suggested to regulate breast cancer metastasis based on analyses of human breast tumor transcriptomes and experiments using cancer cell lines and xenografts. However, in vivo genetic experimental support for a role for SNAIL1 in breast cancer metastasis that develops in an immunocompetent tumor microenvironment has not been determined. To address this question, we created a genetic SNAIL1 model by coupling an endogenous SNAIL1 reporter with an inducible SNAIL1 transgene. Using multiple genetic models of breast cancer, we demonstrated that endogenous SNAIL1 expression was restricted to primary tumors that ultimately disseminate. SNAIL1 gene deletion either during the premalignant phase or after primary tumors have reached a palpable size blunted metastasis, indicating that late metastasis was the main driver of metastasis and that this was dependent on SNAIL1. Importantly, SNAIL1 expression during breast cancer metastasis was transient and forced transient, but not continuous, SNAIL1 expression in breast tumors was sufficient to increase metastasis.
Citation Format: Hung D. Tran, Michael Kim, Krishna Luitel, Kun Zhang, Gregory Longmore, David D. Tran. Transient SNAIL1 expression is necessary for metastatic competence in breast cancer. [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 4084. doi:10.1158/1538-7445.AM2015-4084
Abstract 4085: Depletion of Runx1 promotes epithelial to mesenchymal transition in breast cancer
Authors: Hong Deli , Lian Jane , Stein Janet , Stein Gary 
Published: August 2015

Abstract
Runx1 is an essential transcription factor for definitive hematopoiesis and Runx1 translocations are well established as the causative factor of various leukemias. Recent studies have identified Runx1 as one of the most frequently mutated genes in breast cancer patients, and also that Runx1 expression levels are decreased in high-grade primary breast tumors compared to low/mid-grade tumors. The recognition of Runx1 expression in epithelial lining cells of glands suggests that Runx1 functions in maintaining the integrity of that cell layer. Therefore we examined the role of Runx1 during cancer progression. We found that Runx1 is highly expressed in immortalized human mammary epithelial cells (MCF10A) compared with breast cancer epithelial cells (MCF7) and invasive breast cancer cells (MDA-MB-231). To test the hypothesis that Runx1 contributes to the epithelial to mesenchymal transition (EMT) in breast cancer, the EMT was induced in MCF10A cells which resulted in a 50% decrease of Runx1 mRNA, but complete loss of Runx1 protein. This finding suggests a role for Runx1 as an EMT suppressor. To further address the relationship between Runx1 and EMT, Runx1 depleted stable cell lines were generated in both MCF10A and MCF7 cells. We observed that Runx1 knockdown (90%) in MCF10A cells leads to a dramatic change in their morphology towards a mesenchymal state, with a concomitant decrease in expression of the epithelial marker E-cadherin. In addition Runx1 depletion in MCF7 cells directly induced EMT state by repression of E-cadherin, as well as increased expression of mesenchymal genes, including vimentin, N-cadherin and fibronectin. Our results highlight a crucial role for Runx1 in preventing epithelial to mesenchymal transition and tumor progression in breast cancer. This Runx1 mediated mechanism points to novel intervention strategies for early stage breast cancer.
Citation Format: Deli Hong, Jane Lian, Janet Stein, Gary Stein. Depletion of Runx1 promotes epithelial to mesenchymal transition in breast cancer. [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 4085. doi:10.1158/1538-7445.AM2015-4085
Abstract 4128: Extensive morphological heterogeneity of circulating and selected high metastatic variants and differential chemosensitivity of human prostate cancer in mouse models
Authors: Zhang Lei , Wu Chengyu , Hoffman Robert. M 
Published: August 2015

Abstract
Circulating PC-3-GFP human prostate cancer cells were collected from the blood from nude mice orthotopically implanted with PC-3-GFP. In parallel experiments, a highly metastatic PC-3-GFP cell line was developed by injecting parental PC-3-GFP to the footpad of nude mice which metastasized to inguinal lymph nodes from which the cancer cells were collected and were re-injected to the footpad. After 6 cycles, the PC-3-GFP cells collected from inguinal lymph nodes (PC-3-GFP-LN) and were injected to the footpad. PC-3-GFP-LN showed 100% metastasis to major lymph nodes (popliteal, inguinal, axillary, and cervical), and 100% metastasis to bone and lung. PC-3-GFP-CTC and PC-3-GFP-LN were cultured in vitro, and their morphology and chemo-sensitivity were comparing to the parental PC-3-GFP cells. Highly pleomorphic subpopulations of prostate cancer cells were identified in PC-3-GFP-CTC and PC-3-GFP-LN. The different cell subtypes included characteristic high malignancy features such as high nucleus to cytoplasmic (N/C) ratios and giant cell formation as a result of abnormal mitoses. Variations in growth rate, plating efficiency, size, shape, and number of the nuclei and nucleoli were observed. The results suggest extensive tumor heterogeneity in both sublines. The giant cells, contain multiple nuclei, cannot survive by themselves and need small cells around them in order to proliferate. However, giant cells also can produce smaller cells, which divide further. The ratio of giant cells/total cells were significantly higher in PC-3-GFP-LN compared to parental cells. However, the morphology of cells from lung metastasis and bone metastasis showed lung and bone epithelial features such as squamous on shape and tightly packed together. PC-3-GFP-CTC had similar sensitivity to both cisplatinum and docetaxel when compared to PC-3-parental cells. PC-3-GFP-LN was resistant. In contrast, PC-3-GFP-LN was sensitive to the traditional Chinese medicine (TCM) herbal mixture LQ similar to the parental cells. These results demonstrate that circulating tumor cells (CTCs) and selected high metastatic variants can be extensively heterogeneous and have different chemosensitivity profiles, suggesting new approaches to treatment such as with TCM.
Citation Format: Lei Zhang, Chengyu Wu, Robert. M Hoffman. Extensive morphological heterogeneity of circulating and selected high metastatic variants and differential chemosensitivity of human prostate cancer in 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 4128. doi:10.1158/1538-7445.AM2015-4128
Abstract 4131: MEK inhibitor diminishes nasopharyngeal carcinoma (NPC) cell growth and NPC-induced osteoclastogenesis via modulating CCL2 and CXCL16 expression
Authors: Zhu Yu , Song Qiong , Lu Yi 
Published: August 2015

Abstract
Nasopharyngeal carcinoma (NPC) is a common malignant cancer in Guangxi, as well as in southern China and Southeast Asia. NPC preferentially metastasizes to bone in advanced patients, major factor resulting in high mortality. The molecular basis of NPC development and cancer-induced bone lesions are still unclear. We and others have reported that chemokine, like CCL2, CXCL16, CXCL12, and their corresponding receptors played important roles in cancer bone metastasis. In this study, we firstly investigated that CCR2 and CXCR6 expressions in clinical specimens. Then, we measured CCL2, CCR2, CXCL16 and CXCR6 expression levels by RT-PCR, ELISA and western blot in NPC cell lines. Further, we used MEK inhibitor, U0126, to treat the NPC cell lines and found CCL2 and CXCL16 expressions significantly decreased. The NPC cell lines proliferation were inhibited by U0126 in dose- and time-dependently manner. Finally, we collected conditioned medium (CM) from the NPC cell lines absent or present U0126 treatments, to treat mouse bone marrow non-adherent cells in order to detect NPC CM-induced multinucleated osteoclast-like formation. The CMs collected from U0126 treated NPC cells were dramatically diminished the numbers of multinucleated osteoclasts. These results indicate that U0126 inhibits NPC cell growth and diminishes cancer-induced osteoclast formation partially through modulating the expression of CCL2 and CXCL16. Thus this study may provide a novel therapeutic strategy for advanced NPC patients, especially for treatment of NPC bone metastasis.
Citation Format: Yu Zhu, Qiong Song, Yi Lu. MEK inhibitor diminishes nasopharyngeal carcinoma (NPC) cell growth and NPC-induced osteoclastogenesis via modulating CCL2 and CXCL16 expression. [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 4131. doi:10.1158/1538-7445.AM2015-4131
Abstract 4133: ODM-203, a novel, selective and balanced FGFR and VEGFR inhibitor with strong activity on primary and metastatic tumor growth in FGFR-dependent and angiogenic cancer models
Authors: Holmström Tim , Moilanen Anu , Björkman Mari , Linnanen Tero , Wohlfahrt Gerd , Karlsson Stefan , Oksala Riikka , Korjamo Timo , Samajdar Susanta , Rajagopalan Srinivasan , Chelur Shekar , Narayan Kishore , Ramachandra Raghuveer , Anthony Thomas , DS Samiulla , Ramachandra Murali , Kallio Pekka 
Published: August 2015

Abstract
Genomic alterations in fibroblast growth factor receptors (FGFR) and upregulation of vascular endothelial growth factor receptors (VEGFR) are often found in the same cancer types such as gastric, lung and breast and these alterations correlate with patient survival and disease progression. In addition, both FGFR and VEGFR signaling promote tumor angiogenesis. Activation of FGFR signaling has also been described to function as a compensatory angiogenic signal following development of resistance to VEGF inhibition.
ODM-203 is a novel and selective inhibitor of the FGFR and VEGFR families exhibiting equal potency to both receptors both in vitro and in vivo. In recombinant kinase assays, ODM-203 inhibits both the FGFR and VEGFR family kinases in the low nanomolar range (IC50 6-35 nM). In cells, ODM-203 suppresses FGFR and VEGFR signaling with similar potency. It also inhibits VEGF-induced endothelial cell (HUVEC) proliferation (IC50 33 nM) with similar potency as it inhibits proliferation in FGFR-dependent cell lines (IC50 50-150 nM). In vivo, ODM-203 shows strong anti-tumor activity in FGFR-dependent xenograft models and in angiogenic xenograft models with similar well tolerated doses. In addition ODM-203 inhibits metastatic tumor growth in angiogenic xenograft models. Lack of activity in a FGFR and VEGFR independent tumor models further supports the selective mode of action of ODM-203. Oral administration of ODM-203 was well tolerated with only FGFR or VEGFR inhibition related physiological events observed in vivo in rat and dog.
Based on our findings, ODM-203 has a unique profile with equal potency for both FGFR and VEGFR kinase families which correlates with with strong activity on primary and metastatic tumor growth in FGFR-dependent and angiogenic tumor models. Therefore, a clinical trial with ODM-203 is ongoing in patients with solid tumors (NCT 02264418).
Citation Format: Tim Holmström, Anu Moilanen, Mari Björkman, Tero Linnanen, Gerd Wohlfahrt, Stefan Karlsson, Riikka Oksala, Timo Korjamo, Susanta Samajdar, Srinivasan Rajagopalan, Shekar Chelur, Kishore Narayan, Raghuveer Ramachandra, Thomas Anthony, Samiulla DS, Murali Ramachandra, Pekka Kallio. ODM-203, a novel, selective and balanced FGFR and VEGFR inhibitor with strong activity on primary and metastatic tumor growth in FGFR-dependent and angiogenic cancer 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 4133. doi:10.1158/1538-7445.AM2015-4133
Abstract 4146: Overexpression of C5a receptor becomes risk factor in gastric cancer
Authors: Kaida Takayoshi , Nitta Hidetoshi , Arima Kota , Takeyama Hideaki , Higashi Takaaki , Taki Katunobu , Hayashi Hiromitsu , Hashimoto Daisuke , Chikamoto Akira , Ishiko Takatoshi , Beppu Toru , Baba Hideo 
Published: August 2015

Abstract
Background: C5a is one of the important factors produced on complement pathway and a strong chemokine. There is emerging evidence that C5a is generated in the cancer microenvironment and C5a receptor (C5aR) is expressed in various cancer cells and associated with invasive ability in several cancer cells. However, the role of C5aR in gastric cancer (GC) is still mostly unknown.
Aim: To investigate the clinical significance of C5aR expression in human GC.
Method: 168 patients underwent gastrectomy after the diagnosis of gastric cancer from January 1st 2001 to December 31th 2009. C5aR-expression of GC cells was investigated in all 168 patients and was analyzed in regard to an association with clinicopathological factors and outcomes in the patients. Additionally, in vitro experiments were used to examine the proliferation and invasion of GC cells by using the GC cell lines that had high-expression of C5aR.
Result: High-expression of C5aR was found in 55 patients (32.7%). High-expression of C5aR was significantly related to depth of invasion, stage, lymphatic and vascular invasion. Among the 146 patients with a tumor stage lower than stageIV, the 5-years recurrence-free and overall survival rates of patients in the high-expression of C5aR group were significantly lower than those in the low-expression of C5aR group (91.0% vs 52.4%, p = 0.007 and 87.2% vs 59.1%, p = 0.003, respectively). The high-expression of C5aR group had more frequently distant metastasis than the low-expression of C5aR group during the follow-up time, presenting itself mainly in liver metastasis and peritoneal dissemination (p = 0.020 and p = 0.026). We found that the gastric cancer cell lines MKN1 and MKN7 had the high-expression of C5aR with western blotting in vitro. Moreover, matrigel chamber assay revealed that 10 nM of recombinant C5a enhances cell invasiveness of MKN1 by 2.55-fold and the cell invasiveness of MKN7 by 2.90-fold, but such an enhancement by C5a was not observed in control cells.
Conclusions: The gastric cancer patients with a high expression of C5aR were associated with poor prognosis, and the invasive ability of gastric cancer cell lines highly expressing of C5aR were promoted by C5a. Thus, targeting this C5a-C5aR axis might provide a useful therapeutic option for gastric cancer treatment.
Citation Format: Takayoshi Kaida, Hidetoshi Nitta, Kota Arima, Hideaki Takeyama, Takaaki Higashi, Katunobu Taki, Hiromitsu Hayashi, Daisuke Hashimoto, Akira Chikamoto, Takatoshi Ishiko, Toru Beppu, Hideo Baba. Overexpression of C5a receptor becomes risk factor in gastric cancer. [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 4146. doi:10.1158/1538-7445.AM2015-4146