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The growth of primary tumors as well as metastatic neoplastic lesions is strongly dependent on the cancer cells’ ability to initiate their own vascular network. This process, angiogenesis, which involves the proliferation, migration, and invasion of endothelial cells, is critically dependent on a variety of signaling molecules that target specific receptors, most notably tyrosine kinases. One receptor tyrosine kinase associated with poor prognosis, metastasis, and outcome in a variety of tumor types, is Axl. Although the role of Axl in tumor cell migration and invasion are well recognized, little is known about the involvement of Axl signaling in the initiation of angiogenesis. Here, we show that Axl inhibition in tumor cells decreases the secretion of pro-angiogenic factors and impairs functional properties of endothelial cells in vitro and in vivo. These data indicate that Axl signaling is an important contributor to tumor angiogenesis.

Transforming growth factor beta (TGF-β) promotes cancer growth in late stage cancers. To inhibit the TGF-β pathway, we investigated a tumor-targeting TGF-β receptor blocker, TTB, and its role in tumor progress. The targeted TTB comprised of the extracellular domain of the TGF-β receptor II, the endoglin domain of TGF-β receptor III, and the human immuno-globin IgG1 constant fragment (Fc). To enhance tumor microenvironment targeting, a RGD peptide was fused at the N-terminal of TTB. The targeted TTB exhibited potent TGF-β neutralization activities, and inhibited cancer cell migration and invasion as well as colony formation. In xenograft models, the TTB had potent tumor inhibition activities. The TTB also attenuated the TGF-β1-induced Smad2 phosphorylation and epithelial to mesenchymal transformation (EMT), and suppressed breast cancer metastasis. Thus, the TTB is an effective TGF-β blocker with a potential for blocking excessive TGF-β induced pathogenesis in vivo.

Cancer is one of the leading causes of death worldwide, and metastasis is a crucial characteristic of malignancy. Recent studies have shown that lncRNAs play an important role in regulating cancer metastasis through various molecular mechanisms. We briefly summarize four known molecular functions of lncRNAs, including their role as a signal, decoy, guide and scaffold. No matter which pattern lncRNAs follow to carry out their functions, the proteins that lncRNAs bind to are important for them to exhibit their gene-regulating properties. We further illustrate that lncRNAs regulate the localization, stabilization or modification of their binding proteins to realize the binding role of lncRNAs. In this review, we focus on the interactions between lncRNAs and their binding proteins; moreover, we focus on the mechanisms of the collaborative work of lncRNAs and their binding proteins in cancer metastasis, thus evaluating the potential of lncRNAs as prospective novel therapeutic targets in cancer.

// Jin-Peng Wang 1, 2, 3 , Yan-Yan Tang 1, 2 , Chun-Mei Fan 2 , Can Guo 2 , Yan-Hong Zhou 2 , Zheng Li 2 , Xiao-Ling Li 2 , Yong Li 2, 4 , Gui-Yuan Li 1, 2, 3 , Wei Xiong 1, 2, 3 , Zhao-Yang Zeng 1, 2, 3 and Fang Xiong 1 1 The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, China 2 The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China 3 Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China 4 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA Correspondence to: Fang Xiong, email: xiongf@csu.edu.cn Zhao-Yang Zeng, email: zengzhaoyang@csu.edu.cn Keywords: exosome; non-coding RNA; tumor microenvironment; tumor metastasis Received: July 10, 2017 Accepted: October 28, 2017 Published: December 21, 2017 ABSTRACT An increasing number of studies has confirmed that many cells can secrete vesicles or exosomes in eukaryotes, which contain important nucleic acids, proteins and lipids and play important roles in cell communication and tumor metastasis. This paper summarizes the comprehensive function of exosomal non-coding RNAs. Although some studies have shown that exosomes mediate tumor signal transduction, the functional mechanism of the tumor metastasis remains to be elucidated. In this paper, we reviewed the role of exosomal non-coding RNAs in mediating cancer metastasis in the tumor microenvironment to provide new ideas for the study of tumor pathophysiology.

Increasing evidence suggests that the abnormality of microRNAs (miRNAs) and their downstream targets is frequently implicated in the pathogenesis of human cancers, however, the clinical benefit of causal miRNA-target interactions has been seldom studied. Here, we proposed a computational method to optimize prognosis-related key miRNA-target interactions by combining transcriptome and clinical data from thousands of TCGA tumors across 16 cancer types. We obtained a total of 1,956 prognosis-related key miRNA-target interactions between 112 miRNAs and 1,443 their targets. Interestingly, these key target genes are specifically involved in tumor progression-related functions, such as 'cell adhesion' and 'cell migration'. Furthermore, they are most significantly correlated with 'tissue invasion and metastasis', a hallmark of metastasis, in ten distinct types of cancer through the hallmark analysis. These results implicated that the prognosis-related key miRNA-target interactions were highly associated with cancer metastasis. Finally, we observed that the combination of these key miRNA-target interactions allowed to distinguish patients with good prognosis from those with poor prognosis both in most TCGA cancer types and independent validation sets, highlighting their roles in cancer metastasis. We provided a user-friendly database named miRNATarget (freely available at http://biocc.hrbmu.edu.cn/miRNATar/), which provides an overview of the prognosis-related key miRNA-target interactions across 16 cancer types.

Discovery of anti-metastatic drugs is of immense clinical significance as metastasis is responsible for 90% of all cancer deaths. Here we report the inhibitory effect of a bis schiff base (M2) on cancer cell migration and invasion in vitro and in vivo. M2 has shown good solubility and permeability across the intestinal cell wall and hence can be classified as BCS (Biopharmaceutical classification system) class I. Microarray studies identified a long non coding intergenic RNA, LINC00273 as a novel molecular target of M2. We report that LINC00273 harbors a unique (4n-1) parallel G-Quadruplex structure in its promoter as validated by DMS footprint. M2 is proposed to stabilize this G-quadruplex structure resulting in the down-regulation of LINC00273 expression. Dual Luciferase reporter assay also suggests inhibition of LINC00273 promoter activity by M2. Involvement of this linc in metastasis is proven by siRNA and shRNA mediated knock down of LINC00273 in vitro and in vivo in nude mice which significantly decelerates cancer cell migration and invasion and also makes the cells unresponsive to TGF-β's pro-metastatic effects. Furthermore, the real time expression of LINC00273 in thirty seven human clinical samples is found to be positively correlated with the histopathological staging of metastasis.

// Ning Zheng 1, 2 , Jiahang Chen 1, 2 , Weiqun Liu 1, 2 , Jian Liu 1, 2 , Tao Li 1, 2 , Hongning Chen 1, 2 , Jichuang Wang 3 and Lee Jia 1, 2 1 Cancer Metastasis Alert and Prevention Center, and Biopharmaceutical Photocatalysis, State Key Laboratory of Photocatalysis on Energy and Environment, Fuzhou University, Fuzhou 350002, China 2 Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou 350002, China 3 Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, Fujian Medical University, Fuzhou 350108, China Correspondence to: Lee Jia, email: pharmlink@gmail.com , cmapcjia1234@163.com Keywords: mifepristone (RU486), the SDF-1/CXCR4 chemokine axis, ovarian cancer, cancer metastasis, actin polymerization Received: October 27, 2016 Accepted: June 29, 2017 Published: July 17, 2017 ABSTRACT SDF-1/CXCR4 signaling axis determines the proliferative potential and site-specific cancer metastasis. Recent studies suggest involvement of the axis and steroidal hormone in ovarian cancer metastasis. Here we hypothesize that mifepristone (RU486), a well-known progesterone-based abortifacient, might interfere this axis and inhibit ovarian cancer metastasis. Mifepristone at concentrations < IC50 inhibited expression of CXCR4 on cell surface of ovarian cancer SKOV-3 and IGROV-1, and reduced expression of the intracellular CXCR4 protein and its related mRNA activated by SDF-1. SDF-1 significantly stimulated proliferation of SKOV-3 and IGROV-1 cells with concomitant increases in intracellular phosphorylation of Akt and ERK. SDF-1 activated cell chemotatic migration and actin polymerization, and up-regulated expression of MMP-2, MMP-9, COX-2, VEGF without influencing the adhesion molecules ICAM-1 and integrins β1, α1, α3, α5, and α6. The above-mentioned effects of SDF-1 could be antagonized by mifepristone concentration-dependently, and CXCR4 antagonist AMD3100. Mifepristone suppressed the SDF-1-induced migration, invasion and adhesion of the cancer cells to extracellular matrixes. Three-day pretreatment of nude mice with mifepristone (5 and 20 mg/kg/day) followed by a single intraperitoneal IGROV-1 inoculation, along with repeated SDF-1 and mifepristone administrations in turn every other day for 36 days significantly reduced ascitic fluid, metastatic foci, tumor weight and immunoreactivity of CXCR4 in comparison with the SDF-1-treated control. Our results suggest that mifepristone inhibit SDF-1/CXCR4 signaling axis, may have preventive and therapeutic effects on ovarian cancer metastasis.

The metastases of malignant tumors develop through a cascade of events. The establishment of a pre-metastatic micro-environment is initiated by communication between tumors and host. Exosomes come into focus as the most potent intercellular communicators playing a pivotal role in this process. Cancer cells release exosomes into the extracellular environment prior to metastasis. Tetraspanin is a type of 4 times transmembrane proteins. It may be involved in cell motility, adhesion, morphogenesis, as well as cell and vesicular membrane fusion. The exosomal tetraspanin network is a molecular scaffold connecting various proteins for signaling transduction. The complex of tetraspanin-integrin determines the recruiting cancer exosomes to pre-metastatic sites. Tetraspanin is a key element for the target cell selection of exosomes uptake that may lead to the reprogramming of target cells. Reprogrammed target cells assist pre-metastatic niche formation. Previous reviews have described the biogenesis, secretion and intercellular interaction of exosomes in various tumors. However, there is a lack of reviews on the topic of exosomal tetraspanin in the context of cancer. In this review, we will describe the main characteristics of exosomal tetraspanin in cancer cells. We will also discuss how the cancer exosomal tetraspanin alters extracellular environment and regulates cancer metastasis.

// Susheng Miao 1, * , Xionghui Mao 1, * , Shu Zhao 3 , Kaibin Song 1 , Cheng Xiang 1 , Yuanjing Lv 1 , Huanyv Jiang 1 , Lei Wang 1 , Baojun Li 1 , Xianguang Yang 1 , Zhennan Yuan 1 , Cheng Xiu 1 , Hongxue Meng 2 and Ji Sun 1 1 Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, China 2 Department of Pathology, Harbin Medical University Cancer Hospital, Harbin 150081, China 3 Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, China * These authors have contributed equally to the work Correspondence to: Hongxue Meng, email: menghongxue15@163.com Ji Sun, email: drsunji@126.com Keywords : laryngeal cancer, metastasis, mir-217, AEG-1, PD-L1 Received: September 26, 2016 Accepted: April 14, 2017 Published: July 10, 2017 ABSTRACT High incidences of laryngeal cancer have been reported recently. Increasing our understanding of the molecular mechanisms underlying this malignancy could reveal more effective approaches to treating laryngeal cancer patients and so improve their prognoses. In this study, we explored the biological effects of miR-217 on laryngeal cancer. miR-217 potently inhibited multiple metastatic traits, including cell migration, invasion, proliferation, apoptosis, and EMT, as well as angiogensis. These effects were achieved through downregulation of the miR-217 target gene, AEG-1 and PD-L1. Clinical expression and animal model studies further confirmed our results. These findings provide new insight into the physiological effects of miR-217 in laryngeal cancer and its potential therapeutic use.

// Pil-Gu Park 1, * , Su Ji Jo 1, 2, * , Min Jung Kim 1, 3 , Hyun Jeong Kim 4 , Ji Hae Lee 5 , Cheol Keun Park 6 , Hyunki Kim 6 , Kang Young Lee 7 , Hoguen Kim 2, 6 , Jeon Han Park 1 , Seung Myung Dong 5, 8 and Jae Myun Lee 1, 2 1 Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Republic of Korea 2 BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea 3 Department of Pediatrics, Severance Hospital, Institute of Allergy, Yonsei University College of Medicine, Seoul, Republic of Korea 4 Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea 5 Research Institute, National Cancer Center, Goyang, Republic of Korea 6 Department of Pathology, Yonsei University, College of Medicine, Seoul, South Korea 7 Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea 8 IMK Bio-Convergence R&D Center, International Vaccine Institute SNU Research Park, Seoul, Republic of Korea * These authors contributed equally to this work Correspondence to: Jae Myun Lee, email: jaemyun@yuhs.ac Seung Myung Dong, email: smdongstar@gmail.com Keywords: colorectal cancer, metastasis, LOXL2, epithelial-mesenchymal transition, tissue microarray analysis Received: March 24, 2017 Accepted: May 11, 2017 Published: May 25, 2017 ABSTRACT Colorectal cancer (CRC) is one of the most dangerous types of malignant tumors, and cancer metastasis is a major factor in the failure of CRC therapy. Recently, LOXL2 (lysyl oxidase-like 2) has been shown to represent a regulator of epithelial-mesenchymal transition (EMT) in different cancer types. However, LOXL2 has not been reported to be involved in CRC metastasis. In this study, we demonstrated that LOXL2 expression is strongly correlated with the rate of CRC metastasis, it participates in the regulation of EMT-related molecule expression in CRC cells in vitro , and it is involved in migratory potential alterations. Additionally, tissue microarray analysis of CRC patients showed an increase in the probability of developing CRC distant metastasis and a decrease in the survival rate of patients with high LOXL2 expression. The results obtained in this study indicate that LOXL2 is involved in the development and progression of CRC metastasis, and therefore, its expression levels may represent a useful prognostic marker.

// He Li 1,2 , Si-Qing Ma 1,2 , Jin Huang 1,2 , Xiao-Ping Chen 1,2,3 and Hong-Hao Zhou 1,2,3 1 Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P.R. China 2 Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P.R. China 3 Hunan Province Cooperation Innovation Center for Molecular Target New Drug Study, Hengyang, P. R. China Correspondence to: Xiao-Ping Chen, email: // Hong-Hao Zhou, email: // Keywords : colorectal cancer, metastasis, lncRNAs, review Received : November 17, 2016 Accepted : February 20, 2017 Published : March 17, 2017 Abstract Colorectal cancer (CRC) is the 3 rd most common malignancies worldwide. Metastasis is responsible for more than 90% CRC patients’ death. Long noncoding RNAs (lncRNAs) are an important class of transcribed RNA molecules greater than 200 nucleotides in length. With the development of whole genome sequencing technologies, they have been gained more attention. Accumulating evidences suggest that abnormal expression of lncRNAs in diverse diseases are involved in various biological functions such as proliferation, apoptosis, metastasis and differentiation by acting as epigenetic, splicing, transcriptional or post-transcriptional regulators. Aberrant expression of lncRNAs has also been found in CRC. Besides, recent studies have indicated that lncRNAs play important roles in tumourigenesis and cancer metastasis. They participate in the process of metastasis by activing or inhibiting the metastatic pathways. However, their functions on the development of cancer metastasis are poorly understood. In this review, we highlight the findings of roles for lncRNAs in CRC metastasis and review the metastatic pathways of lncRNAs leading to cancer metastasis in CRC, including escape of apoptosis, epithelial-mesenchymal transition (EMT), angiogenesis and invasion, migration and proliferation. Furthermore, we also discuss the potential clinical application of lncRNAs in CRC as diagnostic markers and therapeutic targets.

// Yin Peng 1,4,* , Xiaojing Zhang 1,3,* , Xianling Feng 1 , Xinmim Fan 1 and Zhe Jin 1,2,3 1 Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People’s Republic of China 2 Shenzhen Key Laboratory of Micromolecule Innovatal Drugs, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People’s Republic of China 3 Shenzhen Key Laboratory of Translational Medicine in Tumors, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People’s Republic of China 4 Department of Pathology, Wuhan University School of Basic Medical Sciences, Hubei, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Zhe Jin, email: // Keywords : microRNA; Wnt/β-catenin signaling pathway; cancer Received : January 15, 2016 Accepted : October 21, 2016 Published : October 26, 2016 Abstract Mounting evidence has indicated microRNA (miR) dysregulation and the Wnt/β-catenin signaling pathway jointly drive carcinogenesis, cancer metastasis, and drug-resistance. The current review will focus on the role of the crosstalk between miRs and the Wnt/β-catenin signaling pathway in cancer development. MiRs were found to activate or inhibit the canonical Wnt pathway at various steps. On the other hand, Wnt activation increases expression of miR by directly binding to its promoter and activating transcription. Moreover, there are mutual feedback loops between some miRs and the Wnt/β-catenin signaling pathway. Clinical trials of miR-based therapeutic agents are investigated for solid and hematological tumors, however, challenges concerning low bioavailability and possible side effects must be overcome before the final clinical application. This review will describe current understanding of miR crosstalk with the Wnt/β-catenin signaling cascade. Better understanding of the regulatory network will provide insight into miR-based therapeutic development.

// Gabriela Schneider 1 , Ewa Bryndza 1 , Agata Poniewierska-Baran 1, 5 , Karol Serwin 4, 5 , Malwina Suszynska 1 , Zachariah P. Sellers 1 , Michael L. Merchant 3 , Alagammai Kaliappan 2 , Janina Ratajczak 1 , Magda Kucia 1, 4 , Nichola C. Garbett 2 , Mariusz Z. Ratajczak 1, 4, 5 1 Stem Cell Institute at the James Graham Brown Cancer Center, University of Louisville, KY, USA 2 James Graham Brown Cancer Center, Department of Medicine, University of Louisville, KY, USA 3 Kidney Disease Program, Department of Medicine, University of Louisville, KY, USA 4 Department of Regenerative Medicine, Medical University of Warsaw, Poland 5 Department of Physiology, Pomeranian Medical University, Szczecin, Poland Correspondence to: Mariusz Z. Ratajczak, email: mzrata01@louisville.edu Keywords: vitronectin, urokinase plasminogen activator receptor (uPAR), fibrinogen, cancer metastasis, chemotaxis Received: July 18, 2016 Accepted: September 09, 2016 Published: September 13, 2016 ABSTRACT Diluted (1%) plasma induces migration of malignant cell lines much more strongly than potent pro-metastatic factors. To characterize the factor(s) present in diluted plasma responsible for this phenomenon we performed i) heat inactivation, ii) dialysis, iii) proteinase K treatment, and iv) molecular size filtration studies. We found that this remarkable pro-migratory activity of diluted normal plasma is associated with a ~50–100-kD protein that interacts with G αI protein-coupled receptors and activates p42/44 MAPK and AKT signaling in target cells. Since this pro-migratory activity of 1% plasma decreases at higher plasma concentrations (> 20%), but is retained in serum, we hypothesized that fibrinogen may be involved as a chaperone of the protein(s). To identify the pro-migratory protein(s) present in diluted plasma and fibrinogen-depleted serum, we performed gel filtration and hydrophobic interaction chromatography followed by mass spectrometry analysis. We identified several putative protein candidates that were further tested in in vitro experiments. We found that this pro-migratory factor chaperoned by fibrinogen is vitronectin, which activates uPAR, and that this effect can be inhibited by fibrinogen. These results provide a novel mechanism for the metastasis of cancer cells to lymphatics and body cavities, in which the concentration of fibrinogen is low, and thus suggests that free vitronectin stimulates migration of tumor cells.

// Kaikai Shen 1, * , Zhichao Xi 1, * , Jianling Xie 4 , Hua Wang 5 , Chanlu Xie 6 , C.Soon Lee 6, 7 , Paul Fahey 6 , Qihan Dong 6, 7, 8 , Hongxi Xu 1, 2, 3 1 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China 2 Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, Guanghua Integrative Medicine Hospital/ Shanghai University of T.C.M, Shanghai, China 3 Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China 4 Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, Australia 5 Stanley Ho Center for Emerging Infectious Diseases, The Chinese University of Hong Kong, Hong Kong, China 6 School of Science and Health, The University of Western Sydney, Sydney, Australia 7 Central Clinical School and Bosch Institute, The University of Sydney, Sydney, Australia 8 Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia * These authors contributed equally to this work Correspondence to: Hongxi Xu, email: xuhongxi88@gmail.com Qihan Dong, email: q.dong@uws.edu.au Keywords: hepatocellular carcinoma, cancer metastasis, Guttiferone K, profilin1, actin Received: November 20, 2015 Accepted: July 18, 2016 Published: August 01, 2016 ABSTRACT Hepatocellular carcinoma (HCC) is an aggressive malignancy and the 5-year survival rate of advanced HCC is < 10%. Guttiferone K (GUTK) isolated from the Garcinia genus inhibited HCC cells migration and invasion in vitro and metastasis in vivo without apparent toxicity. Proteomic analysis revealed that actin-binding protein profilin 1 (PFN1) was markedly increased in the presence of GUTK. Over-expression of PFN1 mimicked the effect of GUTK on HCC cell motility and metastasis. The effect of GUTK on cell motility was diminished when PFN1 was over-expressed or silenced. Over-expression of PFN1 or incubation with GUTK decreased F-actin levels and the expression of proteins involved in actin nucleation, branching and polymerization. Moreover, a reduction of PFN1 protein levels was common in advanced human HCC and associated with poor survival rate. In conclusion, GUTK effectively suppresses the motility and metastasis of HCC cells mainly by restoration of aberrantly reduced PFN1 protein expression.

// Joo Hoon Kim 1, * , Jae Seok Lee 2, * , Eo Jin Kim 2 , Kyu Hyun Park 3 , Ki Hyang Kim 4 , Seong Yoon Yi 5 , Han Seong Kim 6 , Yong Jin Cho 7 , Kyoo-Ho Shin 7 , Joong Bae Ahn 1 , Hyuk Hu 8 , Kyung Sik Kim 8 , Young Deuk Choi 9 , Sunghoon Kim 10 , Young Han Lee 11 , Jin-Suck Suh 11 , Sung Hoon Noh 8 , Sun Young Rha 1 , Hyo Song Kim 1 1 Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea 2 Department of Pathology, Dongguk University College of Medicine, Dongguk University Ilsan Hospital, Goyang, Korea 3 Cancer Metastasis Research Center, Song Dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea 4 Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea 5 Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Ilsan, Korea 6 Department of Pathology, Ilsan Paik Hospital, Inje University College of Medicine, Ilsan, Korea 7 Department of Orthopedic Surgery, Yonsei University College of Medicine, Seoul, Korea 8 Department of Surgery, Yonsei University College of Medicine, Seoul, Korea 9 Department of Urology, Yonsei University College of Medicine, Seoul, Korea 10 Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul, Korea 11 Department of Radiology, Yonsei University College of Medicine, Seoul, Korea * These authors have contributed equally to this work Correspondence to: Sun Young Rha, e-mail: rha7655@yuhs.ac Hyo Song Kim, e-mail: hyosong77@yuhs.ac Keywords: liposarcoma, PIK3CA, amplification, mutation Received: January 05, 2016 Accepted: March 02, 2016 Published: March 21, 2016 ABSTRACT Background: We investigated the epidemiologic characteristics and prognostic significance of PIK3CA mutations/amplifications in curative resected liposarcoma. Patients and methods: A total of 125 liposarcoma tissue samples were collected over a 12-year period. PIK3CA mutations and gene copy number amplifications were analyzed by pyrosequencing and fluorescence in situ hybridization (FISH). Results: Nine of the 105 liposarcomas (8.6%) had activating PIK3CA mutation. PIK3CA mutations were more frequent in myxoid/round cell and pleomorphic tumors compared with well-differentiated/dedifferentiated tumors (13.3% vs. 2.2%, P=0.043). In FISH PIK3CA analysis, copy number gain was detected in 14 of the 101 tumors (13.9%): 11 (10.9%) tumors had increased gene copy number (polysomy) and 3 (3.0%) exhibited gene amplification. In survival analysis, patients with PIK3CA copy number gain had a worse prognosis compared to patients without PIK3CA amplification (median disease-free survival [DFS] 22.2 vs. 107.6 months p=0.005). By multivariate analysis, PIK3CA copy number gain was an independent prognostic factor for worse DFS (P=0.027; hazard ratio, 2.400; 95% confidence interval 1.105 to 5.213). PIK3CA mutation was not associated with DFS and overall survival. Conclusions: We demonstrated PIK3CA mutation and amplification in liposarcoma. PIK3CA copy number gain was an independent poor prognostic factor for DFS. Further studies are needed to evaluate the potential diagnostic and therapeutic role of PIK3CA mutations and amplifications in liposarcoma.

// Mohit Kumar Jolly 1,2 , Satyendra C. Tripathi 8,* , Dongya Jia 1,5,* , Steven M. Mooney 7 , Muge Celiktas 8 , Samir M. Hanash 8,10 , Sendurai A. Mani 9,11 , Kenneth J. Pienta 12 , Eshel Ben-Jacob 1,5,6,** and Herbert Levine 1,2,3,4 1 Center for Theoretical Biological Physics, Rice University, Houston, TX, USA 2 Department of Bioengineering, Rice University, Houston, TX, USA 3 Department of Physics and Astronomy, Rice University, Houston, TX, USA 4 Department of Biosciences, Rice University, Houston, TX, USA 5 Graduate Program in Systems, Synthetic and Physical Biology, Rice University, Houston, TX, USA 6 School of Physics and Astronomy and The Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel 7 Department of Biology, University of Waterloo, Waterloo, ON, Canada 8 Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA 9 Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA 10 Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer, University of Texas MD Anderson Cancer Center, Houston, TX, USA 11 Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA 12 The James Brady Urological Institute, and Departments of Urology, Oncology, Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA * These authors have contributed equally to this work ** Deceased on June 5, 2015 Correspondence to: Herbert Levine, email: // Keywords : partial EMT, epithelial-mesenchymal transition, cancer stem cells, multistability, cell-fate decisions Received : January 08, 2016 Accepted : March 07, 2016 Published : March 17, 2016 Abstract Epithelial-to-Mesenchymal Transition (EMT) and its reverse – Mesenchymal to Epithelial Transition (MET) – are hallmarks of cellular plasticity during embryonic development and cancer metastasis. During EMT, epithelial cells lose cell-cell adhesion and gain migratory and invasive traits either partially or completely, leading to a hybrid epithelial/mesenchymal (hybrid E/M) or a mesenchymal phenotype respectively. Mesenchymal cells move individually, but hybrid E/M cells migrate collectively as observed during gastrulation, wound healing, and the formation of tumor clusters detected as Circulating Tumor Cells (CTCs). Typically, the hybrid E/M phenotype has largely been tacitly assumed to be transient and ‘metastable’. Here, we identify certain ‘phenotypic stability factors’ (PSFs) such as GRHL2 that couple to the core EMT decision-making circuit (miR-200/ZEB) and stabilize hybrid E/M phenotype. Further, we show that H1975 lung cancer cells can display a stable hybrid E/M phenotype and migrate collectively, a behavior that is impaired by knockdown of GRHL2 and another previously identified PSF - OVOL. In addition, our computational model predicts that GRHL2 can also associate hybrid E/M phenotype with high tumor-initiating potential, a prediction strengthened by the observation that the higher levels of these PSFs may be predictive of poor patient outcome. Finally, based on these specific examples, we deduce certain network motifs that can stabilize the hybrid E/M phenotype. Our results suggest that partial EMT, i.e. a hybrid E/M phenotype, need not be ‘metastable’, and strengthen the emerging notion that partial EMT, but not necessarily a complete EMT, is associated with aggressive tumor progression.

// Kenneth C. Valkenburg 1 , Sarah R. Amend 1 , James E. Verdone 1 , Emma E. van der Toom 1 , James R. Hernandez 1 , Michael A. Gorin 1 , Kenneth J. Pienta 1, 2, 3, 4 1 The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA 2 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA 3 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA 4 Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA Correspondence to: Michael A. Gorin, email: mgorin1@jhmi.edu Kenneth C. Valkenburg, email: kvalken1@jhmi.edu Keywords: disseminated tumor cells, mouse models, bone marrow, bone metastasis, cancer Received: June 17, 2016 Accepted: September 01, 2016 Published: September 13, 2016 ABSTRACT Bone metastasis is a lethal and incurable disease. It is the result of the dissemination of cancer cells to the bone marrow. Due to the difficulty in sampling and detection, few techniques exist to efficiently and consistently detect and quantify disseminated tumor cells (DTCs) in the bone marrow of cancer patients. Because mouse models represent a crucial tool with which to study cancer metastasis, we developed a novel method for the simple selection-free detection and quantification of bone marrow DTCs in mice. We have used this protocol to detect human and murine DTCs in xenograft, syngeneic, and genetically engineered mouse models. We are able to detect and quantify bone marrow DTCs in mice that do not have overt bone metastasis. This protocol is amenable not only for detection and quantification purposes but also to study the expression of markers of numerous biological processes or tissue-specificity.

Accumulated evidence suggests that M2-like polarized tumor associated macrophages (TAMs) plays an important role in cancer progression and metastasis, establishing TAMs, especially M2-like TAMs as an appealing target for therapy intervention. Here we found that metformin significantly suppressed IL-13 induced M2-like polarization of macrophages, as illustrated by reduced expression of CD206, down-regulation of M2 marker mRNAs, and inhibition of M2-like macrophages promoted migration of cancer cells and endothelial cells. Metformin triggered AMPKα1 activation in macrophage and silencing of AMPKα1 partially abrogated the inhibitory effect of metformin in IL-13 induced M2-like polarization. Administration of AICAR, another activator of AMPK, also blocked the M2-like polarization of macrophages. Metformin greatly reduced the number of metastases of Lewis lung cancer without affecting tumor growth. In tumor tissues, the percentage of M2-like macrophage was decreased and the area of pericyte-coated vessels was increased. Further, the anti-metastatic effect of metformin was abolished when the animals were treated with macrophages eliminating agent clodronate liposome. These findings suggest that metformin is able to block the M2-like polarization of macrophages partially through AMPKα1, which plays an important role in metformin inhibited metastasis of Lewis lung cancer.

// Liyuan Wan 1,* , Haiyan Dong 1,* , Huo Xu 1 , Ji Ma 1 , Yewei Zhu 1 , Yusheng Lu 1 , Jichuang Wang 1 , Ting Zhang 1 , Tao Li 1 , Jingjing Xie 1 , Bo Xu 2 , Fangwei Xie 3 , Yu Gao 1 , Jingwei Shao 1 , Xiaohuang Tu 4 and Lee Jia 1 1 Cancer Metastasis Alert and Prevention Center, and Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, China 2 Obstetrics and Gynecology, Fuzhou General Hospital, Fuzhou, China 3 Department of Medicine Oncology, East Hospital of Xiamen University, Fuzhou, China 4 Department of Surgery, East Hospital of Xiamen University, Fuzhou, China * These authors have contributed equally to this work Correspondence to: Lee Jia, email: // Keywords : cancer metastasis, cell adhesion molecules, drug combination, metastasis chemoprevention, HAMPT Received : August 07, 2015 Accepted : September 14, 2015 Published : October 08, 2015 Abstract Recent scientific advances have increased our understanding of the cancer metastatic complexities and provided further impetus for new combination therapies to prevent cancer metastasis. Here, we demonstrated that a combination (HAMPT) of aspirin, lysine, mifepristone and doxycycline can effectively and safely prevent cancer metastasis. The pharmaceutically-formulated HAMPT inhibited adhesion of cancer cells to either endothelial cells or extracellular matrix via down-regulating cell adhesion molecules ICAM-1 and α 4 -integrin. HAMPT inhibited the cloak effect by activated platelets on cancer cells, thereby interfering adhesion and invasion of cancer cells to the underlying stroma. At the effective concentration, HAMPT induced cancer cells into dormancy with minor inhibition on cell viability. Four-day pretreatment followed by 30-day oral administration of HAMPT (33.5-134 mg/kg) to the mice inoculated with cancer cells produced significant inhibition on cancer metastasis dose-dependently without marked side effects. Fifty-day rat toxicity study with HAMPT at doses (335-1340 mg/kg) 20-fold higher than its therapeutic dose produced no significant toxicity. Interestingly, the acute toxic death could not be reached at the maximum administrable dose (5 g/kg). This proof-of-concept study provides the first conceptual evidence that cancer metastasis can be controlled by using affordable old drugs to restrain circulating tumor cells from gemmating on the metastatic soil without the need for cytotoxicity.

// Md. Asaduzzaman Khan 1 , Mousumi Tania 1 , Chunli Wei 1 , Zhiqiang Mei 1 , Shelly Fu 1, 2 , Jingliang Cheng 1 , Jianming Xu 1, 3, 4 , Junjiang Fu 1 1 Key Laboratory of Epigenetics and Oncology, the Research Center for Preclinical Medicine, Sichuan Medical University, Luzhou, Sichuan, China 2 Michael E. DeBakey High School for Health Professions, Houston, TX, USA 3 College of Basic Medical Sciences and Institute for Cancer Medicine, Sichuan Medical University, Luzhou, Sichuan, China 4 Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA Correspondence to: Junjiang Fu, e-mail: fujunjiang@hotmail.com , e-mail: fujunjiang@lzmc.edu.cn Keywords: thymoquinone, cancer metastasis, TWIST1, epithelial to mesenchymal transition, DNA methylation Received: February 10, 2015 Accepted: May 06, 2015 Published: May 19, 2015 ABSTRACT Proteins that promote epithelial to mesenchymal transition (EMT) are associated with cancer metastasis. Inhibition of EMT regulators may be a promising approach in cancer therapy. In this study, Thymoquinone (TQ) was used to treat cancer cell lines to investigate its effects on EMT-regulatory proteins and cancer metastasis. We show that TQ inhibited cancer cell growth, migration and invasion in a dose-dependent manner. At the molecular level, TQ treatment decreased the transcriptional activity of the TWIST1 promoter and the mRNA expression of TWIST1, an EMT-promoting transcription factor. Accordingly, TQ treatment also decreased the expression of TWIST1-upregulated genes such as N-Cadherin and increased the expression of TWIST1-repressed genes such as E-Cadherin, resulting in a reduction of cell migration and invasion. TQ treatment also inhibited the growth and metastasis of cancer cell-derived xenograft tumors in mice but partially attenuated the migration and invasion in TWIST1-overexpressed cell lines. Furthermore, we found that TQ treatment enhanced the promoter DNA methylation of the TWIST1 gene in BT 549 cells. Together, these results demonstrate that TQ treatment inhibits TWIST1 promoter activity and decreases its expression, leading to the inhibition of cancer cell migration, invasion and metastasis. These findings suggest TQ as a potential small molecular inhibitor of cancer growth and metastasis.

// Seo Hee Nam 1 , Doyeun Kim 2 , Mi-Sook Lee 2 , Doohyung Lee 2 , Tae Kyoung Kwak 2 , Minkyung Kang 2,3 , Jihye Ryu 2 , Hye-Jin Kim 2 , Haeng Eun Song 2 , Jungeun Choi 1 , Gyu-Ho Lee 2 , Sang-Yeob Kim 4 , Song Hwa Park 2 , Dae Gyu Kim 2 , Nam Hoon Kwon 2 , Tai Young Kim 2 , Jean Paul Thiery 5,6,7 , Sunghoon Kim 1,2 and Jung Weon Lee 1,2 1 Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul, Republic of Korea 2 Department of Pharmacy, Medicinal Bioconvergence Research Center, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea 3 Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea 4 Department of Medicine, University of Ulsan, College of Medicine, Seoul, Republic of Korea 5 Cancer Science Institute, National University of Singapore, Singapore 6 Institute of Molecular and Cell Biology, A*STAR, Singapore 7 Department of Biochemistry, School of Medicine, National University of Singapore, Singapore Correspondence to: Jung Weon Lee, email: // Keywords : 3D culture; cancer metastasis; cell-ECM adhesion; lysyl-tRNA synthetase; signal transduction Received : January 15, 2015 Accepted : April 30, 2015 Published : May 12, 2015 Abstract The adhesion properties of cells are involved in tumor metastasis. Although KRS at the plasma membrane is shown important for cancer metastasis, additionally to canonical roles of cytosolic KRS in protein translation, how KRS and its downstream effectors promote the metastatic migration remains unexplored. Disseminative behaviors (an earlier metastatic process) of colon cancer cell spheroids embedded in 3D collagen gels were studied with regards to cell adhesion properties, and relevance in KRS -/+ knocked-down animal and clinical colon cancer tissues. Time-lapse imaging revealed KRS-dependent cell dissemination from the spheroids, whereas KRS-suppressed spheroids remained static due to the absence of outbound movements supported by cell-extracellular matrix (ECM) adhesion. While keeping E-cadherin at the outward disseminative cells, KRS caused integrin-involved intracellular signaling for ERK/c-Jun, paxillin, and cell-ECM adhesion-mediated signaling to modulate traction force for crawling movement. KRS-suppressed spheroids became disseminative following ERK or paxillin re-expression. The KRS-dependent intracellular signaling activities correlated with the invasiveness in clinical colon tumor tissues and in KRS -/+ knocked-down mice tissues. Collectively, these observations indicate that KRS at the plasma membrane plays new roles in metastatic migration as a signaling inducer, and causes intracellular signaling for cancer dissemination, involving cell-cell and cell-ECM adhesion, during KRS-mediated metastasis.

// Chun-Ming Wong 1 , Lai Wei 1 , Sandy Leung-Kuen Au 1 , Dorothy Ngo-Yin Fan 1 , Yuan Zhou 2 , Felice Ho-Ching Tsang 1 , Cheuk-Ting Law 1 , Joyce Man-Fong Lee 1 , Xianghuo He 3 , Jue Shi 2 , Carmen Chak-Lui Wong 1 and Irene Oi-Lin Ng 1 1 Department of Pathology and State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China 2 Department of Physics and Department of Biology, Centre for Quantitative Systems Biology, Hong Kong Baptist University, Hong Kong, China 3 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China Correspondence to: Chun-Ming Wong, email: // Irene Oi-Lin Ng, email: // Keywords : hepatocellular carcinoma, miR-200 family, cytoskeletal reorganization, Rho/ROCK signaling pathway, cancer metastasis Received : January 16, 2015 Accepted : March 02, 2015 Published : March 30, 2015 Abstract MiR-200 family is an important regulator of epithelial-mesenchymal transition and has been implicated in human carcinogenesis. However, their expression and functions in human cancers remain controversial. In the work presented here, we showed that miR-200 family members were frequently down-regulated in hepatocellular carcinoma (HCC). Although all five members of miR-200 family inhibited ZEB1/2 expression in HCC cell lines, we showed that overexpression only of the miR-200b/200c/429 subfamily, but not the miR-200a/141 subfamily, resulted in impeded HCC cell migration. Further investigations led to the identification of RhoA and ROCK2 as specific down-stream targets of the miR-200b/200c/429 subfamily. We demonstrated that the miR-200b/200c/429 subfamily inhibited HCC cell migration through modulating Rho/ROCK mediated cell cytoskeletal reorganization and cell-substratum adhesion. Re-expression of miR-200b significantly suppressed lung metastasis of HCC cells in an orthotopic liver implantation model in vivo . In conclusion, our findings identified the miR-200b/200c/429 subfamily as metastasis suppressor microRNAs in human HCC and highlighted the functional discrepancy among miR-200 family members.

// Brock Humphries 1, 2 , Chengfeng Yang 1, 2, 3 1 Department of Physiology, Michigan State University, East Lansing, MI 48824, USA 2 Cellular and Molecular Biology Graduate Program, Michigan State University, East Lansing, MI 48824, USA 3 Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA Correspondence to: Chengfeng Yang, e-mail: yangcf@msu.edu Keywords: microRNA, miR-200, cancer initiation, cancer metastasis, cancer therapeutic target Received: November 14, 2014 Accepted: January 06, 2015 Published: January 30, 2015 ABSTRACT MicroRNAs (miRNAs) are a large family of small non-coding RNAs that negatively regulate protein-coding gene expression post-transcriptionally via base pairing between the 5′ seed region of a miRNA and the 3′ untranslated region (3′UTR) of a messenger RNA (mRNA). Recent evidence has supported the critical role that miRNAs play in many diseases including cancer. The miR-200 family consisting of 5 members (miR-200a, -200b, -200c, -141, -429) is an emerging miRNA family that has been shown to play crucial roles in cancer initiation and metastasis, and potentially be important for the diagnosis and treatment of cancer. While miR-200s were found to be critically involved in the metastatic colonization to the lungs in mouse mammary xenograft tumor models, a large number of studies demonstrated their strong suppressive effects on cell transformation, cancer cell proliferation, migration, invasion, tumor growth and metastasis. This review aims to discuss research findings about the role of the miR-200 family in cancer initiation, each step of cancer metastatic cascade, cancer diagnosis and treatment. A comprehensive summary of currently validated miR-200 targets is also presented. It is concluded that miR-200 family may serve as novel targets for the therapy of multiple types of cancer.

Metastatic dissemination of cancer cells from the primary tumor and their spread to distant sites in the body is the leading cause of mortality in breast cancer patients. While researchers have identified treatments that shrink or slow metastatic tumors, no treatment that permanently eradicates metastasis exists at present. Here, we show that the ABL kinase inhibitors imatinib, nilotinib, and GNF-5 impede invadopodium precursor formation and cortactin-phosphorylation dependent invadopodium maturation, leading to decreased actin polymerization in invadopodia, reduced extracellular matrix degradation, and impaired matrix proteolysis-dependent invasion. Using a mouse xenograft model we demonstrate that, while primary tumor size is not affected by ABL kinase inhibitors, the in vivo matrix metalloproteinase (MMP) activity, tumor cell invasion, and consequent spontaneous metastasis to lungs are significantly impaired in inhibitor-treated mice. Further proteogenomic analysis of breast cancer patient databases revealed co-expression of the Abl-related gene (Arg) and cortactin across all hormone- and human epidermal growth factor receptor 2 (HER2)-receptor status tumors, which correlates synergistically with distant metastasis and poor patient prognosis. Our findings establish a prognostic value for Arg and cortactin as predictors of metastatic dissemination and suggest that therapeutic inhibition of ABL kinases may be used for blocking breast cancer metastasis.

MicroRNA-34a (miR-34a) is down-regulated in colorectal cancers (CRC) and required for interleukin-6 (IL-6)-induced CRC metastasis. Mice lacking miR-34a developed more invasive cancer in a colitis-associated cancer model. In the same model, S-adenosylmethionine (SAMe) and methylthioadenosine (MTA) inhibited IL-6/STAT3 and lowered tumor burden. SAMe and MTA reduce the expression of methionine adenosyltransferase 2A (MAT2A) and there are consensus binding sites for miR-34a/b in the MAT2A 3'UTR. Here we examined whether SAMe/MTA influence miR-34a/b expression and cancer metastasis. We found SAMe and MTA raised miR-34a/b expression in CRC cell lines, inhibited migration and invasion in vitro and liver metastasis in vivo. Like CRC, MAT2A and MAT2B expression is induced in human pancreas and prostate cancers. Treatment with SAMe, MTA, miR-34a or miR-34b inhibited MAT2A expression mainly at the protein level. MAT2B protein level also fell because MAT2A and MAT2B enhance each other's protein stability. Overexpressing miR-34a or miR-34b inhibited while MAT2A or MAT2B enhanced CRC migration and invasion. Co-expressing either miR-34a/b had minimal to no effect on MAT2A/MAT2B's ability to increase migration, invasion and growth. Taken together, MAT2A and MAT2B are important targets of miR-34a/b and SAMe and MTA target this axis, suppressing MAT2A/MAT2B while raising miR-34a/b expression, inhibiting cancer metastasis.

// Fei Fei 1, 2 , Jie Qu 1, 2 , Mingqing Zhang 3 , Yuwei Li 3 and Shiwu Zhang 2 1 Nankai University School of Medicine, Nankai University, Tianjin, 300071, P.R.China 2 Department of Pathology, Tianjin Union Medical Center, Tianjin, 300121, P.R. China 3 Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, P.R. China Correspondence to: Shiwu Zhang, email: zhangshiwu666@aliyun.com Keywords: S100A4, metastasis, malignant tumor, epithelial-mesenchymal transition Received: April 11, 2017 Accepted: May 08, 2017 Published: May 19, 2017 ABSTRACT Metastasis is the leading cause of cancer-related death and directly associates with cancer progression, resistance to anticancer therapy, and poor patient survival. Current efforts focusing on the underlying molecular mechanisms of cancer metastasis attract a special attention to cancer researchers. The epithelial-mesenchymal transition is a complex of molecular program during embryogenesis, inflammation, tissue fibrosis, and cancer progression and metastasis. S100A4, an important member of S100 family proteins, functions to increase the tumor progression and metastasis. The molecular mechanisms of S100A4 involving in the progression and metastasis are diverse in various malignant tumors. Detection of S100A4 expression becomes a promising candidate biomarker in cancer early diagnosis and prediction of cancer metastasis and therefore, S100A4 may be a therapeutic target. This review summarized up to date advancement on the role of S100A4 in human cancer development, progression, and metastasis and the underlying molecular events and then strategies to target S100A4 expression experimentally.

// Takashi Nojiri 1, 2, * , Miki Arai 3, 4, * , Yutaka Suzuki 4 , Motofumi Kumazoe 1 , Takeshi Tokudome 1 , Koichi Miura 1 , Jun Hino 1 , Hiroshi Hosoda 5 , Mikiya Miyazato 1 , Meinoshin Okumura 2 , Shinpei Kawaoka 3, 6 and Kenji Kangawa 1 1 Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita-City, Osaka, Japan 2 Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan 3 Advanced Telecommunications Research Institute International (ATR), The Thomas N. Sato BioMEC-X Laboratories, Kyoto, Japan 4 The University of Tokyo, Graduate School of Frontier Science, Kashiwa, Japan 5 Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center Research Institute, Suita-City, Osaka, Japan 6 ERATO Sato Live Bio-Forecasting Project, Japan Science and Technology Agency, Kyoto, Japan * These authors contributed equally to this work and are co-first authors Correspondence to: Takashi Nojiri, email: nojiri@ri.ncvc.go.jp Kenji Kangawa, email: kangawa@ri.ncvc.go.jp Shinpei Kawaoka, email: kawaokashinpei@gmail.com Keywords: cancer metastasis, pre-metastatic niche, atrial natriuretic peptide, vascular endothelial cells, RNA-seq analyses Received: February 08, 2017 Accepted: May 10, 2017 Published: May 25, 2017 ABSTRACT Cancer establishes a microenvironment called the pre-metastatic niche in distant organs where disseminated cancer cells can efficiently metastasize. Pre-metastatic niche formation requires various genetic factors. Previous studies suggest that inhibiting a single niche-factor is insufficient to completely block pre-metastatic niche formation especially in human patients. Here we show that the atrial natriuretic peptide (ANP), an endogenous hormone produced by the heart, inhibits pre-metastatic niche formation and metastasis of murine solid cancer models when pharmacologically supplied in vivo . On the basis of a wealth of comprehensive RNA-seq data, we demonstrated that ANP globally suppressed expression of cancer-induced genes including known niche-factors in the lung. The lungs of mice overexpressing GC-A, a receptor for ANP in endothelial cells, were conferred resistance against pre-metastatic niche formation. Importantly, neither ANP administration nor GC-A overexpression had a detrimental effect on lung gene expression in a cancer-free condition. The current study establishes endothelial ANP-GC-A signaling as a therapeutic target to control the pre-metastatic niche.

// Pierre Danhier 1 , Gladys Deumer 2 , Nicolas Joudiou 1 , Caroline Bouzin 3 , Philippe Leveque 1 , Vincent Haufroid 2 , Benedicte F. Jordan 1 , Olivier Feron 4 , Pierre Sonveaux 4 , Bernard Gallez 1 1 Louvain Drug Research Institute, Biomedical Magnetic Resonance Research Group, Universite Catholique de Louvain (UCL), Brussels, Belgium 2 Louvain Center for Toxicology and Applied Pharmacology, Universite Catholique de Louvain (UCL), Brussels, Belgium 3 Institut de Recherche Experimentale et Clinique (IREC), IREC Imaging Platform, Universite Catholique de Louvain (UCL), Brussels, Belgium 4 Institut de Recherche Experimentale et Clinique (IREC), Pole of Pharmacology, Universite Catholique de Louvain (UCL), Brussels, Belgium Correspondence to: Bernard Gallez, email: bernard.gallez@uclouvain.be Keywords: MRI, EPR, cell tracking, cancer metastasis, iron oxides Received: January 06, 2017 Accepted: March 29, 2017 Published: April 13, 2017 ABSTRACT Magnetic resonance imaging (MRI) cell tracking of cancer cells labeled with superparamagnetic iron oxides (SPIO) allows visualizing metastatic cells in preclinical models. However, previous works showed that the signal void induced by SPIO on T 2 (*)-weighted images decreased over time. Here, we aim at characterizing the fate of iron oxide nanoparticles used in cell tracking studies and the role of macrophages in SPIO metabolism. In vivo MRI cell tracking of SPIO positive 4T1 breast cancer cells revealed a quick loss of T 2 * contrast after injection. We next took advantage of electron paramagnetic resonance (EPR) spectroscopy and inductively coupled plasma mass spectroscopy (ICP-MS) for characterizing the evolution of superparamagnetic and non-superparamagnetic iron pools in 4T1 breast cancer cells and J774 macrophages after SPIO labeling. These in vitro experiments and histology studies performed on 4T1 tumors highlighted the quick degradation of iron oxides by macrophages in SPIO-based cell tracking experiments. In conclusion, the release of SPIO by dying cancer cells and the subsequent uptake of iron oxides by tumor macrophages are limiting factors in MRI cell tracking experiments that plead for the use of (MR) reporter-gene based imaging methods for the long-term tracking of metastatic cells.

// Ming-Yi Ho 1 , Shao-Wen Hung 2 , Chi-Ming Liang 1,3 , Shu-Mei Liang 1,2 1 Genomics Research Center, Academia Sinica, Taipei, Taiwan, ROC 2 Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC 3 Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan, ROC Correspondence: Chi-Ming Liang, email: // Shu-Mei Liang, email: // Keywords : Migration inducting gene-7 (MIG-7), Cyclooxygenase-2 (COX-2), Integrin-linked kinase (ILK), rVP1, Cancer metastasis, EMT Received : March 24, 2014 Accepted : May 27, 2014 Published : May 29, 2014 Abstract Recombinant capsid protein VP1 (rVP1) of foot-and-mouth disease virus binds to integrins to modulate Akt/GSK3-β signaling and suppress migration/invasion and metastasis of cancer cells, but the underlying molecular mechanism is unclear. Here, we showed that the rVP1-mediated inhibition of Akt/GSK3-β signaling and cell migration/invasion was accompanied by downregulation in phosphatidylinositol (3,4,5)-triphosphate (PIP3), integrin-linked kinase (ILK) and IKK/NF-κB signaling as well as suppression of COX-2/PGE2 and MIG-7. Addition of PIP3 or overexpression of ILK reversed the rVP1-induced inhibition of IKK/NF-κB signaling, COX-2 and MIG-7. The rVP1-mediated downregulation of COX-2/PGE2 and MIG-7 led to not only attenuation of epithelial-mesenchymal transition, MMP2 activity and invasion of lung cancer cells in vitro but also decreased tumor growth and metastasis of lung cancer in xenograft mice. Moreover, downregulation of COX-2/PGE2 and MIG-7 significantly prolonged the overall and disease-free survival of lung cancer-bearing mice. These results suggest that rVP1 inhibits cancer invasion/metastasis, partly if not mainly, via downregulating integrin/PI3K/Akt, ILK and IKK/NF-κB signaling to suppress expression of COX-2/PGE2 and MIG-7.

// Seok-Jun Kim 1,8 , Yuan-Guo Wang 2 , Hyun-Woo Lee 1,3 , Hyeok Gu Kang 1,8 , Sun-Hyuk La 1,3 , Il Ju Choi 4 , Tatsuro Irimura 5 , Jae Y. Ro 6 , Robert S. Bresalier 7 and Kyung-Hee Chun 1,8 1 Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea. 2 Minimally Invasive Tumor Therapy Laboratory, Radiology Department, Beth Israel Deaconess Medical Center, Boston, MA, USA. 3 Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea. 4 Center for Gastric Cancer, Division of Translational & Clinical Research I, National Cancer Center, Gyeonggi-do, Republic of Korea. 5 Institute of medical innovation, St. Luke’s international Hospital, Chuo-ku, Tokyo, Japan. 6 The Methodist Hospital, Department of Pathology and Genomic Medicine, Weil Medical College of Cornell University, Houston, TX, USA. 7 Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. 8 Brain Korea 21 PLUS Project for Medical Science, Yonsei University. Correspondence: Kyung-Hee Chun, email: // Keywords : Neogenin-1, Galectin-3, Heat shock factor (HSF)-1, Cancer metastasis, Gastric cancer Received : March 5, 2014 Accepted : May 12, 2014 Published : May 13, 2014 Abstract Although elevated expression of neogenin-1 has been detected in human gastric cancer tissue, its role in gastric tumorigenesis remains unclear due to the lack of neogenin-1 studies in cancer. Therefore, we demonstrated here the function and regulatory mechanism of neogenin-1 in gastric cancer. Neogenin-1 ablation decreased proliferation and migration of gastric cancer cells, whereas its over-expression reversed these effects. Xenografted analyses using gastric cancer cells displayed statistically significant inhibition of tumor growth by neogenin-1 depletion. Interestingly, galectin-3 interacted with HSF-1 directly, which facilitated nuclear-localization and binding on neogenin-1 promoter to drive its transcription and gastric cancer cell motility. The galectin-3-increased gastric cancer cell motility was down-regulated by HSF-1 depletion. Moreover, the parallel expression patterns of galectin-3 and neogenin-1, as well as those of HSF-1 and neogenin-1, were detected in the malignant tissues of gastric cancer patients. Taken together, high-expression of neogenin-1 promotes gastric cancer proliferation and motility and its expression is regulated by HSF-1 and galectin-3 interaction. In addition, we propose further studies for neogenin-1 and its associated pathways to provide them as a proper target for gastric cancer therapy.

// Sandra Cascio, 1,2 Adam M. Farkas 1 , Rebecca P. Hughey 3 and Olivera J. Finn 1 1 Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261 2 Fondazione Ri.Med, via Bandiera, Palermo, 90133, Italy 3 Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261. Correspondence: Sandra Cascio, email: // Olivera J. Finn, email: // Keywords : MUC1/CIN85 complex, protein-protein interaction, cell migration, invadopodia-like structures, cancer metastasis Received : August 8, 2013 Accepted : September 5, 2013 Published : September 7, 2013 Abstract MUC1 is a transmembrane glycoprotein abnormally expressed in human adenocarcinomas. The extracellular domain of MUC1 contains a variable number of tandem repeats (VNTR) region that is extensively O-glycosylated in normal epithelia and underglycosylated in tumor cells. This change in posttranslational modification of MUC1 leads to changes in its normal functions including, we hypothesized, its interaction with other molecules. We identified CIN85, an adaptor protein involved in multiple cellular processes including signal transduction, cytoskeletal remodeling and cancer cell invasion, as one of several proteins that associate with MUC1 in tumor cells. CIN85 associates with both the cytosolic tail and the extracellular VNTR of MUC1. Co-immunoprecipitation and confocal immunofluorescence confirmed that MUC1 and CIN85 co-localize primarily at the plasma membrane but the complex can be found also in the cytosol and on the cytoskeleton. MUC1 and CIN85 are both over-expressed in early as well as advanced clinical stages of breast cancer and co-localize on invadopodia-like structures implicated in cell invasion. siRNA-mediated silencing of CIN85 and/or MUC1 revealed that MUC1 enhances CIN85-dependent breast cancer cell migration and invasion in vitro . However, ectopic expression of MUC1 enhances the motility induced by CIN85. When tested in vivo in a tumor metastasis model of B16 melanoma, mice injected with CIN85-depleted melanoma cells exhibited few or no lung metastasis and, similarly to the in vitro results, overexpression of MUC1 recovered the shCIN85-reduced metastatic process . Our findings implicate this newly identified CIN85/MUC1 complex associated with invadopodia-related molecules in promoting the invasive and metastatic potential of breast cancer.

// Meijian Liao 1, 2, * , Bing Li 1, 2, * , Shikuan Zhang 2 , Qing Liu 1, 2 , Weijie Liao 1, 2 , Weidong Xie 2, 3 , Yaou Zhang 2, 3 1 School of Life Sciences, Tsinghua University, Beijing 100084, P.R. China 2 Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, P.R. China 3 Open FIESTA Center, Tsinghua University, Shenzhen 518055, P.R. China * These authors contributed equally to this work Correspondence to: Weidong Xie, email: xiewd@sz.tsinghua.edu.cn Yaou Zhang, email: zhangyo@sz.tsinghua.edu.cn Keywords: LncRNA, LINC00341, metastasis, meta-analysis, prognostication Received: November 15, 2016 Accepted: January 17, 2017 Published: January 27, 2017 ABSTRACT LINC00341 is a novel long intergenic non-protein coding RNA with unknown functions. In our report, we investigated LINC00341 expression and its prognostic value in cancer patients. DNA over-methylation triggered low expression of LINC00341 and that was associated with poor prognosis in cancers. A meta-analysis further confirmed that high expression of LINC00341 was associated with a better prognosis in cancer patients. Both gene set enrichment analysis and meta-analysis showed that LINC00341 inhibited cancer metastasis. Finally, a large-scale multicentre analysis supported a prognostic value of LINC00341 in cancers.

// Ming-xin Cao 1,2 , Ya-ping Jiang 3 , Ya-ling Tang 1,4 and Xin-hua Liang 1,2 1 State Key Laboratory of Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu Sichuan, People’s Republic of China 2 Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology (Sichuan University), Chengdu Sichuan, People’s Republic of China 3 Department of Implant, The Affiliated Hospital of Qingdao University, Qingdao,Shandong, People’s Republic of China 4 Department of Oral Pathology, West China Hospital of Stomatology (Sichuan University), Chengdu Sichuan, People’s Republic of China Correspondence to: Xin-hua Liang, email: // Ya-ling Tang, email: // Keywords : lncRNA, microRNA, epithelial-mesenchymal plasticity, cancer metastasis Received : October 15, 2016 Accepted : December 12, 2016 Published : December 15, 2016 Abstract Noncoding RNAs (ncRNAs) have been demonstrated to closely associate with gene regulation and encompass the well-known microRNAs (miRNAs), as well as the most recently acknowledged long noncoding RNAs (lncRNAs). Current evidence indicates that lncRNAs can interact with miRNAs and these interactions play crucial roles in cancer metastasis, through regulating critical events especially the epithelial-mesenchymal transition (EMT). This review summarizes the types of lncRNA-miRNA crosstalk identified to-date and discusses their influence on the epithelial-mesenchymal plasticity and clinical metastatic implication.

// Sheryl L. Coutermarsh-Ott 1, * , Katherine M. Broadway 2, * , Birgit E. Scharf 2 , Irving C. Allen 1 1 Virginia Tech, VA-MD College of Veterinary Medicine, Department of Biomedical Sciences and Pathobiology, Blacksburg, VA, USA 2 Virginia Tech, Department of Biological Sciences, Blacksburg, VA, USA * These authors contributed equally to this work Correspondence to: Irving C. Allen, email: icallen@vt.edu Birgit E. Scharf, email: bscharf@vt.edu Keywords: bacterial therapeutic, breast cancer, chemotaxis, CheY, metastasis Received: October 12, 2016 Accepted: March 27, 2017 Published: April 04, 2017 ABSTRACT A variety of bacterial strains have been evaluated as bio-therapeutic and immunomodulatory agents to treat cancer. One such strain, Salmonella enterica serovar Typhimurium VNP20009, which is attenuated by a purine auxotrophic mutation and modified lipid A, is characterized in previous models as a safely administered, tumor colonizing agent. However, earlier work tended to use less aggressive cancer cell lines and immunocompromised animal models. Here, we investigated the safety and efficacy of VNP20009 in a highly malignant murine model of human breast cancer. Additionally, as VNP20009 has recently been found to have a defective chemotaxis system, we tested whether restoring chemotaxis would improve anti-cancer properties in this model system. Exposure to VNP20009 had no significant effect on primary mammary tumor size or pulmonary metastasis, and the tumor colonizing process appeared chemotaxis independent. Moreover, tumor-bearing mice exposed to Salmonella exhibited increased morbidity that was associated with significant liver disease. Our results suggest that VNP20009 may not be safe or efficacious when used in aggressive, metastatic breast cancer models utilizing immunocompetent animals.

// Chen Jixiang 1, * , Dang Shengchun 1, * , Qu Jianguo 1 , Mao Zhengfa 1 , Fan Xin 1 , Wang Xuqing 1 , Zhang Jianxin 1 , Cui Lei 1 1 General Surgery Department, Affiliated Hospital, Jiangsu University, Zhenjiang City, Jiangsu Province, 212000 China * These authors have contributed equally to this work Correspondence to: Cui Lei, email: cuileidoc@qq.com Keywords: YEATS4, pancreatic cancer, beta-catenin/TCF signaling, cancer metastasis Received: September 24, 2016 Accepted: November 23, 2016 Published: February 23, 2017 ABSTRACT Beta-catenin/TCF signaling has been reported to promote the growth and metastasis of pancreatic cancer cells. However, the regulation for the beta-catenin/TCF transcriptional complex remains largely unknown. Here, we have found that YEATS4 is a positive regulator for Beta-catenin/TCF signaling. The expression of YEATS4 was elevated in clinical pancreatic cancer samples and pancreatic cancer mouse model. Up-regulation of YEATS4 promoted the growth, migration and invasion of pancreatic cancer cells, while knocking down the expression of YEATS4 inhibited the growth, migration, invasion and metastasis of pancreatic cancer cells. Moreover, the mechanism study revealed that YEATS4 interacted with beta-catenin and activated beta-catenin/TCF signaling. Furthermore, knocking down the expression of YEATS4 impaired the malignant transformation of normal pancreatic cells (HPDE6C7) by the oncogenic Ras. Taken together, our study demonstrated the oncogenic roles of YEATS4 in the progression of pancreatic cancer by activating beta-catenin/TCF signaling and suggested that YEATS4 might be a promising therapeutic target for pancreatic cancer.

// Jitao Zhou 1,* , Xin Ma 1,* , Feng Bi 1 and Ming Liu 1 1 Department of Medical Oncology/Laboratory of Signal Transduction & Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China * These authors have contributed equally to this work Correspondence to: Ming Liu, email: // Keywords : CTC; gastric cancer; EMT; Cellsearch; cancer metastasis Received : August 29, 2016 Accepted : January 16, 2017 Published : January 28, 2017 Abstract Circulating tumor cells (CTCs) are rare cancer cells released from tumors into the blood stream that are thought to have a key role in cancer metastasis. Investigation of CTCs is an exciting area of research but remains in its infancy, and the presence of CTCs has been associated with worse prognosis in several major cancer types. Gastric cancer (GC) is a highly lethal malignancy and a serious public health concern in East Asia especially in China. There is an urgent need for identifying new, better prognostic markers to enhance diagnosis and prognosis, facilitate drug development, and to improve the treatment of gastric cancer patients. There are considerable interests in gastric CTCs given their potential use as gastric cancer biomarkers. This review highlights recent advances in studies of gastric CTCs, including the isolation and biological molecular characteristics of gastric CTCs, and their clinical significance.

// Rae-Kwon Kim 1, * , Neha Kaushik 1, * , Yongjoon Suh 1 , Ki-Chun Yoo 1 , Yan-Hong Cui 1 , Min-Jung Kim 2 , Hae-June Lee 3 , In-Gyu Kim 4 , Su-Jae Lee 1 1 Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, Korea 2 Laboratory of Radiation Exposure and Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul, Korea 3 Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul, Korea 4 Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, Daejeon, Korea * These authors contributed equally to this work Correspondence to: Su-Jae Lee, email: sj0420@hanyang.ac.kr Keywords: radiation, EMT, Notch signaling, interleukin-6, breast cancer Received: May 23, 2016 Accepted: July 13, 2016 Published: July 23, 2016 ABSTRACT Epithelial to mesenchymal transition (EMT) is developmental process associated with cancer metastasis. Here, we found that breast carcinoma cells adopt epithelial-to-mesenchymal transition (EMT) in response to fractionated-radiation. Importantly, we show that Notch signaling is highly activated in fractionally-irradiated tumors as compared to non-irradiated tumors that are accompanied by an EMT. Moreover, we uncovered the mechanism of Notch-driven EMT, in which Notch enhanced EMT through IL-6/JAK/STAT3 signaling axis in mammary tumor cells. Collectively, we present converging evidence from our studies that Notch2 is a critical mediator of radiation-induced EMT and responsible for induced malignant tumor growth.

CA extern

The CCL2-CCR2 signaling axis has generated increasing interest in recent years due to its association with the progression of cancer. Although first described as a chemotactic molecule with physiological roles in regulating inflammation, recent studies have revealed a pro-tumorigenic function for CCL2 in favoring cancer development and subsequent metastasis. CCL2 binds the cognate receptor CCR2, and together this signaling pair has been shown to have multiple pro-tumorigenic roles, from mediating tumor growth and angiogenesis to recruiting and usurping host stromal cells to support tumor progression. The importance of CCL2-CCR2 signaling has been further championed by the establishment of clinical trials targeting this signaling pair in solid and metastatic cancers. Here we review the roles of CCL2-CCR2 signaling in the development and progression of cancer metastasis. We further evaluate the outcome of several clinical trials targeting either CCL2 or CCR2, and discuss the prospects and challenges of manipulating CCL2-CCR2 interaction as a potential approach for combating metastatic disease.

// Ting-Fang Che 1 , Ching-Wen Lin 2 , Yi-Ying Wu 5 , Yu-Ju Chen 6 , Chia-Li Han 7 , Yih-leong Chang 8 , Chen-Tu Wu 8 , Tzu-Hung Hsiao 9 , Tse-Ming Hong 5, * , Pan-Chyr Yang 1, 2, 3, 4, * 1 Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan 2 Institute of Biomedical Science, Academia Sinica, Taipei 115, Taiwan 3 NTU Center for Genomic Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan 4 Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan 5 Institute of Clinical Medicine, College of Medicine, National Cheng-Kung University, Tainan 701, Taiwan 6 Institute of Chemistry, Academia Sinica 115, Taipei, Taiwan 7 Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University 110, Taipei, Taiwan 8 Department of Pathology and Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei 100, Taiwan 9 Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan * These authors have contributed equally to this work Correspondence to: Pan-Chyr Yang, e-mail: pcyang@ntu.edu.tw Tse-Ming Hong, e-mail: tmhong@mail.ncku.edu.tw Keywords: cancer metastasis, EGFR, mitochondria dynamics Received: May 19, 2015 Accepted: October 06, 2015 Published: October 19, 2015 ABSTRACT Dysfunction of the mitochondria is well-known for being associated with cancer progression. In the present study, we analyzed the mitochondria proteomics of lung cancer cell lines with different invasion abilities and found that EGFR is highly expressed in the mitochondria of highly invasive non-small-cell lung cancer (NSCLC) cells. EGF induces the mitochondrial translocation of EGFR; further, it leads to mitochondrial fission and redistribution in the lamellipodia, upregulates cellular ATP production, and enhances motility in vitro and in vivo . Moreover, EGFR can regulate mitochondrial dynamics by interacting with Mfn1 and disturbing Mfn1 polymerization. Overexpression of Mfn1 reverses the phenotypes resulting from EGFR mitochondrial translocation. We show that the mitochondrial EGFR expressions are higher in paired samples of the metastatic lymph node as compared with primary lung tumor and are inversely correlated with the overall survival in NSCLC patients. Therefore, our results demonstrate that besides the canonical role of EGFR as a receptor tyrosine, the mitochondrial translocation of EGFR may enhance cancer invasion and metastasis through regulating mitochondria dynamics.