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// Yu-Wen Yeh 1, 2 , Ching-Chia Cheng 3, 4 , Shu-Ting Yang 4 , Chi-Feng Tseng 4 , Ting-Yu Chang 4 , Sin-Ying Tsai 5 , Earl Fu 6 , Chien-Ping Chiang 7 , Li-Chuan Liao 8 , Pei-Wen Tsai 9 , Yung-Luen Yu 5, 10, 11 , Jen-Liang Su 4, 5, 10, 11 1 Division of Dermatology, Tri-Service General Hospital Songshan Branch, National Defense Medical Center, Taipei 10581, Taiwan 2 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan 3 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan 4 National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan 5 Department of Biotechnology, Asia University, Taichung 41354, Taiwan 6 Department of Periodontology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan 7 Department of Dermatology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan 8 Bioresource Collection and Research Center, Food Industry Research and Development Institute, Hsinchu 30062, Taiwan 9 Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 30013, Taiwan 10 Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan 11 Center for Molecular Medicine, China Medical University Hospital, Taichung 40447, Taiwan Correspondence to: Jen-Liang Su, email: jlsu@nhri.org.tw Yung-Luen Yu, email: ylyu@mail.cmu.edu.tw Keywords: VEGF-C, YAP1, metastasis, cancer stemness, skin cancer Received: August 08, 2016 Accepted: November 07, 2016 Published: November 25, 2016 ABSTRACT Vascular endothelial growth factor-C (VEGF-C) has been implicated in epithelial-mesenchymal transition (EMT) processes and various human cancers, including skin cancer. Skin cancer is an aggressive human malignancy with increasing incidence worldwide; however, the underlying mechanisms involved in VEGF-C-induced skin cancer stemness and metastasis remain unclear. Here, we report that VEGF-C enhances skin cancer migration, invasion and stemness through Slug up-regulation. Oncomine database analysis indicated that the KRAS/MAPK (mitogen-activated protein kinases) pathway and YAP1 (yes-associated protein 1) expression are positively correlated with metastatic skin cancer. We show that VEGF-C triggers the activation of KRAS/MAPK signaling to increase YAP1 and downstream Slug expression, which are suppressed by an anti-VEGFR3 (VEGF receptor 3) peptide, a specific peptide targeting VEGFR3. The VEGF-C-induced migration, invasion and stemness of skin cancer cells are also abrogated by the anti-VEGFR3 peptide. Based on these data, we reveal the role of the VEGF-C/VEGFR3-mediated KRAS/MAPK-YAP1/Slug pathway in skin cancer progression and propose that the VEGF-C/VEGFR3 axis is a promising target for the anti-VEGFR3 peptide.

Human embryonic stem cells (hESCs), due to their self-renewal capacity and pluripotency, have become a potential source of transplantable β-cells for the treatment of diabetes. However, it is imperative that the derived cells fulfill the criteria for clinical treatment. In this study, we replaced common Matrigel with a synthetic peptide-acrylate surface (Synthemax) to expand undifferentiated hESCs and direct their differentiation in a defined and serum-free medium. We confirmed that the cells still expressed pluripotent markers, had the ability to differentiate into three germ layers, and maintained a normal karyotype after 10 passages of subculture. Next, we reported an efficient protocol for deriving nearly 86% definitive endoderm cells from hESCs under serum-free conditions. Moreover, we were able to obtain insulin-producing cells within 21 days following a simple three-step protocol. The results of immunocytochemical and quantitative gene expression analysis showed that the efficiency of induction was not significantly different between the Synthemax surface and the Matrigel-coated surface. Thus, we provided a totally defined condition from hESC culture to insulin-producing cell differentiation, and the derived cells could be a therapeutic resource for diabetic patients in the future.

The novel concept of modifying and enhancing the properties of existing functional micelles through self-complementary interactions has significant potential. In this study, a practical approach to living polymerization of functionalized thermoresponsive monomers enabled the incorporation of self-constituted multiple hydrogen bonded groups into micelles that have potential as supramolecular drug-delivery systems. Phase transitions and morphological studies in aqueous solution showed that the microstructure can be controlled to achieve well-defined vesicle-like micelles with respect to the strength of the hydrogen bond segment. Thus, the resulting micelles have a very low critical micellization concentration and very high loading capacity (16.1%), making the loading process extremely stable and efficient. Incorporation of the anticancer drug doxorubicin (DOX) affected the micellization process in aqueous solution and enabled fine-tuning of drug loading and precise control of drug release rate with excellent sensitivity. Release studies in vitro showed that DOX-loaded micelles exerted dose-dependent cytotoxicity against human liver carcinoma (HepG2) cells at the physiological temperature of 37 °C. In addition, DOX-loaded micelles were efficiently endocytosed by the cancer cells, which may enable the micelles to serve as suitable vehicles for effective delivery of anticancer drugs to primary tumors and metastatic disease. This newly developed material may provide a potential route towards next-generation drug delivery vehicles. Statement of Significance A breakthrough innovation in water-based thermo-responsive polymers has enabled significant progress in developing smart stimuli-responsive nanocarriers by generating novel “supramolecular polymeric micelles” via self-complementary hydrogen-bonding interactions. These newly developed micelles exhibit extremely high micellar stability and drug loading capacity (up to 16%), excellent thermo-responsive behavior and precise control of drug release rate due to hydrogen-bond-induced physical cross-linking. In addition, doxorubicin-loaded micelles were efficiently endocytosed by the cancer cells, which allows them to serve as suitable vehicles for effective delivery of anticancer drugs to primary tumors and metastatic disease. Thus, this work provides a potential route for the development of next generation multifunctional nanocarriers that have improved safety and to increase the therapeutic efficacy of anticancer therapy.