Activin A Is Anti-Lymphangiogenic in a Melanoma Mouse Model

Slides:



Advertisements
Similar presentations
2-Methoxyestradiol Inhibits Hypoxia-Inducible Factor-1α and Suppresses Growth of Lesions in a Mouse Model of Endometriosis  Christian M. Becker, Nadine.
Advertisements

Vascular Endothelial Growth Factor (VEGF)-Mediated Angiogenesis Is Associated with Enhanced Endothelial Cell Survival and Induction of Bcl-2 Expression 
Volume 17, Issue 5, Pages (May 2015)
Enhanced Vascularization of Cultured Skin Substitutes Genetically Modified to Overexpress Vascular Endothelial Growth Factor1  Dorothy M. Supp, Andrew.
Stefanie Krenzer, Heike Peterziel, Cornelia Mauch, Sachiko I
Cell Surface CD74–MIF Interactions Drive Melanoma Survival in Response to Interferon-γ  Keiji Tanese, Yuuri Hashimoto, Zuzana Berkova, Yuling Wang, Felipe.
A Signal Transduction Pathway from TGF-β1 to SKP2 via Akt1 and c-Myc and its Correlation with Progression in Human Melanoma  Xuan Qu, Liangliang Shen,
The Tumor Necrosis Factor Superfamily Molecule LIGHT Promotes Keratinocyte Activity and Skin Fibrosis  Rana Herro, Ricardo Da S. Antunes, Amelia R. Aguilera,
Interleukin-22 Promotes Wound Repair in Diabetes by Improving Keratinocyte Pro- Healing Functions  Simona Avitabile, Teresa Odorisio, Stefania Madonna,
MicroRNA-31 Promotes Skin Wound Healing by Enhancing Keratinocyte Proliferation and Migration  Dongqing Li, X.I. Li, Aoxue Wang, Florian Meisgen, Andor.
A Previously Unknown Dermal Blood Vessel Phenotype in Skin Inflammation  Marion Gröger, Heide Niederleithner, Dontscho Kerjaschki, Peter Petzelbauer  Journal.
3,3′,4,4′,5,5′-Hexahydroxystilbene Impairs Melanoma Progression in a Metastatic Mouse Model  Verena Paulitschke, Nikolaus Schicher, Thomas Szekeres, Walter.
Exogenous Smad3 Accelerates Wound Healing in a Rabbit Dermal Ulcer Model  Koji Sumiyoshi, Atsuhito Nakao, Yasuhiro Setoguchi, Ko Okumura, Hideoki Ogawa 
Fibroblast Activation Protein: Differential Expression and Serine Protease Activity in Reactive Stromal Fibroblasts of Melanocytic Skin Tumors  Margit.
Gregory D. Rak, Lisa C. Osborne, Mark C. Siracusa, Brian S
Decreased Expression of the Chromatin Remodeler ATRX Associates with Melanoma Progression  Zulekha A. Qadeer, Sara Harcharik, David Valle-Garcia, Chen.
Zhuo Li, Dieter Metze, Dorothea Nashan, Carsten Müller-Tidow, Hubert L
Epidermal Growth Factor Facilitates Melanoma Lymph Node Metastasis by Influencing Tumor Lymphangiogenesis  Andreas Bracher, Ana Soler Cardona, Stefanie.
Stromal Fibroblast–Specific Expression of ADAM-9 Modulates Proliferation and Apoptosis in Melanoma Cells In Vitro and In Vivo  Anna N. Abety, Jay W. Fox,
Tumor Necrosis Factor-α-Activated Human Adipose Tissue–Derived Mesenchymal Stem Cells Accelerate Cutaneous Wound Healing through Paracrine Mechanisms 
Complexity of VEGF Responses in Skin Carcinogenesis Revealed through Ex Vivo Assays Based on a VEGF-A Null Mouse Keratinocyte Cell Line  Isabel Mirones,
CXCL5 as Regulator of Neutrophil Function in Cutaneous Melanoma
Manuela Schmidt, Danny Gutknecht, Jan C
Rainer Kunstfeld, Sonja Lechleitner, Klaus Wolff, Peter Petzelbauer 
Osteopontin Expression Correlates with Melanoma Invasion
IL-1R1 Signaling Facilitates Munro’s Microabscess Formation in Psoriasiform Imiquimod-Induced Skin Inflammation  Mireia Uribe-Herranz, Li-Hua Lian, Kirsten.
Combination of Dacarbazine and Dimethylfumarate Efficiently Reduces Melanoma Lymph Node Metastasis  Teresa Valero, Silvia Steele, Karin Neumüller, Andreas.
Differential Expression of Matrix Metalloproteinases During Impaired Wound Healing of the Diabetes Mouse  Steven J. Wall, Dr, Damon Bevan, David W. Thomas,
Opposing Roles of JNK and p38 in Lymphangiogenesis in Melanoma
Pro-Invasive Activity of the Hippo Pathway Effectors YAP and TAZ in Cutaneous Melanoma  Flore Nallet-Staub, Véronique Marsaud, Ling Li, Cristèle Gilbert,
Inhibition of KLF4 by Statins Reverses Adriamycin-Induced Metastasis and Cancer Stemness in Osteosarcoma Cells  Yangling Li, Miao Xian, Bo Yang, Meidan.
RANK Is Expressed in Metastatic Melanoma and Highly Upregulated on Melanoma- Initiating Cells  Verena Kupas, Carsten Weishaupt, Dorothee Siepmann, Maria-Laura.
Wei Xu, Shengxian Jia, Ping Xie, Aimei Zhong, Robert D
Brian Poligone, Elaine S. Gilmore, Carolina V
Absence of Distinguishing Senescence Traits in Human Melanocytic Nevi
Einar K. Rofstad, Bjørn A. Graff  Journal of Investigative Dermatology 
SPARC Endogenous Level, rather than Fibroblast-Produced SPARC or Stroma Reorganization Induced by SPARC, Is Responsible for Melanoma Cell Growth  Federico.
Calmodulin-Like Protein Upregulates Myosin-10 in Human Keratinocytes and Is Regulated during Epidermal Wound Healing In Vivo  Richard D. Bennett, Amy.
Paola Zigrino, Isolde Kuhn, Tobias Bäuerle, Jan Zamek, Jay W
Human Mitochondrial NAD(P)+–Dependent Malic Enzyme Participates in Cutaneous Melanoma Progression and Invasion  Yung-Lung Chang, Hong-Wei Gao, Chien-Ping.
Overexpression of CD109 in the Epidermis Differentially Regulates ALK1 Versus ALK5 Signaling and Modulates Extracellular Matrix Synthesis in the Skin 
IL-22 Promotes Fibroblast-Mediated Wound Repair in the Skin
14-3-3σ Regulates Keratinocyte Proliferation and Differentiation by Modulating Yap1 Cellular Localization  Sumitha A.T. Sambandam, Ramesh B. Kasetti,
Yabin Cheng, Guangdi Chen, Magdalena Martinka, Vincent Ho, Gang Li 
Leah C. Biggs, Lindsey Rhea, Brian C. Schutte, Martine Dunnwald 
Epidermal Langerhans Cells Rapidly Capture and Present Antigens from C-Type Lectin- Targeting Antibodies Deposited in the Dermis  Vincent Flacher, Christoph.
Hermine Schlagbauer-Wadl, Marieke Griffioen, Andrea van Elsas, Peter I
Epithelial Overexpression of SOCS-3 in Transgenic Mice Exacerbates Wound Inflammation in the Presence of Elevated TGF-β1  Andreas Linke, Itamar Goren,
The Suppressor of Cytokine Signaling (SOCS)-3 Determines Keratinocyte Proliferative and Migratory Potential during Skin Repair  Andreas Linke, Itamar.
CD63 Tetraspanin Is a Negative Driver of Epithelial-to-Mesenchymal Transition in Human Melanoma Cells  Antonella Lupia, Silvia Peppicelli, Ewa Witort,
Evidence for Altered Wnt Signaling in Psoriatic Skin
Pathophysiological Characteristics of Melanoma In-Transit Metastasis in a Lymphedema Mouse Model  Kohei Oashi, Hiroshi Furukawa, Hiroshi Nishihara, Michitaka.
YAP and TAZ Regulate Skin Wound Healing
Erythroid Differentiation Regulator 1, an Interleukin 18-Regulated Gene, Acts as a Metastasis Suppressor in Melanoma  Min Kyung Jung, Yoorim Park, Seok.
Wnt1 Is Anti-Lymphangiogenic in a Melanoma Mouse Model
Green Tea Polyphenol Epigallocatechin-3-Gallate Suppresses Collagen Production and Proliferation in Keloid Fibroblasts via Inhibition of the STAT3-Signaling.
Increased Expression of Wnt2 and SFRP4 in Tsk Mouse Skin: Role of Wnt Signaling in Altered Dermal Fibrillin Deposition and Systemic Sclerosis  Julie Bayle,
Opposing Roles of JNK and p38 in Lymphangiogenesis in Melanoma
Overexpression of Fetuin-A Counteracts Ectopic Mineralization in a Mouse Model of Pseudoxanthoma Elasticum (Abcc6−/−)  Qiujie Jiang, Florian Dibra, Michael.
HGF-Promoted Motility in Primary Human Melanocytes Depends on CD44v6 Regulated via NF-kappa B, Egr-1, and C/EBP-beta  Sabine Damm, Petra Koefinger, Martina.
Javed Mohammed, Andrew Ryscavage, Rolando Perez-Lorenzo, Andrew J
TAK1 Is Required for Dermal Wound Healing and Homeostasis
Melanoma Cells Control HA Synthesis in Peritumoral Fibroblasts via PDGF-AA and PDGF-CC: Impact on Melanoma Cell Proliferation  Anja Willenberg, Anja Saalbach,
Suppression of VEGFR2 Expression in Human Endothelial Cells by Dimethylfumarate Treatment: Evidence for Anti-Angiogenic Action  Markus Meissner, Monika.
The Non-Receptor-Associated Tyrosine Kinase Syk is a Regulator of Metastatic Behavior in Human Melanoma Cells  Christoph Hoeller, Christiane Thallinger,
The Angiogenesis Inhibitor Vasostatin does not Impair Wound Healing at Tumor- Inhibiting Doses  Bernhard Lange-Asschenfeldt, Paula Velasco, Michael Streit,
CDNA Microarray Analysis of Gene Expression Profiles in Human Fibroblast Cells Irradiated with Red Light  Shipeng Song  Journal of Investigative Dermatology 
Keratinocyte-Derived Granulocyte-Macrophage Colony Stimulating Factor Accelerates Wound Healing: Stimulation of Keratinocyte Proliferation, Granulation.
Role and Regulation of STAT3 Phosphorylation at Ser727 in Melanocytes and Melanoma Cells  Masanobu Sakaguchi, Masahiro Oka, Tetsushi Iwasaki, Yasuo Fukami,
B7-H3 Associated with Tumor Progression and Epigenetic Regulatory Activity in Cutaneous Melanoma  Jinhua Wang, Kelly K. Chong, Yoshitaka Nakamura, Linhda.
Presentation transcript:

Activin A Is Anti-Lymphangiogenic in a Melanoma Mouse Model Magdalena Heinz, Heide Leb Niederleithner, Emmi Puujalka, Ana Soler-Cardona, Michael Grusch, Hubert Pehamberger, Robert Loewe, Peter Petzelbauer  Journal of Investigative Dermatology  Volume 135, Issue 1, Pages 212-221 (January 2015) DOI: 10.1038/jid.2014.328 Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Human primary melanomas have an increased INHBA to follistatin ratio compared with nevi and metastasis. (a) Quantified expression of immunohistochemistry staining for the inhibin βA subunit (INHBA) and follistatin (FST) in human nevi (n=19), primary melanoma (SSM; n=10), and metastasized melanoma (Mel met; n=81). *P<0.05. (b) Examples for immunohistochemistry stainings for FST and INHBA expression in a nevus and a primary melanoma. Antibody binding is visualized by red color; counterstaining with hematoxylin is blue. Isotype controls for the respective antibodies are shown at the bottom; corresponding H&E sections are shown at the right side. Bars = 100 μm. H&E, hematoxylin and eosin; INHBA, inhibin βA subunit; SSM, superficial spreading melanoma. Journal of Investigative Dermatology 2015 135, 212-221DOI: (10.1038/jid.2014.328) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Protein and gene expression profiles of melanomas transduced with the indicated transgenes. After intradermal injection of A375 cells overexpressing the indicated genes, arising tumors were excised at day 22 and tested for the expression of transgenes by immunohistochemistry (a) and real-time PCR (b). (a) Cell lines used are indicated in the top row; respective primary antibodies are shown at the left border; antibody binding is visualized by red color, and counterstaining with hematoxylin is blue. Images in the right row are isotype controls. Bar = 100 μm (for anti-vimentin stains 500 μm). (b) mRNA expression determined by real-time PCR. Of note, INHBA does not reduce VEGF-C expression; mean±SD; *P<0.05; n=5 per group. FST, follistatin; INHBA, inhibin βA subunit; VEGF, vascular endothelial growth factor. Journal of Investigative Dermatology 2015 135, 212-221DOI: (10.1038/jid.2014.328) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Activin does not interfere with melanoma metastasis. (a) Examples for anti-Lyve-1 stainings (red color) for lymphatic vessels in primary melanoma overexpressing indicated genes; arrows indicate lymphatic vessels filled with tumor cells in control and INHBA tumors, but narrow and empty vessels in Wnt1+ melanoma. Bar = 100 μm. (b) Lymph vessels surrounding primary tumors that contained tumor cells were counted and calculated as the percentage of the total lymph vessels in each section. Mean±SD; *P<0.05. (c) Summary of positive sentinel lymph nodes through an observation time of 70 days following tumor excision. An example for a negative and a positive lymph node metastasis, as determined by anti-vimentin stainings (red color), is exemplified in the inserted images. Bar = 200 μm. FST, follistatin; INHBA, inhibin βA subunit. Journal of Investigative Dermatology 2015 135, 212-221DOI: (10.1038/jid.2014.328) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Activin A reduces lymph vessel formation. (a) Peritumoral Lyve-1+ lymphatic vessels and (b) CD31+ vessels were counted in immunohistochemistry sections stained with the respective antibody. Positive vessels were counted in a 250-μm zone surrounding the tumor, as exemplified in images to the right (bar = 100 μm). Data summarize the results of two independent experiments with n>5 in each group. In addition, Lyve-1 mRNA expression was determined in melanoma samples by real-time PCR and is expressed as fold change compared with controls (insert in a), n=5 per group; mean±SD; *P<0.05. FST, follistatin; INHBA, inhibin βA subunit. Journal of Investigative Dermatology 2015 135, 212-221DOI: (10.1038/jid.2014.328) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Activin A increases melanoma migration in vitro. (a) A375 cells overexpressing the indicated genes were seeded in 96-well plates (2,000 cells per well), and proliferation was determined using the EZ4U kit, n=6 per group. (b) In vitro wound healing assay of indicated melanoma cells, representative example of three independent experiments. (c) Comparative analysis of human melanoma cells VM-1, -30, and -34, stimulated with medium as control, human recombinant Wnt3a (25 ng), ActA (10 ng), or TGF-β (10 ng). Top: western blot for SMAD2 (loading control) and phosphorylated SMAD2 (pSMAD2); the quantification of pSMAD2 is given as % increase compared with controls. Middle: proliferation assays (104 cells per well in 24-well plates; quantification by Picogreen kit). Bottom: migration is depicted as percent wound closure. ActA, activin A; FST, follistatin; INHBA, inhibin βA subunit; TGF-β, transforming growth factor-β. Journal of Investigative Dermatology 2015 135, 212-221DOI: (10.1038/jid.2014.328) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Activin A decreases lymphatic sprout formationin vitro. In vitro spheroid sprouting assay of lymphatic endothelial cells; summary of three independent experiments with n=10 per group. VEGF-C was used as a positive control. Fresh medium without the addition of growth factors served as a negative (Neg.) control; mean±SD; *P<0.05. Inserted images are examples of spheroids stimulated with supernatants of control or INHBA A375 cells. INHBA, inhibin βA subunit; VEGF, vascular endothelial growth factor. Journal of Investigative Dermatology 2015 135, 212-221DOI: (10.1038/jid.2014.328) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions