Thrombospondin 1 and 2 along with PEDF inhibit angiogenesis and promote lymphangiogenesis in intrahepatic cholangiocarcinoma.

Angiogenesis Inducing Agents / metabolism Angiogenesis Inhibitors / pharmacology Animals Cholangiocarcinoma / etiology Disease Models, Animal Lymphangiogenesis / drug effects Mice Proteomics / methods Thrombospondin 1 / administration & dosage Thrombospondins / administration & dosage Tumor Microenvironment / drug effects
Tumor microenvironment angiogenesis extracellular matrix lymphangiogenesis proteomics

Journal

Journal of hepatology
ISSN: 1600-0641
Titre abrégé: J Hepatol
Pays: Netherlands
ID NLM: 8503886

Informations de publication

Date de publication:
12 2021
Historique:
received: 28 01 2021
revised: 13 07 2021
accepted: 15 07 2021
pubmed: 31 7 2021
medline: 9 2 2022
entrez: 30 7 2021
Statut: ppublish

Résumé

The microenvironment of intrahepatic cholangiocarcinoma (iCCA) is hypovascularized, with an extensive lymphatic network. This leads to rapid cancer spread into regional lymph nodes and the liver parenchyma, precluding curative treatments. Herein, we investigated which factors released in the iCCA stroma drive the inhibition of angiogenesis and promote lymphangiogenesis. Quantitative proteomics was performed on extracellular fluid (ECF) proteins extracted both from cancerous and non-cancerous tissues (NCT) of patients with iCCA. Computational biology was applied on a proteomic dataset to identify proteins involved in the regulation of vessel formation. Endothelial cells incubated with ECF from either iCCA or NCT specimens were used to assess the role of candidate proteins in 3D vascular assembly, cell migration, proliferation and viability. Angiogenesis and lymphangiogenesis were further investigated in vivo by a heterotopic transplantation of bone marrow stromal cells, along with endothelial cells in SCID/beige mice. Functional analysis of upregulated proteins in iCCA unveils a soluble angio-inhibitory milieu made up of thrombospondin (THBS)1, THBS2 and pigment epithelium-derived factor (PEDF). iCCA ECF was able to inhibit in vitro vessel morphogenesis and viability. Antibodies blocking THBS1, THBS2 and PEDF restored tube formation and endothelial cell viability to levels observed in NCT ECF. Moreover, in transplanted mice, the inhibition of blood vessel formation, the de novo generation of the lymphatic network and the dissemination of iCCA cells in lymph nodes were shown to depend on THBS1, THBS2 and PEDF expression. THBS1, THBS2 and PEDF reduce blood vessel formation and promote tumor-associated lymphangiogenesis in iCCA. Our results identify new potential targets for interventions to counteract the dissemination process in iCCA. Intrahepatic cholangiocarcinoma is a highly aggressive cancer arising from epithelial cells lining the biliary tree, characterized by dissemination into the liver parenchyma via lymphatic vessels. Herein, we show that the proteins THBS1, THBS2 and PEDF, once released in the tumor microenvironment, inhibit vascular growth, while promoting cancer-associated lymphangiogenesis. Therefore, targeting THBS1, THBS2 and PEDF may be a promising strategy to reduce cancer-associated lymphangiogenesis and counteract the invasiveness of intrahepatic cholangiocarcinoma.

Sections du résumé

BACKGROUND & AIMS
The microenvironment of intrahepatic cholangiocarcinoma (iCCA) is hypovascularized, with an extensive lymphatic network. This leads to rapid cancer spread into regional lymph nodes and the liver parenchyma, precluding curative treatments. Herein, we investigated which factors released in the iCCA stroma drive the inhibition of angiogenesis and promote lymphangiogenesis.
METHODS
Quantitative proteomics was performed on extracellular fluid (ECF) proteins extracted both from cancerous and non-cancerous tissues (NCT) of patients with iCCA. Computational biology was applied on a proteomic dataset to identify proteins involved in the regulation of vessel formation. Endothelial cells incubated with ECF from either iCCA or NCT specimens were used to assess the role of candidate proteins in 3D vascular assembly, cell migration, proliferation and viability. Angiogenesis and lymphangiogenesis were further investigated in vivo by a heterotopic transplantation of bone marrow stromal cells, along with endothelial cells in SCID/beige mice.
RESULTS
Functional analysis of upregulated proteins in iCCA unveils a soluble angio-inhibitory milieu made up of thrombospondin (THBS)1, THBS2 and pigment epithelium-derived factor (PEDF). iCCA ECF was able to inhibit in vitro vessel morphogenesis and viability. Antibodies blocking THBS1, THBS2 and PEDF restored tube formation and endothelial cell viability to levels observed in NCT ECF. Moreover, in transplanted mice, the inhibition of blood vessel formation, the de novo generation of the lymphatic network and the dissemination of iCCA cells in lymph nodes were shown to depend on THBS1, THBS2 and PEDF expression.
CONCLUSIONS
THBS1, THBS2 and PEDF reduce blood vessel formation and promote tumor-associated lymphangiogenesis in iCCA. Our results identify new potential targets for interventions to counteract the dissemination process in iCCA.
LAY SUMMARY
Intrahepatic cholangiocarcinoma is a highly aggressive cancer arising from epithelial cells lining the biliary tree, characterized by dissemination into the liver parenchyma via lymphatic vessels. Herein, we show that the proteins THBS1, THBS2 and PEDF, once released in the tumor microenvironment, inhibit vascular growth, while promoting cancer-associated lymphangiogenesis. Therefore, targeting THBS1, THBS2 and PEDF may be a promising strategy to reduce cancer-associated lymphangiogenesis and counteract the invasiveness of intrahepatic cholangiocarcinoma.

Identifiants

DOI: 10.1016/j.jhep.2021.07.016 PMID: 34329660
pubmed: 34329660
pii: S0168-8278(21)01947-4
doi: 10.1016/j.jhep.2021.07.016
pii:
doi:

Substances chimiques

Angiogenesis Inducing Agents 0
Angiogenesis Inhibitors 0
Thrombospondin 1 0
Thrombospondins 0
thrombospondin 2 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1377-1386

Informations de copyright

Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Conflict of interest The authors of this study have no conflict of interest to declare. Please refer to the accompanying ICMJE disclosure forms for further details.

Auteurs

Guido Carpino (G)

Division of Health Sciences, Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy.

Vincenzo Cardinale (V)

Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza University of Rome, Rome, Italy.

Alessandra Di Giamberardino (A)

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.

Diletta Overi (D)

Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy.

Samantha Donsante (S)

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.

Tania Colasanti (T)

Rheumatology Unit, Department of Clinical Internal, Anesthetic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

Gaia Amato (G)

Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.

Gianluca Mennini (G)

General Surgery and Organ Transplantation Unit, Department of General Surgery and Surgical Specialties P. Stefanini, Sapienza University of Rome, Rome, Italy.

Matteo Franchitto (M)

Department of Medical-Surgical Sciences and Translation Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy.

Fabrizio Conti (F)

Rheumatology Unit, Department of Clinical Internal, Anesthetic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

Massimo Rossi (M)

General Surgery and Organ Transplantation Unit, Department of General Surgery and Surgical Specialties P. Stefanini, Sapienza University of Rome, Rome, Italy.

Mara Riminucci (M)

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.

Eugenio Gaudio (E)

Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy.

Domenico Alvaro (D)

Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.

Carmine Mancone (C)

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy. Electronic address: carmine.mancone@uniroma1.it.

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Classifications MeSH

questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Substances de croissance › Modulateurs d'angiogenèse › Agents angiogéniques › Thrombospondin 1 and 2 along with PEDF inhibit...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › Inhibiteurs de l'angiogenèse › Thrombospondin 1 and 2 along with PEDF inhibit...
questionsmedicales.fr › Eucaryotes › Animaux › Thrombospondin 1 and 2 along with PEDF inhibit...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs épithéliales épidermoïdes et glandulaires › Carcinomes › Adénocarcinome › Cholangiocarcinome › Thrombospondin 1 and 2 along with PEDF inhibit...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Thrombospondin 1 and 2 along with PEDF inhibit...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Morphogenèse › Lymphangiogenèse › Thrombospondin 1 and 2 along with PEDF inhibit...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Thrombospondin 1 and 2 along with PEDF inhibit...
questionsmedicales.fr › Disciplines des sciences naturelles › Chimie › Biochimie › Protéomique › Thrombospondin 1 and 2 along with PEDF inhibit...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Glycoprotéines membranaires › Thrombospondines › Thrombospondine-1 › Thrombospondin 1 and 2 along with PEDF inhibit...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Glycoprotéines membranaires › Thrombospondines › Thrombospondin 1 and 2 along with PEDF inhibit...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Microenvironnement cellulaire › Microenvironnement tumoral › Thrombospondin 1 and 2 along with PEDF inhibit...