Header

UZH-Logo

Maintenance Infos

The Role of Endothelium in Organ-Specific Metastasis


Biglieri, Elisabetta. The Role of Endothelium in Organ-Specific Metastasis. 2021, University of Zurich, Faculty of Medicine.

Abstract

Metastasis is a complex multistep process where tumor cells interact with endothelial cells, fibroblasts and immune cells during seeding and survival in the metastatic niche. The crosstalk between activated endothelial cells, which express well-known adhesion molecules E-selectin, VCAM-1 and ICAM-1, and tumor cells, is essential for extravasation and metastatic progression. However, the specific role of endothelial cells in organ-specific metastasis remains poorly understood. This study aimed to identify potential endothelial-derived factors essential for liver and lung metastasis.
From the transcriptomic analysis of liver endothelial cells from two colon cancer mouse models, we identified overexpressed genes involved in leukocyte migration, cell adhesion, regulation of vascular development and inflammatory response. In parallel, liver endothelial cells from breast cancer model upregulate genes involved extracellular matrix remodeling, cell adhesion and angiogenesis. We identified potential factors, such as fibronectin, Egfr, Tubb3 and Tnfrsf9, which need further investigations for their role in liver metastasis in vivo.
The analysis of endothelial expression profile from metastatic lungs of two cancer models highlighted genes involved in leukocyte migration, cell chemotaxis, cell adhesion, regulation of inflammatory response and vascular development. We identified the TNF family protein receptor Tnfrsf9, or CD137, to be upregulated in the metastatic foci and further studied its role in metastasis. Endothelial deletion of CD137 enhanced tumor growth of LLC1.1 tumors through alterations in tumor angiogenesis. Specifically, reduced number of vessels as well as size of vessels was associated with enhanced functionality, perfusion. Further tumor analysis showed a decreased infiltration and cytotoxic function of lymphocytes in endothelial CD137-deficient mice, which is in line with the enhanced tumorigenesis. Importantly, experimental and spontaneous metastasis of LLC1.1 tumor cells were increased in endothelial CD137-deficient mice. The analysis of lung metastatic foci showed a decrease infiltration of interstitial macrophages, alveolar macrophages and decreased activation of M1 polarized macrophages in metastatic lungs of ecCD137-deficient mice. In addition, reduced infiltration and cytotoxic activity of CD8+ T cells was observed in metastatic foci of ecCD137-deficient mice.
Overall, our study opens a new research area of potential endothelial-derived factors essential for liver and lung metastasis. Furthermore, we provide a novel role of endothelial CD137 in tumor growth, angiogenesis, immune modulation and metastasis. Targeting endothelial CD137 represent a promising treatment strategy to prevent tumorigenesis and metastatic spread to the lung.

Abstract

Metastasis is a complex multistep process where tumor cells interact with endothelial cells, fibroblasts and immune cells during seeding and survival in the metastatic niche. The crosstalk between activated endothelial cells, which express well-known adhesion molecules E-selectin, VCAM-1 and ICAM-1, and tumor cells, is essential for extravasation and metastatic progression. However, the specific role of endothelial cells in organ-specific metastasis remains poorly understood. This study aimed to identify potential endothelial-derived factors essential for liver and lung metastasis.
From the transcriptomic analysis of liver endothelial cells from two colon cancer mouse models, we identified overexpressed genes involved in leukocyte migration, cell adhesion, regulation of vascular development and inflammatory response. In parallel, liver endothelial cells from breast cancer model upregulate genes involved extracellular matrix remodeling, cell adhesion and angiogenesis. We identified potential factors, such as fibronectin, Egfr, Tubb3 and Tnfrsf9, which need further investigations for their role in liver metastasis in vivo.
The analysis of endothelial expression profile from metastatic lungs of two cancer models highlighted genes involved in leukocyte migration, cell chemotaxis, cell adhesion, regulation of inflammatory response and vascular development. We identified the TNF family protein receptor Tnfrsf9, or CD137, to be upregulated in the metastatic foci and further studied its role in metastasis. Endothelial deletion of CD137 enhanced tumor growth of LLC1.1 tumors through alterations in tumor angiogenesis. Specifically, reduced number of vessels as well as size of vessels was associated with enhanced functionality, perfusion. Further tumor analysis showed a decreased infiltration and cytotoxic function of lymphocytes in endothelial CD137-deficient mice, which is in line with the enhanced tumorigenesis. Importantly, experimental and spontaneous metastasis of LLC1.1 tumor cells were increased in endothelial CD137-deficient mice. The analysis of lung metastatic foci showed a decrease infiltration of interstitial macrophages, alveolar macrophages and decreased activation of M1 polarized macrophages in metastatic lungs of ecCD137-deficient mice. In addition, reduced infiltration and cytotoxic activity of CD8+ T cells was observed in metastatic foci of ecCD137-deficient mice.
Overall, our study opens a new research area of potential endothelial-derived factors essential for liver and lung metastasis. Furthermore, we provide a novel role of endothelial CD137 in tumor growth, angiogenesis, immune modulation and metastasis. Targeting endothelial CD137 represent a promising treatment strategy to prevent tumorigenesis and metastatic spread to the lung.

Statistics

Downloads

8 downloads since deposited on 26 Jan 2022
3 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Dissertation (monographical)
Referees:Borsig Lubor, Hennet Thierry, Halin Winter Cornelia, Ruegg Curzio
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

UZH Dissertations
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Place of Publication:Zurich
Date:15 July 2021
Deposited On:26 Jan 2022 13:11
Last Modified:26 Jan 2022 13:11
OA Status:Closed