Loss of cIAP1 in Endothelial Cells Limits Metastatic Extravasation through Tumor-Derived Lymphotoxin Alpha
Lazaros Vasilikos1, Kay Hänggi1, Lisanne M Spilgies1
1Institute of Experimental Immunology, University of Zurich, CH-8057 Zurich, Switzerland.
Abstract:
In this study, we determined whether Smac mimetics play a role in metastasis, specifically in circulation, tumor extravasation and growth in a metastatic site. Reports suggest inducing the degradation of IAPs through use of Smac mimetics, alters the ability of the tumor cell to metastasize. However, a role for the immune or stromal compartment in affecting the ability of tumor cells to metastasize upon loss of IAPs has not been defined. To address this open question, we utilized syngeneic tumor models in a late-stage model of metastasis. Loss of cIAP1 in the endothelial compartment, rather than depletion of cIAP2 or absence of cIAP1 in the hematopoietic compartment, caused reduction of tumor load in the lung. Our results underline the involvement of the endothelium in hindering tumor cell extravasation upon loss of cIAP1, in contrast to the immune compartment. Endothelial specific depletion of cIAP1 did not lead to cell death but resulted in an unresponsive endothelium barrier to permeability factors causing a decrease in tumor cell extravasation. Surprisingly, lymphotoxin alpha (LTA), and not TNF, secreted by the tumor cells, was critical for the extravasation. Using TCGA, we found high LTA mRNA expression correlated with decreased survival in kidney carcinoma and associated with advanced disease stage. Our data suggest that Smac mimetics, targeting cIAP1/2, reduce metastasis to the lung by inhibiting tumor cell extravasation.
Insights
Smac mimetics targeting cellular inhibitor of apoptosis proteins (cIAPs) reduce lung metastasis by inhibiting tumor cell extravasation. Endothelial cIAP1 loss hinders metastasis, with lymphotoxin alpha (LTA) being critical for extravasation.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Smac mimetics degrade inhibitor of apoptosis proteins (IAPs), potentially altering tumor metastasis.
- The role of immune or stromal compartments in metastasis following IAP loss is undefined.
Purpose of the Study:
- To investigate the role of Smac mimetics in metastasis, focusing on tumor cell circulation, extravasation, and growth.
- To define the specific roles of endothelial, hematopoietic, and stromal compartments in metastasis upon IAP loss.
Main Methods:
- Utilized syngeneic tumor models in a late-stage metastasis setting.
- Investigated the effects of cIAP1 and cIAP2 depletion in various cellular compartments (endothelial, hematopoietic).
- Analyzed the role of lymphotoxin alpha (LTA) and TNF in tumor cell extravasation using TCGA data.
Main Results:
- Endothelial cIAP1 loss, not cIAP2 depletion or hematopoietic absence of cIAP1, reduced lung tumor load.
- Endothelial cIAP1 depletion hindered tumor cell extravasation without causing cell death.
- Tumor cell-secreted lymphotoxin alpha (LTA), not TNF, was critical for extravasation.
- High LTA mRNA expression correlated with decreased survival and advanced disease in kidney carcinoma.
Conclusions:
- Endothelium, specifically endothelial cIAP1, plays a crucial role in hindering tumor cell extravasation.
- Smac mimetics targeting cIAP1/2 can reduce lung metastasis by inhibiting tumor cell extravasation.
- LTA is a key mediator of tumor cell extravasation and a potential prognostic marker.
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