Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is a hallmark of cancer. In fact, tumor vascularization is required to support cancer growth, supplying oxygen and nutrients to tumor cells, and represents also an important route for metastatization. In this context, Multimerin-2 an extracellular matrix protein specifically deposited along blood vessels, plays an important role. This study started from the observation that in ovarian, breast, gastric and colon cancer samples the expression of Multimerin-2 is lost in a number of vessels. We next verified the effects of Multimerin-2 down-regulating its expression in endothelial cells and demonstrated that Multimerin-2 was necessary for proper cell-to-cell contact formation thus exerting a homeostatic function. In particular, Multimerin-2 loss led to the dismantlement of VE-cadherin lining, causing a strong increase of cell permeability to small molecules. Mechanistically, Multimerin-2 knockdown triggered the phosphorylation of VEGFR2 at Y951, leading to Src activation, and, ultimately VE-cadherin phosphorylation at Y568, which in turn is targeted for internalization and degradation. These results were corroborated in vivo exploiting the Multimerin-2-/- mouse model, in fact blood vessels from Multimerin-2-/- mice displayed abnormal VE-cadherin lining and increased vascular leakage. Furthermore, B16F10 tumor-bearing Multimerin-2-/- mice showed impaired tumor vasculature, characterized by increased permeability and reduced perfusion. As a consequence, the compromised tumor vessels functionality in Multimerin-2-/- mice associated with impaired drug delivery and decreased chemotherapy efficacy. Given that blood vessels represent an important route for the dissemination of cancer cells, we next verified if loss of Multimerin-2 could affect cancer cell dissemination. Indeed, we found that Multimerin-2 depletion favoured cancer cells transmigration through the endothelial barrier through VEGF-A-independent mechanisms. Instead, the down-regulation of Multimerin-2 in endothelial cells associated with a strong increase in the adhesion molecule VCAM1 only under tumor conditions. Consistently, the intravenous injection of B16F10 cells in Multimerin-2-/- mice led to the formation of a higher number of lung metastatic lesions compared to the wild type animals. Taken together these results pinpoint Multimerin-2 as a key molecule for the maintenance of vascular homeostasis. Depending on the levels of Multimerin-2 loss, these pre-clinical results open the possibility to develop a new prognostic marker to predict clinical outcome of cancer patients.

Multimerin-2 maintains vascular homeostasis and controls cancer cells dissemination / Evelina Poletto , 2021 May 06. 33. ciclo, Anno Accademico 2019/2020.

Multimerin-2 maintains vascular homeostasis and controls cancer cells dissemination

POLETTO, EVELINA
2021-05-06

Abstract

Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is a hallmark of cancer. In fact, tumor vascularization is required to support cancer growth, supplying oxygen and nutrients to tumor cells, and represents also an important route for metastatization. In this context, Multimerin-2 an extracellular matrix protein specifically deposited along blood vessels, plays an important role. This study started from the observation that in ovarian, breast, gastric and colon cancer samples the expression of Multimerin-2 is lost in a number of vessels. We next verified the effects of Multimerin-2 down-regulating its expression in endothelial cells and demonstrated that Multimerin-2 was necessary for proper cell-to-cell contact formation thus exerting a homeostatic function. In particular, Multimerin-2 loss led to the dismantlement of VE-cadherin lining, causing a strong increase of cell permeability to small molecules. Mechanistically, Multimerin-2 knockdown triggered the phosphorylation of VEGFR2 at Y951, leading to Src activation, and, ultimately VE-cadherin phosphorylation at Y568, which in turn is targeted for internalization and degradation. These results were corroborated in vivo exploiting the Multimerin-2-/- mouse model, in fact blood vessels from Multimerin-2-/- mice displayed abnormal VE-cadherin lining and increased vascular leakage. Furthermore, B16F10 tumor-bearing Multimerin-2-/- mice showed impaired tumor vasculature, characterized by increased permeability and reduced perfusion. As a consequence, the compromised tumor vessels functionality in Multimerin-2-/- mice associated with impaired drug delivery and decreased chemotherapy efficacy. Given that blood vessels represent an important route for the dissemination of cancer cells, we next verified if loss of Multimerin-2 could affect cancer cell dissemination. Indeed, we found that Multimerin-2 depletion favoured cancer cells transmigration through the endothelial barrier through VEGF-A-independent mechanisms. Instead, the down-regulation of Multimerin-2 in endothelial cells associated with a strong increase in the adhesion molecule VCAM1 only under tumor conditions. Consistently, the intravenous injection of B16F10 cells in Multimerin-2-/- mice led to the formation of a higher number of lung metastatic lesions compared to the wild type animals. Taken together these results pinpoint Multimerin-2 as a key molecule for the maintenance of vascular homeostasis. Depending on the levels of Multimerin-2 loss, these pre-clinical results open the possibility to develop a new prognostic marker to predict clinical outcome of cancer patients.
6-mag-2021
angiogenesis; extracellular matrix; vascular homeostasis; tumor vasculature; tumor growth
tumor growth
Multimerin-2 maintains vascular homeostasis and controls cancer cells dissemination / Evelina Poletto , 2021 May 06. 33. ciclo, Anno Accademico 2019/2020.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11390/1206778
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