Abstract
We have investigated the role of vascular-endothelial (VE)-cadherin in melanoma and breast cancer metastasis. We found that VE-cadherin is expressed in highly aggressive melanoma and breast cancer cell lines. Remarkably, inactivation of VE-cadherin triggered a significant loss of malignant traits (proliferation, adhesion, invasion and transendothelial migration) in melanoma and breast cancer cells. These effects, except transendothelial migration, were induced by the VE-cadherin RGD motifs. Co-immunoprecipitation experiments demonstrated an interaction between VE-cadherin and α2β1 integrin, with the RGD motifs found to directly affect β1 integrin activation. VE-cadherin-mediated integrin signaling occurred through specific activation of SRC, ERK and JNK, including AKT in melanoma. Knocking down VE-cadherin suppressed lung colonization capacity of melanoma or breast cancer cells inoculated in mice, while pre-incubation with VE-cadherin RGD peptides promoted lung metastasis for both cancer types. Finally, an in silico study revealed the association of high VE-cadherin expression with poor survival in a subset of melanoma patients and breast cancer patients showing low CD34 expression. These findings support a general role for VE-cadherin and other RGD cadherins as critical regulators of lung and liver metastasis in multiple solid tumours. These results pave the way for cadherin-specific RGD targeted therapies to control disseminated metastasis in multiple cancers.
Highlights
Metastasis, the final step of malignant transformation, is a complex process with numerous distinct and sequential steps
Compared to non-invasive MCF7, vascular endothelial (VE)-cadherin overexpression was observed in metastatic breast cancer cells (SKBR3, MDA-MB-231 and MDAMB-468) and metastatic melanoma cell lines
We have demonstrated that VE-cadherin plays a major role in the induction of pro-metastatic properties—adhesion, invasion and proliferation—in different melanoma and breast cancer cell lines
Summary
Metastasis, the final step of malignant transformation, is a complex process with numerous distinct and sequential steps. CDH17 activates the α2β1 integrin pathway through specific RGD motifs to promote cell adhesion, proliferation and liver colonization in colorectal cancer metastasis [3, 4]. VE-cadherin is a type II cadherin that contains RGD motifs within different domains (e.g. 1, 2 or 3) in many mammals and birds, but not in rodents or dogs (Supplementary Data Figure 1). VE-cadherin has been used as a target to control tumour angiogenesis www.impactjournals.com/oncotarget in vivo [8] It is expressed in Ewing sarcoma [9], highly aggressive cutaneous melanomas [10] and it is involved in vasculogenic mimicry (the ability to form novel blood vessel-like structures) in uveal melanomas [11]. VE-cadherin is expressed in a subset of acute lymphoblastic leukemia cells, where contributes to cell survival [12], and in a subset of cancer stem cells CD133+ in osteosarcoma, ovarian cancer and glioblastoma, contributing to vasculogenic mimicry by VEGFindependent tumour cell differentiation [13]
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