Abstract
Vasculogenic mimicry (VM) formed by aggressive tumor cells to create vascular networks connected with the endothelial cells, plays an important role in breast cancer progression. WISP2 has been considered as a tumor suppressor protein; however, the relationship between WISP2 and VM formation remains unclear. We used the in vitro tube formation assay and in vivo immunohistochemical analysis in a mouse model, and human breast tumors were used to evaluate the effect of WISP2 on VM formation. Here we report that WISP2 acts as a potent inhibitor of VM formation in breast cancer. Enforced expression of WISP2 decreased network formation while knockdown of WISP2 increased VM. Mechanistically, WISP2 increased retention of oncogenic activators YAP/TAZ in cytoplasm, leading to decreased expression of the angiogenic factor CYR61. Studies using an in vivo mouse model and human breast tumors confirmed the in vitro cell lines data. In conclusion, our results indicate that WISP2 may play a critical role in VM and highlight the critical role of WISP2 as a tumor suppressor.
Highlights
Breast cancer is the leading cause of cancer death in women due mainly to its ability to metastasize to vital tissues
Because WNT1 inducible signaling pathway protein-2 (WISP2) may act as a dominant-negative regulator of other Cysteine-rich 61/Nephroblastoma overexpressed (CCN) family members, we investigated the impact of WISP2 on the expression levels of cysteine-rich angiogenic inducer 61 (CYR61) known as a pro-angiogenic factor [33,34]
Our study demonstrated an important role of WISP2 in vascular mimicry formation in breast cancer
Summary
Breast cancer is the leading cause of cancer death in women due mainly to its ability to metastasize to vital tissues. It is widely accepted that tumors require blood supply to survive, grow, and metastasize [1]. This concept has been inextricably linked to angiogenesis, a process that corresponds to the growth of new blood vessels within a tumor. Angiogenesis is an important mechanism for tumor growth, survival, and metastatic processes, antiangiogenic drugs were not effective in all cancers, and resistance to these drugs could occur [2,3]. It is well established that tumor vasculogenesis is not necessarily attributed to endothelial cells alone. In some tumors, cancerous tissues may become vascularized by the networks created by the tumor cells themselves through their acquisition of plasticity to mimic endothelial function, a phenomenon called vascular mimicry (VM) [4]. A vascular mimicry–angiogenesis junction has been suggested based on the presence of blood flow in the vascular channels [7]
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