Endothelial Progenitor Cells Promote Osteosarcoma Progression and Invasiveness via AKT/PI3K Signaling

Abstract

Background: Osteosarcoma (OS) mortality is attributed to lung metastases. Endothelial progenitor cells (EPCs) mediate the angiogenic switch in several cancers. The spatial proximity between EPCs and OS in the bone led to the hypothesis that EPCs-osteosarcoma interactions may possibly promote OS progression and aggressiveness. Methods: A PI3K inhibitor, Bevacizumab (an anti-VEGF-A antibody), and an anti-FGF2 antibody were added to the EPCs’ conditioned medium (EPC-CM), and their impacts on OS cell (U2-OS and 143B) proliferation, migration, invasion, MMP9 expression, and AKT phosphorylation were determined. The autocrine role of VEGF-A was assessed using Bevacizumab treatment and VEGF-A silencing in OS cells. Toward this end, an orthotopic mouse OS model was established. Mouse and human tumors were immunolabeled with antibodies to the abovementioned factors. Results: EPC-CM enhanced osteosarcoma MMP9 expression, invasiveness, and migration via the PI3K/AKT pathway. The addition of Bevacizumab and an anti-FGF2 antibody to the EPC-CM diminished OS cell migration. The autocrine role of VEGF-A was assessed using Bevacizumab and VEGF-A silencing in OS cells, resulting in decreased AKT phosphorylation and, consequently, diminished invasiveness and migration. Consistently, OS xenografts in mice displayed high VEGF-A and FGF2 levels. Remarkably, lung metastasis specimens derived from OS patients exhibited marked immunolabeling of CD31, VEGF-A, and FGF2. Conclusions: EPCs promote OS progression not only by physically incorporating into blood vessels, but also by secreting cytokines, which act via paracrine signaling. EPCs induced in vitro MMP9 overexpression, invasion, and migration. Additional animal studies are warranted to further expand these results. These findings may pave the way toward the development of novel EPCs-targeted therapeutics aimed at blocking OS metastasis.

Deciphering the Signaling Mechanisms of Osteosarcoma Tumorigenesis

“…AKT phosphorylates several substrates and downstream effectors, including mTOR, matrix metalloproteinase (MMP), cyclin-dependent kinases (CDKs), and VEGF, associated with tumor progression and metastasis [44,45]. The secretion of VEGF-A and FGF2 from OS cells promotes migration and invasion by activating the PI3K and AKT pathways, eventually leading to MMP9 overexpression [46]. Human epidermal growth factor receptor 4 (HER4), a member of the ERBB family, is upregulated in OS tumor tissue and cell lines, promoting OS progression by inactivating the PTEN-PI3K/AKT pathway [47].…”

CircTMEM165 facilitates endothelial repair by modulating mitochondrial fission via miR-192/SCP2 in vitro and in vivo

“… 26 , 27 One such strategy is the use of circulating endothelial progenitor cells (EPCs), which can differentiate into mature endothelial cells and promote endothelial repair. 28 Studies have shown that the transplantation of EPCs can improve endothelial function and reduce neointimal hyperplasia in animal models of stent implantation. In summary, the adhesion, proliferation and migration, and cell death of endothelial cells are considered as the most important factors in the development of ISR.…”