Endothelial precursor cell-based therapy to target the pathologic angiogenesis and compensate tumor hypoxia

Abstract

Hypoxia-inducing pathologies as cancer develop pathologic and inefficient angiogenesis which rules tumor facilitating microenvironment, a key target for therapy. As such, the putative ability of endothelial precursor cells (EPCs) to specifically home to hypoxic sites of neovascularization prompted to design optimized, site-specific, cell-mediated, drug-/gene-targeting approach. Thus, EPC lines were established from aorta-gonad-mesonephros (AGM) of murine 10.5 dpc and 11.5 dpc embryo when endothelial repertoire is completed. Lines representing early endothelial differentiation steps were selected: MAgEC10.5 and MagEC11.5. Distinct in maturation, they differently express VEGF receptors, VE-cadherin and chemokine/receptors. MAgEC11.5, more differentiated than MAgEC 10.5, displayed faster angiogenesis in vitro, different response to hypoxia and chemokines. Both MAgEC lines cooperated to tube-like formation with mature endothelial cells and invaded tumor spheroids through a vasculogenesis-like process. In vivo, both MAgEC-formed vessels established blood flow. Intravenously injected, both MAgECs invaded Matrigel(TM)-plugs and targeted tumors. Here we show that EPCs (MAgEC11.5) target tumor angiogenesis and allow local overexpression of hypoxia-driven soluble VEGF-receptor2 enabling drastic tumor growth reduction. We propose that such EPCs, able to target tumor angiogenesis, could act as therapeutic gene vehicles to inhibit tumor growth by vessel normalization resulting from tumor hypoxia alleviation.

Capn4 regulates migration and invasion of ovarian carcinoma cells via targeting osteopontin‑mediated PI3K/AKT signaling pathway

“…The results of the present study indicated that Capn4 regulated ovarian cancer cell migration and invasion via the PI3K/AKT signaling pathway. Targeted therapy has much potential as a treatment approach, as it exhibits lower toxicity to normal cells, but not to tumor cells (30)(31)(32). Capn4 is a secreted protein with relevant interactions with numerous migration-and invasion-associated proteins (33).…”

Colony, hanging drop, and methylcellulose three dimensional hypoxic growth optimization of renal cell carcinoma cell lines

“…Cell viability assays using Alamar Blue or MTT solutions can be performed to monitor cell number and health, as in other 3D models (Bonnier et al 2015). Also, obtained structures can be moved and utilized in co-cultures and migration assays (Collet et al 2016). …”

A multi-targeted tyrosine kinase inhibitor lenvatinib for the treatment of mice with advanced glioblastoma

“…Different targeted therapy drugs for cancer treatment are being studied clinically. The targeted therapy agents frequently use tumor cell-specific recognition to inhibit tumor angiogenesis, mediated by suppression of tumor-derived vascular endothelial cells, and have demonstrated encouraging results in the treatment of certain advanced tumors (34,35). However, more targeted therapy agents require development to cater to the needs of an ever-increasing number of cancer patients.…”