Embryonic endothelial progenitor cells armed with a suicide gene target hypoxic lung metastases after intravenous delivery

Abstract

We show that mouse embryonic endothelial progenitor cells (eEPCs) home preferentially to hypoxic lung metastases when administered intravenously. This specificity is inversely related to the degree of perfusion and vascular density in the metastasis and directly related to local levels of hypoxia and VEGF. Ex vivo expanded eEPCs that were genetically modified with a suicide gene specifically and efficiently eradicated lung metastases with scant patent blood vessels. eEPCs do not express MHC I proteins, are resistant to natural killer cell-mediated cytolysis, and can contribute to tumor vessel formation also in nonsyngeneic mice. These results indicate that eEPCs can be used in an allogeneic setting to treat hypoxic metastases that are known to be resistant to conventional therapeutic regimes.

Endothelial progenitor cells for cancer gene therapy

“…These cells have the potential for systemic cancer gene therapy, as shown in a proof-of-principle study. 54 However, mature embryonic stem cell derivatives are immunogenic and ethical considerations may limit their generation. Thus, additional sources of EPCs have been explored.…”

“…This might circumvent some hurdles that aggravate targeting of solid tumors, such as poor tissue penetration. Tumor vessels are an Achilles' heel of tumors, however, only a minority of systemically administered EPCs incorporate into tumor vessels 15,16,54,59,63 (Figure 1a). This limits the ability of therapeutic EPCs to destroy tumor vessels.…”

“…preferentially home to hypoxic areas of lung metastases. 54 As embryonic EPCs do not express major histocompatibility complex I proteins and are not killed by nonactivated NK cells, they were able to evade immunological rejection. When modified to express the cytosine deaminase gene, these embryonic EPCs exerted a bystander effect on tumor cells upon administration of 5-FC, thus prolonging the life of tumor-bearing mice.…”

“…Looking at EPC recruitment from the tumor's side, inter-and intratumoral heterogeneity has to be taken into account. Hypoxia, for example, is unequally distributed within a tumor and EPCs predominantly home into hypoxic areas 54 ( Figure 1a). Additional investigations are required to define tumors or tumor environments that depend on the recruitment of EPCs and to delineate the molecular mechanisms determining their recruitment.…”

Hypoxia-induced pathological angiogenesis mediates tumor cell dissemination, invasion, and metastasis in a zebrafish tumor model

“…These unusual features often create a hypoxic environment owning to poor blood perfusion, high interstitial fluid pressure (IFP), acidosis, and fast growth as well as metabolic rates of malignant tissues (7,8). Although hypoxia often results in necrosis of the central core of a fast-growing tumor, it could potentially persuade tumor cells to invade neighboring healthy vasculatures for survival, eventually leading to metastasis, which is one of the hallmarks for cancer therapy (9)(10)(11)(12)(13).…”