The cytokine pigment epithelium–derived factor (PEDF) is downregulated in brain metastases of breast cancer by approximately 14-fold compared with primary breast tumors, suggesting that promoting its expression might inhibit metastatic spread. Normal breast epithelial cells express high levels of PEDF; loss of expression of PEDF from these cells is correlated with cancer progression, and level of expression is inversely related to survival in breast cancer.
PEDF was discovered as a secreted factor from human retinal pigment epithelial cells that showed potent neuronal differentiation activity. It has a broad expression pattern, with high levels also being found in brain and blood. A number of studies have shown that PEDF has a striking ability to protect neurons from a variety of insults, and it has been implicated as a regulatory factor in numerous processes, including lipid metabolism, stem cell renewal, modulation of inflammatory response, antiangiogenesis, and tumor suppression.
New Pharmacologic Targets
In a recent study, Fitzgerald and colleagues from the National Institutes of Health, Bethesda, Maryland, showed that treatment with PEDF exerted tumor-suppressive and neuroprotective effects in experimental brain metastases. Growth of brain-tropic human (231-BR) and mouse (4T1-BR5) breast cancer cells was suppressed in vitro by treatment with PEDF. Expression of PEDF by breast cancer cells (induced via transduction with a human PEDF transgene) rapidly inhibited proliferation and activated apoptosis of breast cancer cells in the mouse brain. The suppressive effects of PEDF were rapid and independent of antiangiogenic effects. Further, PEDF had a prosurvival effect on neurons that shielded the brain from tumor-induced damage, as indicated by a relative 3.5-fold reduction in the number of dying neurons adjacent to tumors expressing PEDF.
As stated by the investigators, “[Our findings] prompt the exciting hypothesis that PEDF can prevent some of the neuronal and cognitive sequelae associated with the development of brain metastases, both by tumor-suppressive and neuroprotective effects…. Differential expression of [PEDF] receptors on neuronal, endothelial, and cancer cells may provide a partial explanation for the differential effects on these cell populations. Identification of which of these PEDF receptors are present on cancer cells, as well as further elucidation of signaling downstream of PEDF, could lead to the identification of new pharmacologic targets for both anti-cancer and neuronal survival therapies.” ■
Fitzgerald DP, et al: Cancer Res 72:144-153, 2012.