The Role of Pigment Epithelium‐Derived Factor’s Anti‐Angiogenic Properties on Tumor Suppression

Abstract

Pigment epithelium‐derived factor (PEDF) is a multimodal secreted glycoprotein of roughly 50kDa size and 418 amino acids in length and is found in the interphotoreceptor matrix (ICM) that holds a variety of biological functions. It is a member of the non‐inhibitory serpin family and was first identified as a neurotrophic factor in retinal pigment epithelial cells, however, it has also been identified in several tissues throughout the body including the heart, lung, brain, and pancreas. PEDF is highly conserved throughout evolution and is known to possess neurotrophic, neuroprotective, anti‐tumorigenic, anti‐metastatic properties, and anti‐angiogenic properties. Indeed, PEDF is known as one of the most potent naturally occurring anti‐angiogenic agent. Angiogenesis plays a critical role in the development of cancer because it stimulates the formation of new blood vessels which carry blood to the tumor thereby providing it unlimited access to critical nutrients and oxygen needed for sustained growth and metastatic spread. Hence, the ability of PEDF to block angiogenesis highlights its potential as a novel anti‐cancer agent. Apart from inhibiting angiogenesis, PEDF also inhibits cancer cell proliferation and induces programmed cell death (apoptosis) through activation of FasR/FasL death signaling pathway. The importance of PEDF in cancer is validated by the fact that its expression is significantly reduced in several types of cancers and that loss of PEDF expression is associated with aggressive disease and poor overall survival. Indeed, PEDF expression has been shown to be markedly reduced in breast tumors compared with normal breast tissue and loss of PEDF is associated with resistance to anti‐endocrine therapy due to activation of two critical breast cancer proteins; the estrogen receptor (ER) and the Rearranged during Transfection (RET) proteins. The unique biology of the PEDF protein is directly related to its structure. PEDF is asymmetrically charged, one side being highly acidic the other highly basic, giving it a polar structure that has two functional epitopes. The acidic region contains a 34‐mer peptide that interacts with the PEDF‐RA receptor identified in endothelial cells. When this interaction occurs, apoptosis is initiated, epithelial cell migration is blocked, and corneal angiogenesis is induced. On the other hand, the basic region consists of a 44‐mer peptide that interacts with the PEDF‐RN receptor which has been identified on Y‐79 cells, cerebellar and motor neurons, and in the neural retina. When this epitope is activated, PEDF assists in conducting neural differentiation.Support or Funding InformationThe Olathe North MSOE Center for BioMolecular Modeling SMART Team used 3‐D modeling and printing technology to examine structure‐function of PEDF