Pigment Epithelium-Derived Factor and Sex Hormone-Responsive Cancers

Abstract

Oestrogens and androgens play important roles in normal and cancerous tissue and have been shown to negatively regulate pigment epithelium-derived factor (PEDF) expression in sex hormone-responsive tumours. PEDF suppresses tumour growth and its downregulation by oestrogen is implicated in tumorigenesis, metastasis, and progression. PEDF expression is reduced in cancerous tissue of the prostate, breast, ovary, and endometrium compared to their normal tissue counterparts, with a link between PEDF downregulation and sex hormone signalling observed in pre-clinical studies. PEDF reduces growth and metastasis of tumour cells by promoting apoptosis, inhibiting angiogenesis, increasing adhesion, and reducing migration. PEDF may also prevent treatment resistance in some cancers by downregulating oestrogen receptor signalling. By interacting with components of the tumour microenvironment, PEDF counteracts the proliferative and immunosuppressive effects of oestrogens, to ultimately reduce tumorigenesis and metastasis. In this review, we focus on sex hormone regulation of PEDF's anti-tumour action in sex hormone-responsive tumours.

Keywords: androgen; cancer; metastasis; oestrogen; pigment epithelium-derived factor.

Figure 1

The complex interplay between sex hormones and pigment epithelium-derived factor (PEDF) in tumorigenesis and metastasis. This figure focuses on the inhibitory effects of PEDF. Key: ARE, androgen response element; ER, oestrogen receptor; ERE, oestrogen response element; FAK, focal adhesion kinase; Il, interleukin; M2, type of macrophage; MMP, matrix metalloproteinase; PEDFR, PEDF receptor; ROS, reactive oxygen species,; TME, tumour microenvironment; TNF, tumour necrosis factor; uPA, urokinase plasminogen activator; uPAR, uPA receptor; VEGF, vascular endothelial growth factor; ↑↑, increased; ↓↓, decreased. Red arrows and crosses indicate pathways blocked by PEDF; green arrows indicate pathways activated by PEDF. Red fields represent pro-tumour mechanisms and green fields represent anti-tumour mechanisms.

Figure 2

Roles of PEDF in osteotropic tumours and in bone. The metastasis of tumours, such as those in the breast and prostate to bone, requires the activities of such pro-metastatic factors as MT-1-MMP and uPA. Key: dc42, cell division control protein 42 homolog; HSP47, heat shock protein-47; Mcl-1, myeloid cell leukemia 1; MMP, matrix metalloproteinase; MT1-MMP, membrane type-1 metalloproteinase/MMP-14; OPG, osteoprotegerin; PAI-1, plasminogen inhibitor activator-1; VEGF, vascular endothelial growth factor; p-FAK, phosphorylated focal adhesion kinase; RANKL, receptor activator of nuclear factor kappa-Β ligand; RhoA, Ras homolog family member A; red arrow—downregulation; green arrow—upregulation; red markers in bone—tumour cells.