Excerpt
Prostate-specific membrane antigen (PSMA) is a transmembrane aminopeptidase with catalytic activity, encoded by the FOLH1 (folate hydrolase 1) gene [
1], consisting of a large extracellular domain, a small transmembrane domain, and a short cytoplasmic tail [
2]. This protein is physiologically expressed in both prostatic epithelial cells and other healthy tissues, including the renal cortex, duodenum, ileum, salivary and lacrimal glands, coeliac, and stellate ganglia [
3]. PSMA is involved in folate and glutamate uptake, metabolism, and signalling, and it plays a role in several processes, including the promotion of excitatory neural transmission in glial cells and the uptake of dietary folates in the duodenum [
4]. Nevertheless, the physiological function of PSMA in the prostate is less clear, although it is suggested to contribute to genomic stability [
5]. The complex regulation of PSMA involves different molecular pathways including the androgen receptor, DNA damage response, and PI3K/Akt/mTOR signalling pathways [
6]. Moreover, PSMA might be involved in cancer-related angiogenesis, playing a role in extracellular matrix degradation, tumor invasion, and integrin signal transduction [
7]. Prostate cancer cells have up to 1000-fold higher PSMA expression than benign tissue. Previous studies reported an enhanced PSMA expression in high-grade or metastatic disease, whereas low PSMA levels were found in low-risk disease [
3]; in addition, elevated PSMA expression was associated with hormone-refractory prostate cancer [
8], poor clinical outcome [
9], and the presence of deficient DNA damage repair pathways [
5]. These findings promoted theranostic applications of radio-labelled PSMA ligands that reached an established role in the management of prostate cancer [
6,
10‐
12]. Furthermore, increased PSMA expression has also been found in the neovascular endothelial cells of various malignancies, including renal clear cell carcinoma, hepatocarcinoma, salivary gland cancer, and glioblastoma [
13], raising the possibility of PSMA-targeting in many other tumors. …
