Prostate-Specific Membrane Antigen Biology and Pathophysiology in Prostate Carcinoma, an Update: Potential Implications for Targeted Imaging and Therapy
Abstract
:1. Introduction
2. Prostate Specific Membrane Antigen (PSMA)
2.1. Structure
2.2. Enzymatic Function
2.3. Internalization of PSMA and Routing to the Endocytic Compartment
2.4. Regulation of PSMA Expression and PSMA Splice Variants
3. PSMA in Prostate Carcinoma
3.1. Pathophysiology
3.2. PSMA and ADT in Prostate Carcinoma
4. Discussion
4.1. Altered PSMA-Glycosylation on Prostate Carcinoma, Potential for Optimization of RLT Efficacy
4.2. Evidence Linking Folates to the Development and Growth of Prostate Carcinoma
4.3. Glutamate Released from Gamma-Polyglutamated-Folates by PSMA, Not Such an Innocent Bystander
4.4. PSMA Expression in Prostate Carcinoma, Its Evolution over Time and Relationship with Androgen Signaling and Changes in DNA Methylation
4.5. Imaging Options in PSMA Low/Negative Prostate Carcinoma
4.6. Impact of ADT on PSMA Expression in Prostate Carcinoma and Implications for PSMA-Targeted Imaging and RLT
Funding
Conflicts of Interest
References
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Authors | Technique | Material Derived from | Results |
---|---|---|---|
Sweat et al. [31] | IHC | −232 pts, RP+lymphadenectomy | 100% of ppc +, 98% of LN PSMA+ |
Mannweiler et al. [32] | IHC | −51 pts, ppc and distant lesions | 49/51 ppc+, 43/51 distant lesions + |
Sayar et al. [26] | IHC Gene set enrichment analysis | UW-TAN cohort), 636 samples, 339 distant metastatic sites), LuCa PDX, UW-TAN, and SU2C cohorts | - trend ↓ PSMA expression in AR- v. AR+, bimodal expression, intra-tumoral PSMA heterogeneity, PSMA expression on neovasculature - PSMA low/-lesions show ↑ glycolysis, hypoxia, inflammation, upregulation of MUC1, gain of CpG methylation and loss of histone3lysine27 acetylation |
Bakht et al. [22] | - transcriptome analysis | - SUC2 and PCF cohorts | ↓ PSMA expression in liver M+, associated with promotor histone 3 lysine methylation and ↑neutral amino acid transporters, a subset of AR-/PSMA++ |
Paschalis et al. [33] | - IHC | - 38CSPC tissue samples, 59 mCRPC biopsies (matched) | Ratio PSMA expression mCRPC/CSPC approximating 3, 16/38 CSPC and 16/59mCRPC PSMA- |
Kaiitanis et al. [29] | genomic data analysis, IHC, and gene enrichment analysis, tissue microarray analysis | MSCKK cohort PMID 25024180 −6 pts | ↑ PSMA expression is associated with faster biochemical recurrence and metastases changes in transcription of mTOR-regulated genes- Akt phosphorylation |
Su et al. [34] | RNAse protection assays | normal/hyperplastic and cancerous prostate tissue | PSM/PSMA ratio’s; 0.075–045 in normal tissue, 0.75–1.6 in hyperplastic tissue, and 3–6 in cancerous tissue |
Schmittgen et al. [35] | Quantitative PCR | normal/cancerous tissue (45 ppc/6 involvedLN/14 M+) | PSM’ ↑↑ in metastases |
Authors | Study Type | Nb of Patients | Treatment Duration, Range | Results |
---|---|---|---|---|
Afshar Oromieh et al. [43] | retrospective | 10 | 42–396 d | 14/31 lesions + in 8 pts, 1/3rd of lesions still + in 6 pts with a complete PSA response |
Höberuck et al. [44] | retrospective | 21 | 61–289 d | ↓in all pts, in pts with post-therapy PSA <1 ng/mL, 49 lesions no longer visible |
Gupta et al. [45] | retrospective | 43 | 3–12 m | After a median treatment duration of 6 months, 23.3% of LN and 17.6% of M+ were no longer visible, ↓ in the PSMA signal ↑ in M0 vs. M1 disease |
Emmett et al. [46] | prospective | 15 | 28 d (imaging on d9, d18 and d28 post-treatment | In 8 hormone-sensitive patients, uptake progressively ↓ (LHRH +/− bicalutamide) In the 7 castration-resistant pts, uptake progressively ↑ (enzalutamide or arbiraterone)) |
Ettala et al. [47] | prospective | 9 | 6.2 w (imaging at 1.5 w, 2.9 w and 6.2 weeks post-treatment) | In 1 pt, 3 new bone M+ were identified; in 7 pts, lesion count ↑; in 2 pts, no change was found |
Malaspina et al. [48] | prospective | 25 | 3–4 w | 104/404 bone M+,33/314 LN and 6/57 ppc showed an ↑ in tracer uptake, in 22/23 pts with bone M+ a flare phenomenon was found |
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Maes, J.; Gesquière, S.; De Spiegeleer, A.; Maes, A.; Van de Wiele, C. Prostate-Specific Membrane Antigen Biology and Pathophysiology in Prostate Carcinoma, an Update: Potential Implications for Targeted Imaging and Therapy. Int. J. Mol. Sci. 2024, 25, 9755. https://doi.org/10.3390/ijms25179755
Maes J, Gesquière S, De Spiegeleer A, Maes A, Van de Wiele C. Prostate-Specific Membrane Antigen Biology and Pathophysiology in Prostate Carcinoma, an Update: Potential Implications for Targeted Imaging and Therapy. International Journal of Molecular Sciences. 2024; 25(17):9755. https://doi.org/10.3390/ijms25179755
Chicago/Turabian StyleMaes, Justine, Simon Gesquière, Anton De Spiegeleer, Alex Maes, and Christophe Van de Wiele. 2024. "Prostate-Specific Membrane Antigen Biology and Pathophysiology in Prostate Carcinoma, an Update: Potential Implications for Targeted Imaging and Therapy" International Journal of Molecular Sciences 25, no. 17: 9755. https://doi.org/10.3390/ijms25179755