Abstract
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors arising from chromaffin cells of adrenal medulla or sympathetic or parasympathetic paraganglia, respectively. To identify new therapeutic targets, we performed a detailed membrane-focused proteomic analysis of five human paraganglioma (PGL) samples. Using the Pitchfork strategy, which combines specific enrichments of glycopeptides, hydrophobic transmembrane segments, and non-glycosylated extra-membrane peptides, we identified over 1800 integral membrane proteins (IMPs). We found 45 “tumor enriched” proteins, i.e., proteins identified in all five PGLs but not found in control chromaffin tissue. Among them, 18 IMPs were predicted to be localized on the cell surface, a preferred drug targeting site, including prostate-specific membrane antigen (PSMA), a well-established target for nuclear imaging and therapy of advanced prostate cancer. Using specific antibodies, we verified PSMA expression in 22 well-characterized human PPGL samples. Compared to control chromaffin tissue, PSMA was markedly overexpressed in high-risk PPGLs belonging to the established Cluster 1, which is characterized by worse clinical outcomes, pseudohypoxia, multiplicity, recurrence, and metastasis, specifically including SDHB, VHL, and EPAS1 mutations. Using immunohistochemistry, we localized PSMA expression to tumor vasculature. Our study provides the first direct evidence of PSMA overexpression in PPGLs which could translate to therapeutic and diagnostic applications of anti-PSMA radio-conjugates in high-risk PPGLs.
Highlights
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors arising from neural crest-derived chromaffin cells
PGL tumor samples, all belonging to the Cluster 1 representing PPGLs with highest risk of metastasis, multiplicity, or recurrence
Our study shows that Cluster 1 PPGLs markedly overexpress prostate-specific membrane antigen (PSMA) compared to the healthy adrenal medulla, with the most likely location being in tumor neovasculature
Summary
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors arising from neural crest-derived chromaffin cells. The distinction between the two tumor types is based primarily on anatomical location. Tumors originating from the adrenal medulla are known as pheochromocytomas (PHEOs), while those arising from sympathetic or parasympathetic ganglia are known as paragangliomas (PGLs). Clusters 1 and 2 make up a majority of the susceptibility genes causing the most common hereditary PPGLs. Clusters 1 and 2 make up a majority of the susceptibility genes causing the most common hereditary PPGLs Mutations in these genes are important in the clinical diagnosis of these tumors, with the ability to predict and anticipate their phenotypic patterns including symptomatology, biochemistry, metastatic potential, predilection to other cancers, and therapeutic options
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