Abstract
BackgroundPrimary and secondary brain cancers are highly treatment resistant, and their marked angiogenesis attracts interest as a potential therapeutic target. Recent observations reveal that the microvascular endothelium of primary high-grade gliomas expresses prostate specific membrane antigen (PSMA). Breast cancers express PSMA and they frequently form secondary brain tumors. Hence we report here our pilot study addressing the feasibility of PSMA targeting in brain and metastatic breast tumors, by examining PSMA levels in all glioma grades (19 patients) and in breast cancer brain metastases (5 patients).MethodsTumor specimens were acquired from archival material and normal brain tissues from autopsies. Tissue were stained and probed for PSMA, and the expression levels imaged and quantified using automated hardware and software. PSMA staining intensities of glioma subtypes, breast tumors, and breast tumor brain metastases were compared statistically versus normals.ResultsNormal brain microvessels (4 autopsies) did not stain for PSMA, while a small proportion (<5%) of healthy neurons stained, and were surrounded by an intact blood brain barrier. Tumor microvessels of the highly angiogenic grade IV gliomas showed intense PSMA staining which varied between patients and was significantly higher (p < 0.05) than normal brain. Grade I gliomas showed moderate vessel staining, while grade II and III gliomas had no vessel staining, but a few (<2%) of the tumor cells stained. Both primary breast cancer tissues and the associated brain metastases exhibited vascular PSMA staining, although the intensity of staining was generally less for the metastatic lesions.ConclusionsOur results align with and extend previous data showing PSMA expression in blood vessels of gliomas and breast cancer brain metastases. These results provide a rationale for more comprehensive studies to explore PSMA targeted agents for treating secondary brain tumors with PSMA expressing vasculature. Moreover, given that PSMA participates in angiogenesis, cell signaling, tumor survival, and invasion, characterizing its expression may help guide later investigations of the poorly understood process of low grade glioma progression to glioblastoma.
Highlights
Primary and secondary brain cancers are highly treatment resistant, and their marked angiogenesis attracts interest as a potential therapeutic target
All glioma samples were acquired before the patients initiated therapy, while the breast tumor metastases were acquired after treatment for the primary tumor, which may be presumed to have been standard this could not be confirmed for all specimens
prostate specific membrane antigen (PSMA) expression in glioma Figure 2A provides a visual comparison of all four glioma grades I through IV, and shows that grade IV glioma blood vessels stained heavily for PSMA, while grades II (n = 4) and III (n = 5) exhibited some staining of tumor parenchyma cells but little vessel staining
Summary
Primary and secondary brain cancers are highly treatment resistant, and their marked angiogenesis attracts interest as a potential therapeutic target. Breast cancers express PSMA and they frequently form secondary brain tumors. Primary and secondary brain cancers are difficult to treat and are a major cause of cancer-related death [1,2,3]. Gliomas are the most common primary brain tumors, with grades I, II, and III usually progressing to a poor outcome over 2 to 10 years, while the aggressive grade IV (glioblastoma; GBM) advances very rapidly within 2–3 years, causing approximately 13,000 deaths per year [1]. 200,000 women develop breast cancer annually, and 2–3 years after diagnosis nearly 30% develop brain metastases [6,7]. There are few treatment options for this relatively late and lethal complication, which is more frequent in younger patients [8]
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