The growth of solid tumor is critically dependent on their capacity to acquire blood supply, and it has been demonstrated that targeted destruction of tumor vasculature is an effective strategy for solid tumor treatment. Angiogenesis inhibitors have been shown to have effective antitumor activity in a broad spectrum of cancer types (1,27). However, novel molecular targets that are specifically expressed in tumor-associated vasculature are urgently needed.
PSMA is a transmembrane protein, which was originally found to be expressed in normal prostate tissue. Later, its expression was found to be upregulated in almost all stages of PCa tissues, making it an ideal target for the therapy of PCa (8–10). In recent years, researchers have found that PSMA is also selectively expressed in tumor-associated vasculature in a variety of solid tumors (11–25). Thus, PSMA has also been considered to be an effective vascular target for these cancer types (8,10).
Vascular PSMA expression has been shown to be correlated with other clinicopathological features and may predict prognosis in certain cancer types. For example, in oral squamous cell carcinoma, significant difference in OS was observed between high/low vascular PSMA expression, and high PSMA expression can be used as an independent marker for poor prognosis (11). In breast cancer, vascular PSMA expression has also been shown to be correlated with other clinicopathological features, such as tumor size, Ki-67 proliferation index, and 10-year OS (13).
Until now, the expression pattern of PSMA in HCC has not been systemically studied. Recently, Kesler et al. reported that 68Ga-PSMA PET-CT (positron emission tomography-computed tomography) can be used for the imaging of HCC, and 68Ga-PSMA was mainly taken up by tumor microvessels in HCC lesions. Based on these findings, they performed IHC staining of PSMA in 5 HCC samples and found that PSMA was intensely expressed in tumor microvessel in these samples (28).
In our study, we evaluated PSMA expression in 103 patients with HCC using IHC staining and confirmed that PSMA is specifically expressed in the vasculature of HCC, and its vascular expression is significantly correlated with other clinicopathological features such as tumor stage, tumor differentiation, lymph node metastasis, TNM stage, and Ki-67 index. We also found that patients with high vascular PSMA expression tended to have shorter OS than patients with low vascular PSMA expression. In addition, using Cox regression analysis, we found that high vascular PSMA expression is closely correlated with poor prognosis of patients with HCC and can be used as an independent prognostic marker in HCC. Because the sample number in this study is still not big enough, we believe that more studies with increased sample numbers are still needed to confirm the prognostic value of vascular PSMA expression in HCC.
Previously, PSMA has been shown to play an important role in angiogenesis. Conway et al. found that angiogenesis is severely impaired in PSMA-null animals, and PSMA may promote endothelial cell invasion and angiogenesis through an autoregulatory loop involving laminin-specific integrin and PAK1 (p21-activated kinase 1) (29). They also found that matrix metalloproteinase 2 and PSMA sequentially digest laminin into small peptides, which can enhance endothelial cell adhesion and migration through integrin α6β1 and focal adhesion kinase, thus promoting angiogenesis (30,31). However, more studies are still needed to clarify the detailed mechanism how PSMA regulates angiogenesis.
PSMA has a large extracellular domain, which can be recognized by antibodies, peptides, RNA aptamers, and small molecules, making it an ideal molecule for targeted therapy (32–34). PSMA-targeted therapy has been well studied in metastatic PCa (35–37). Because of its specific vascular expression in nonprostatic solid tumors, PSMA has also been examined as a vascular target for the therapy of these tumors. For example, phase I trials of 111In-labeled monoclonal antibody J591 against PSMA were performed in multiple solid tumor types including kidney, bladder, lung, breast, colorectal and pancreatic cancers, and melanoma. Results confirmed that tumor vasculature of these solid tumors can be selectively and safely targeted using this antibody (38,39). Because PSMA was also specifically expressed in the vasculature of HCC, these PSMA targeting strategies may also be applied for HCC treatment.
In summary, the current findings confirmed that vascular PSMA expression exists in a subset of HCC samples, and vascular PSMA expression is correlated with other clinicopathological features and can be used as an independent prognostic marker for HCC. Thus, we conclude that PSMA can be used as a novel prognostic marker and a therapeutic vascular target in HCC.
We thank Mrs. Honglei Li (Department of Pathology of Xijing Hospital, Fourth Military Medical University, China) for detailed pathology diagnosis. We thank Mrs. Lijun Wang (Department of Pathology, Fourth Military Medical University, China) for IHC staining analysis. We also thank Dr. Hongxiang Bao (Department of Statistics, Fourth Military Medical University, China) for statistical analysis.
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