Aim

Since its discovery Prostate Specific Antigen (PSA), also referred to as kallikrein-3 (KLK3), has been used as standard circulating biomarker for prostate cancer (PCa). However, its specificity remains not adequate and its mechanism of action still elusive. Therefore, deciphering PSA role throughout PCa-pathobiology would be relevant in improving both cancer diagnosis and outcome prediction. We investigated the possible role played by PSA on/in the tumor microenvironment and over the first steps of cancer invasion.

Methods

Fresh PCa-specimens and cell lines were used for ex-vivo/in-vitro invasion assays and assessment of prostate tissue-PSA (tPSA), type 1 collagen (COL1A1) and ß1-integrin expression. Tissue Cancer Genome Atlas (TCGA) and Decipher® datasets were considered to estimate tPSA clinical relevance.

Results

A more precise, inverse, correspondence between tPSA and clinical/pathological parameters was found than for circulating PSA. KLK3 combined with Gleason grade and pathologic stage, better predicted cancer-related mortality. Consistently, we demonstrated that PSA inhibits prostate extracellular-matrix (ECM) invasion by PCa cells. As for the mechanism of action, we provided novel information that PSA is able to cleave COL1A1, a main component of the ECM. Finally, ß1-integrin, a crucial COL1A1 transducing-receptor involved in tumor adhesion/invasion, resulted to be downregulated in PCa specimens with higher levels of tPSA.

Conclusions

By interfering with type 1 collagen and its downstream targets, PSA may hamper adhesion and path of the cancer cells through ECM and their migration ability, thus explaining the inverse correlation highlighted between prostate tPSA levels and clinically significant disease.

中文翻译：

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对前列腺特异性抗原抗转移作用的机制洞察

目的

自从发现前列腺特异性抗原 (PSA)，也称为激肽释放酶-3 (KLK3) 以来，它已被用作前列腺癌 (PCa) 的标准循环生物标志物。然而，其特异性仍然不够，其作用机制仍然难以捉摸。因此，破译 PSA 在整个 PCa 病理学中的作用将与改善癌症诊断和结果预测相关。我们研究了 PSA 在肿瘤微环境中/在肿瘤微环境中以及在癌症侵袭的第一步中可能发挥的作用。

方法

新鲜的 PCa 样本和细胞系用于离体/体外侵袭测定和前列腺组织 PSA (tPSA)、1 型胶原蛋白 (COL1A1) 和 ß1-整合素表达的评估。组织癌症基因组图谱 (TCGA) 和 Decipher® 数据集被认为是用来估计 tPSA 临床相关性的。

结果

与循环 PSA 相比，发现了 tPSA 与临床/病理参数之间更精确的反向对应关系。KLK3结合 Gleason 分级和病理分期，可以更好地预测癌症相关死亡率。一致地，我们证明了 PSA 抑制了 PCa 细胞对前列腺细胞外基质 (ECM) 的侵袭。至于作用机制，我们提供了 PSA 能够切割 COL1A1（ECM 的主要成分）的新信息。最后，ß1-整合素，一种参与肿瘤粘附/侵袭的关键 COL1A1 转导受体，导致在具有较高 tPSA 水平的 PCa 标本中下调。

结论

通过干扰 1 型胶原及其下游靶标，PSA 可能会阻碍癌细胞通过 ECM 的粘附和路径及其迁移能力，从而解释了前列腺 tPSA 水平与临床显着疾病之间突出的负相关。