Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with low survival rates. We explored an innovative therapeutic approach by leveraging prognostic oncogenic markers. Instead of inhibiting these marker genes, we harnessed their tumor-modifying potential in the extracellular domain. Surprisingly, many of the proteins highly expressed in PDAC, which is linked to poor survival, exhibited tumor-suppressing qualities in the extracellular environment. For instance, prostate stem cell antigens (PSCA), associated with reduced survival, acted as tumor suppressors when introduced extracellularly. We performed in vitro assays to assess the proliferation and migration and evaluated the tumor-modifying capacity of extracellular factors from peripheral blood mononuclear cells (PBMCs) in PDAC tissues. Molecular docking analysis, immunoprecipitation, Western blotting, and RNA interference were employed to study the regulatory mechanism. Extracellular PSCA recombinant protein notably curtailed the viability, motility, and transwell invasion of PDAC cells. Its anti-PDAC effects were partially mediated by Mesothelin (MSLN), another highly expressed tumor-associated antigen in PDAC. The anti-tumor effects of extracellular PSCA complemented those of chemotherapeutic agents like Irinotecan, 5-Fluorouracil, and Oxaliplatin. PSCA expression increased in a conditioned medium derived from PBMCs and T lymphocytes. This study unveils the paradoxical anti-PDAC potential of PSCA, hinting at the dual roles of oncoproteins like PSCA in PDAC suppression.
胰腺导管腺癌（PDAC）是一种侵袭性强、生存率低的恶性肿瘤。本研究基于预后相关的致癌标志物探索了一种创新性治疗策略：不直接抑制这些标志基因，而是利用其在细胞外域发挥的肿瘤调控潜能。令人意外的是，许多与不良预后相关且在PDAC中高表达的蛋白质，在细胞外环境中却表现出肿瘤抑制特性。例如，与生存期缩短相关的前列腺干细胞抗原（PSCA）在细胞外导入时竟发挥抑癌作用。我们通过体外实验评估了细胞增殖与迁移能力，并检测了外周血单个核细胞（PBMCs）来源的细胞外因子对PDAC组织的肿瘤调控作用。采用分子对接分析、免疫共沉淀、蛋白质印迹及RNA干扰等技术探究其调控机制。细胞外PSCA重组蛋白显著抑制了PDAC细胞的活力、运动能力及Transwell侵袭，其抗PDAC作用部分由间皮素（MSLN）介导——这是PDAC中另一种高表达的肿瘤相关抗原。细胞外PSCA的抗肿瘤效应与伊立替康、5-氟尿嘧啶、奥沙利铂等化疗药物具有协同作用。在PBMCs及T淋巴细胞来源的条件培养基中，PSCA表达水平显著升高。本研究揭示了PSCA在PDAC中矛盾性的抗肿瘤潜能，暗示PSCA等癌蛋白在PDAC抑制中可能具有双重作用。
Exploring the Tumor-Suppressing Potential of PSCA in Pancreatic Ductal Adenocarcinoma
肿瘤(癌症)患者之家