Halin Bergström Sofia, Semenas Julius, Nordstrand Annika, Thysell Elin, Wänman Johan, Crnalic Sead, Widmark Anders, Thellenberg-Karlsson Camilla, Andersson Pernilla, Gidlund Susanne, Lundholm Marie, Welén Karin, Josefsson Andreas, Wikström Pernilla, Bergh Anders
Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
Department of Diagnostics and Interventions, Orthopedics, Umeå University, Umeå, Sweden.
Clin Exp Metastasis. 2025 Aug 21;42(5):49. doi: 10.1007/s10585-025-10365-y.
We previously identified three molecular subtypes of prostate cancer (PC) bone metastases, MetA-C, with MetB linked to poor prognosis after androgen deprivation therapy (ADT). This study analyzed epithelial and stromal markers using immunohistochemistry, focusing on their relationship to MetA-C subtypes, spatial heterogeneities, and clinical outcomes after ADT. High tumor proliferation and low PSA expression were associated with MetB and poor outcomes after ADT. Most metastases contained tumor epithelial subclones with different morphologies. In the metastasis stroma, blood vessels and fibroblast-like cells expressed smooth muscle actin (SMA), platelet-derived growth factor β, stroma-derived factor 1 (SDF1), periostin (POSTN), and decorin (DCN). Compared to each other, MetB metastases had higher SMA and ERG + endothelial cell densities, while MetA cases showed higher SDF1 and DCN levels. Accordingly, high POSTN and ERG + densities were associated with poor outcomes after ADT, whereas high DCN indicated favorable prognosis. Low levels of AR-positive stromal cells were linked to poor outcomes. Macrophage and T-lymphocyte densities showed no significant associations with metastases subtypes or outcome. Two stroma subtypes were identified: subtype 1 with higher bone content, lower vessel density, MetA-enrichment and better prognosis compared to subtype 2 that exhibited higher tumor proliferation and lower PSA expression. Most metastases contained regions of both stroma subtypes.
我们之前确定了前列腺癌（PC）骨转移的三种分子亚型，即MetA-C，其中MetB与雄激素剥夺治疗（ADT）后的不良预后相关。本研究使用免疫组织化学分析上皮和基质标志物，重点关注它们与MetA-C亚型的关系、空间异质性以及ADT后的临床结果。高肿瘤增殖和低PSA表达与MetB及ADT后的不良结果相关。大多数转移灶包含具有不同形态的肿瘤上皮亚克隆。在转移瘤基质中，血管和成纤维细胞样细胞表达平滑肌肌动蛋白（SMA）、血小板衍生生长因子β、基质衍生因子1（SDF1）、骨膜蛋白（POSTN）和核心蛋白聚糖（DCN）。相比之下，MetB转移灶的SMA和ERG + 内皮细胞密度更高，而MetA病例的SDF1和DCN水平更高。因此，高POSTN和ERG + 密度与ADT后的不良结果相关，而高DCN表明预后良好。低水平的AR阳性基质细胞与不良结果相关。巨噬细胞和T淋巴细胞密度与转移亚型或结果无显著关联。确定了两种基质亚型：与表现出较高肿瘤增殖和较低PSA表达的亚型2相比，亚型1的骨含量更高、血管密度更低、富含MetA且预后更好。大多数转移灶包含两种基质亚型的区域。
