The tumor microenvironment plays a central role in cancer initiation and progression. CD248 is expressed in tumor-associated stromal cells, particularly fibroblasts and pericytes. Exploring the function of CD248 has the potential to provide biological insights into tumor-supportive stroma and potential therapeutic targets. Here, we investigated the role of stromal CD248 in lung cancer. In orthotopic lung cancer transplantation models, tumor volume, density of vessels and pericytes, and functionality of tumor vessels were all lower in mice lacking Cd248 (Cd248LacZ/LacZ) compared with Cd248 wild-type or haploinsufficient mice. Two angiogenic factors, OPN and SERPINE1, were decreased in Cd248LacZ/LacZ pericytes, and supplementation with both factors rescued their proliferation and endothelial cell tube formation–promoting ability. Mechanistically, Wnt/β-catenin signaling induced Opn and Serpine1 expression and was suppressed in Cd248LacZ/LacZ pericytes. CD248 interacted with Wnt pathway repressors IGFBP4 and LGALS3BP, leading to increased Wnt/β-catenin signaling. Correspondingly, administration of a β-catenin inhibitor in Cd248+/LacZ mice mimicked the effect of Cd248 loss and blocked the growth of transplanted lung tumor cells that were resistant to this inhibitor in vitro. In addition, CD248+ pericytes coexpressed OPN and SERPINE1 and correlated with increased tumor size in human lung cancer. Additionally, high expression of CD248, OPN, and SERPINE1 was associated with poor survival in lung cancer patients. In summary, CD248 derepresses Wnt signaling and upregulates OPN and SERPINE1 in pericytes, resulting in enhanced angiogenesis and lung cancer growth. This novel axis of CD248–Wnt signaling–angiogenic factors in pericytes provides a potential target for lung cancer therapy. Significance: These findings demonstrate that CD248 maintains pericyte function in lung cancer through the Wnt signaling pathway and present CD248 as a potential therapeutic target.

中文翻译：

---

CD248 调节周细胞中的 Wnt 信号转导促进肺癌中的血管生成和肿瘤生长

肿瘤微环境在癌症的发生和进展中发挥着核心作用。CD248 在肿瘤相关基质细胞中表达，特别是成纤维细胞和周细胞。探索 CD248 的功能有可能为肿瘤支持基质和潜在治疗靶点提供生物学见解。在这里，我们研究了基质 CD248 在肺癌中的作用。在原位肺癌移植模型中，与 Cd248 野生型或单倍剂量不足的小鼠相比，缺乏 Cd248 (Cd248LacZ/LacZ) 的小鼠的肿瘤体积、血管和周细胞密度以及肿瘤血管功能均较低。Cd248LacZ/LacZ 周细胞中的两种血管生成因子 OPN 和 SERPINE1 减少，补充这两种因子可恢复其增殖和内皮细胞管形成促进能力。从机械上来说，Wnt/β-连环蛋白信号传导诱导 Opn 和 Serpine1 表达，并在 Cd248LacZ/LacZ 周细胞中受到抑制。CD248 与 Wnt 通路阻遏物 IGFBP4 和 LGALS3BP 相互作用，导致 Wnt/β-连环蛋白信号传导增强。相应地，在 Cd248+/LacZ 小鼠中施用 β-连环蛋白抑制剂模拟了 Cd248 缺失的效果，并阻止了体外对该抑制剂具有抗性的移植肺肿瘤细胞的生长。此外，CD248+ 周细胞共表达 OPN 和 SERPINE1，并与人类肺癌中肿瘤大小的增加相关。此外，CD248、OPN 和 SERPINE1 的高表达与肺癌患者的较差生存率相关。总之，CD248 去抑制 Wnt 信号传导并上调周细胞中的 OPN 和 SERPINE1，从而增强血管生成和肺癌生长。周细胞中 CD248-Wnt 信号传导-血管生成因子的这一新轴为肺癌治疗提供了潜在的靶点。意义：这些发现表明 CD248 通过 Wnt 信号通路维持肺癌中的周细胞功能，并将 CD248 作为潜在的治疗靶点。