文章：

理解默克尔细胞癌：致病信号传导、细胞外基质动态与新型治疗策略

Understanding Merkel Cell Carcinoma: Pathogenic Signaling, Extracellular Matrix Dynamics, and Novel Treatment Approaches

原文发布日期：2 April 2025

DOI: 10.3390/cancers17071212

类型: Article

开放获取: 是

英文摘要：

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer, driven by either Merkel cell polyomavirus (MCPyV) integration or ultraviolet (UV)-induced mutations. In MCPyV-positive tumors, viral T antigens inactivate tumor suppressors pRb and p53, while virus-negative MCCs harbor UV-induced mutations that activate similar oncogenic pathways. Key signaling cascades, including PI3K/AKT/mTOR and MAPK, support tumor proliferation, survival, and resistance to apoptosis. Histologically, MCC consists of small round blue cells with neuroendocrine features, high mitotic rate, and necrosis. The tumor microenvironment (TME) plays a central role in disease progression and immune escape. It comprises a mix of tumor-associated macrophages, regulatory and cytotoxic T cells, and elevated expression of immune checkpoint molecules such as PD-L1, contributing to an immunosuppressive niche. The extracellular matrix (ECM) within the TME is rich in proteoglycans, collagens, and matrix metalloproteinases (MMPs), facilitating tumor cell adhesion, invasion, and interaction with stromal and immune cells. ECM remodeling and integrin-mediated signaling further promote immune evasion and therapy resistance. Although immune checkpoint inhibitors targeting PD-1/PD-L1 have shown promise in treating MCC, resistance remains a major hurdle. Therapeutic strategies that concurrently target the TME—through inhibition of ECM components, MMPs, or integrin signaling—may enhance immune responses and improve clinical outcomes.

摘要翻译： 

默克尔细胞癌（MCC）是一种罕见但具有侵袭性的神经内分泌皮肤癌，其发生机制主要源于默克尔细胞多瘤病毒（MCPyV）整合或紫外线（UV）诱导的基因突变。在MCPyV阳性肿瘤中，病毒T抗原通过使抑癌蛋白pRb和p53失活驱动癌变；而病毒阴性MCC则携带UV诱导的突变，激活相似的致癌通路。PI3K/AKT/mTOR和MAPK等关键信号级联反应促进了肿瘤增殖、存活及凋亡抵抗。组织学上，MCC表现为具有神经内分泌特征的小圆蓝细胞，伴有高核分裂率和坏死现象。肿瘤微环境（TME）在疾病进展和免疫逃逸中发挥核心作用，其中包含肿瘤相关巨噬细胞、调节性与细胞毒性T细胞的复杂混合，以及PD-L1等免疫检查点分子的高表达，共同构成免疫抑制性微环境。TME内的细胞外基质（ECM）富含蛋白聚糖、胶原蛋白和基质金属蛋白酶（MMPs），这些成分促进肿瘤细胞黏附、侵袭以及与基质细胞和免疫细胞的相互作用。ECM重塑和整合素介导的信号传导进一步加剧了免疫逃逸和治疗抵抗。尽管靶向PD-1/PD-L1的免疫检查点抑制剂在MCC治疗中展现出潜力，但耐药性仍是主要障碍。通过抑制ECM成分、MMPs或整合素信号通路来协同靶向TME的治疗策略，有望增强免疫应答并改善临床预后。

原文链接：

Understanding Merkel Cell Carcinoma: Pathogenic Signaling, Extracellular Matrix Dynamics, and Novel Treatment Approaches