文章：

恶性内吞作用：癌症的新特征

Derailed endocytosis: an emerging feature of cancer

原文发布日期：2008-11-01

DOI: 10.1038/nrc2521

类型: Review Article

开放获取: 否

要点：

1. Along with material uptake, endocytosis regulates signal transduction, as well as morphogenetic aspects of normal physiology (such as cell adhesion and migration). The multiple routes of endocytosis share a canonical, convergent structure: they begin at coated invaginations of the plasma membrane, progress through several endosomal compartments and culminate in lysosomes. An escape pathway enables internalized proteins to return to the plasma membrane through a recycling compartment.
2. Endocytic pathways present multiple abnormalities in human tumours. For example, dissolution of cell–cell junctions (adherens and tight junctions) and loss of morphological polarity precedes full malignant transformation; the underlying process encompasses enhanced internalization and unbalanced partitioning of junctional proteins (such as epithelial cadherin) between the lysosomal pathway and the recycling route.
3. A burgeoning body of evidence indicates that tumours gain self-sufficiency in growth signals by delaying endocytosis-mediated inactivation of growth factor receptors. Multiple oncogenic mechanisms intercept receptor endocytosis: defects in key endosomal proteins, evasion of ubiquitylation-mediated sorting to degradation, and malfunctioning of collaborative processes such as actin remodelling.
4. To conquer tissue barriers and colonize distant organs, tumour cells dynamically disintegrate cell-to-matrix adhesion sites and re-assemble them at the front of invading protrusions. This polar re-distribution is propelled by enhanced recycling of adhesion molecules of the integrin family, a process enabled by aberrant microtubules and small GTP-binding proteins of the Rab family.
5. Future studies are likely to uncover additional links between cancer and endocytosis, as well as unravel common biochemical interfaces (such as phosphoinositol homeostasis and cytoskeletal perturbations) amenable for therapeutic interventions.

要点翻译：

1. 除物质摄取外，内吞作用还调控信号转导以及正常生理过程的形态发生（如细胞黏附与迁移）。多种内吞途径具有典型的汇聚结构：起始于质膜包被内陷，经历数个内体区室，最终进入溶酶体。逃逸途径使内化蛋白可通过循环区室返回质膜。
2. 人类肿瘤中存在多种内吞通路异常。例如，在完全恶性转化前会出现细胞间连接（黏着连接与紧密连接）解离和形态极性丧失，其潜在机制包括连接蛋白（如上皮钙黏蛋白）内吞增强，以及在溶酶体途径与循环路线间的不平衡分配。
3. 新兴证据表明，肿瘤通过延迟生长因子受体的内吞介导失活，获得生长信号自给能力。多种致癌机制干扰受体内吞：关键内体蛋白缺陷、逃避泛素化介导的降解分选，以及肌动蛋白重构等协作过程功能障碍。
4. 为突破组织屏障并定植远端器官，肿瘤细胞动态解离细胞-基质黏附位点，并在侵袭性突起前端重新组装。该极性重分布由整合素家族黏附分子循环增强所驱动，这一过程受异常微管和Rab家族小GTP结合蛋白调控。
5. 未来研究有望揭示癌症与内吞作用间的更多联系，并阐明可用于治疗干预的共同生化界面（如磷酸肌醇稳态与细胞骨架扰动）。

英文摘要：

Once engaged by soluble or matrix-anchored ligands, cell surface proteins are commonly sorted to lysosomal degradation through several endocytic pathways. Defective vesicular trafficking of growth factor receptors, as well as unbalanced recycling of integrin- and cadherin-based adhesion complexes, has emerged in the past 5 years as a multifaceted hallmark of malignant cells. In line with the cooperative nature of endocytic machineries, multiple oncogenic alterations underlie defective endocytosis, such as altered ubiquitylation (Cbl and Nedd4 ubiquitin ligases, for example), altered cytoskeletal interactions and alterations to Rab family members. Pharmaceutical interception of the propensity of tumour cells to derail their signalling and their adhesion receptors may constitute a novel target for cancer therapy.

摘要翻译： 

一旦与可溶性或基质锚定的配体结合，细胞表面蛋白通常会通过多种内吞途径被分选至溶酶体降解。过去五年中，生长因子受体的囊泡运输缺陷，以及整合素和钙黏蛋白黏附复合物回收失衡，已成为恶性细胞的多维度标志。与内吞机制的协同性一致，多种致癌改变共同导致内吞功能障碍，例如泛素化异常（如Cbl和Nedd4泛素连接酶）、细胞骨架相互作用改变以及Rab家族成员的变异。通过药物干预肿瘤细胞使其信号通路和黏附受体脱离异常轨道的倾向，可能构成癌症治疗的新靶点。

原文链接：

Derailed endocytosis: an emerging feature of cancer