文章：

从黑色素细胞到黑色素瘤

From melanocytes to melanomas

原文发布日期：2016-04-29

DOI: 10.1038/nrc.2016.37

类型: Review Article

开放获取: 否

要点：

1. Melanomas on the non-glabrous skin (skin outside the palms and soles) can be broadly classified into those that arise on skin with chronic sun-induced damage (CSD melanomas) or those that arise on skin without such damage (non-CSD melanomas). These two melanoma subtypes differ with regard to their age of onset, associated patterns of exposure to UV radiation, association with precursor lesions, clinical and histopathological appearance and somatic mutations.
2. Melanocytic neoplasms range from benign naevi, which are common and have a negligible risk of progressing, to invasive melanomas, which have the potential to metastasize. In between there are intermediate stages that include dysplastic naevi and non-invasive (in situ) melanoma.
3. Different melanoma subtypes have different evolutionary trajectories. Non-CSD melanomas commonly arise from benign or dysplastic naevi, whereas CSD melanomas commonly arise from melanoma in situ. As melanomas evolve they do not always pass through discernable evolutionary phases but can seemingly skip individual phases and can even appear without any apparent precursor lesion.
4. Several lines of evidence including TERT promoter mutations in benign or pre-malignant phases of evolution suggest that the cells of common and dysplastic naevi are more proliferative and not entirely senescent, as some models of naevi propose. The relatively stable size of the overall lesion can be explained by the fact that their slow rate of proliferation is offset by cell-attritional factors such as immunosurveillance.
5. Transformation of melanocytes to melanoma is prevented by multiple barriers, which are successively disrupted by genetic alterations. Precursor lesions form when initial mutations induce cell proliferation that is subsequently constrained by cell-autonomous and non-autonomous factors. The expanding cell number increases the probability that descendent cells will acquire additional mutations that override these barriers, enabling evolution to the next phase of progression from a less-evolved precursor lesion. We propose that some melanomas without apparent precursor lesions arise from melanocytes in which the genetic alterations disrupting these barriers already pre-existed before the proliferation-inducing mutation occurred, thereby enabling the neoplasm to skip an evolutionary phase.
6. Melanomas can disseminate in parallel to regional and distant sites to form metastases. Once several metastases have formed, cells from each metastasis continue to seed and reseed other tumours, adding considerable complexity to the diversity of metastatic clones.

要点翻译：

1. 非光滑皮肤（手掌和足底以外的皮肤）上的黑色素瘤可大致分为两类：发生于伴有慢性日光损伤皮肤（CSD黑色素瘤）或发生于无此类损伤皮肤（非CSD黑色素瘤）。这两种黑色素瘤亚型在发病年龄、相关的紫外线辐射暴露模式、与前驱病变的关联、临床和组织病理学表现以及体细胞突变方面均有所不同。
2. 黑色素细胞肿瘤的范围从良性痣（常见且进展风险可忽略不计）到侵袭性黑色素瘤（具有转移潜力）。其间存在中间阶段，包括发育不良痣和非侵袭性（原位）黑色素瘤。
3. 不同黑色素瘤亚型具有不同的演化路径。非CSD黑色素瘤通常起源于良性或发育不良痣，而CSD黑色素瘤通常起源于原位黑色素瘤。黑色素瘤在演化过程中并非总是经历可识别的阶段，似乎可能跳过某些阶段，甚至可在无任何明显前驱病变的情况下出现。
4. 包括良性或恶性前演化阶段的TERT启动子突变在内的多项证据表明，常见痣和发育不良痣中的细胞更具增殖性且并非完全衰老，这与某些痣模型提出的观点不同。整体病变相对稳定的大小可通过其缓慢的增殖速率被免疫监视等细胞损耗因素所抵消来解释。
5. 黑色素细胞向黑色素瘤的转化受到多重屏障的阻止，这些屏障被遗传改变相继破坏。当初始突变诱导细胞增殖，随后受到细胞自主和非自主因素限制时，便形成前驱病变。扩增的细胞数量增加了后代细胞获得额外突变以突破这些屏障的可能性，从而使得病变能够从演化程度较低的前驱病变进展至下一阶段。我们提出，一些无明显前驱病变的黑色素瘤起源于在增殖诱导突变发生前已存在破坏这些屏障的遗传改变的黑色素细胞，从而使肿瘤能够跳过一个演化阶段。
6. 黑色素瘤可同时向区域和远处部位播散形成转移灶。一旦多个转移灶形成，每个转移灶的细胞会继续播种和再播种其他肿瘤，极大地增加了转移克隆的多样性。

英文摘要：

Melanomas on sun-exposed skin are heterogeneous tumours, which can be subtyped on the basis of their cumulative levels of exposure to ultraviolet (UV) radiation. A melanocytic neoplasm can also be staged by how far it has progressed, ranging from a benign neoplasm, such as a naevus, to a malignant neoplasm, such as a metastatic melanoma. Each subtype of melanoma can evolve through distinct evolutionary trajectories, passing through (or sometimes skipping over) various stages of transformation. This Review delineates several of the more common progression trajectories that occur in the patient setting and proposes models for tumour evolution that integrate genetic, histopathological, clinical and biological insights from the melanoma literature.

摘要翻译： 

日晒部位皮肤发生的黑色素瘤具有异质性，可根据其累积接受的紫外线（UV）辐射剂量进行亚型分类。黑色素细胞肿瘤还可按其进展程度进行分期，从良性肿瘤（如痣）到恶性肿瘤（如转移性黑色素瘤）。各亚型黑色素瘤可沿不同的演化轨迹发展，依次经过（或有时跳过）多个转化阶段。本文综述了临床中常见的几条进展轨迹，并整合了黑色素瘤研究中的遗传、组织病理、临床及生物学见解，提出肿瘤演化模型。

原文链接：

From melanocytes to melanomas