单个人体组织内多种衰老细胞类型导致恶性肿瘤发展的综合行为尚不清楚。家族性黑色素瘤综合征 (FMS) 患者的编码细胞周期蛋白抑制剂 p16INK4a 的 CDKN2A 基因存在杂合种系缺陷。 FMS 患者皮肤活检中的黑色素细胞表达的 p16INK4a 明显低于成纤维细胞，但表达的 DNA 损伤蛋白 𝛾H2AX a 水平高于成纤维细胞。然而，患者成纤维细胞也表现出缺陷，因为衰老过程中皮肤中的衰老细胞不会增加，并且与体外对照成纤维细胞相比，从患者皮肤中分离出的成纤维细胞的复制能力有所增强，最终导致核形态异常。患者来源的成纤维细胞也比对照细胞分泌更少的 SASP。因此，FMS 患者易患黑色素瘤可能是由于体内多种细胞类型衰老的综合失调所致。 DNA 损伤程度较高，以及 DNA 损伤后黑素细胞对 p16 细胞周期抑制的过度依赖，使得它们极易发生恶性转化。成纤维细胞中与衰老相关的缺陷可能会加剧这种情况，特别是 SASP 分泌减少，这会阻碍稳态下 T 细胞的募集，从而减少体内皮肤免疫监视。© 2024 作者。衰老细胞由解剖学会和约翰·威利出版

The integrated behaviour of multiple senescent cell types within a single human tissue leading to the development of malignancy is unclear. Patients with Familial Melanoma Syndrome (FMS) have heterozygous germline defects in the CDKN2A gene coding for the cyclin inhibitor p16INK4a. Melanocytes within skin biopsies from FMS patients express significantly less p16INK4a but express higher levels of the DNA-damage protein 𝛾H2AX a than fibroblastic cells. However, patient fibroblasts also exhibit defects since senescent cells do not increase in the skin during ageing and fibroblasts isolated from the skin of patients have increased replicative capacity compared to control fibroblasts in vitro, culminating in abnormal nuclear morphology. Patient derived fibroblasts also secreted less SASP than control cells. Predisposition of FMS patients to melanoma may therefore result from integrated dysregulation of senescence in multiple cell types in vivo. The inherently greater levels of DNA damage and the overdependence of melanocytes on p16 for cell cycle inhibition after DNA damage makes them exquisitely susceptible to malignant transformation. This may be accentuated by senescence-related defects in fibroblasts, in particular reduced SASP secretion that hinders recruitment of T cells in the steady state and thus reduces cutaneous immunosurveillance in vivo.© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.