Preclinical Research (MZF, BM, RV, ALG, ME, JV, JA) and Clinical Research Programs (ITR), Vall d'Hebron Institute of Oncology, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain (JA).
J Natl Cancer Inst. 2015 May 13;107(5). doi: 10.1093/jnci/djv020. Print 2015 May.
Oncogene-induced senescence (OIS) is a tumor suppressor mechanism. However, senescent cells remain viable and display a distinct secretome (also known as senescence-associated secretory phenotype [SASP] or senescence messaging secretome, [SMS]) that, paradoxically, includes protumorigenic factors. OIS can be triggered by ectopic overexpression of HER2, a receptor tyrosine kinase and the driving oncogene in a subtype of human breast cancer. However, cellular senescence has not been characterized in HER2-positive tumors.
Using an approach based on their inability to proliferate, we isolated naturally occurring senescent cells from a variety of tumor models including HER2-positive cells, transgenic mice (n = 3), and patient-derived xenografts (PDXs) (n = 6 mice per group from one PDX derived from one patient). Using different biochemical and cell biological techniques, we characterized the secretome of these senescent cells. All statistical tests were two-sided.
We found that senescent cells arise constantly in different models of advanced breast cancers overexpressing HER2 and constitute approximately 5% of tumor cells. In these models, IL-6 and other cytokines were expressed mainly, if not exclusively, by the naturally occurring senescent cells (95.1% and 45.0% of HCC1954 cells and cells from a HER2-positive PDX expressing a senescent marker expressed IL-6, respectively). Furthermore, inhibition of IL-6 impaired the growth of the HER2-positive PDX (mean tumor volume at day 101, control vs anti-huIL-6 treated, 332.2mm(3) [95% confidence interval {CI} = 216.6 to 449.8] vs 114.4mm(3) [95% CI = 12.79 to 216.0], P = .005).
Senescent cells can contribute to the growth of tumors by providing cytokines not expressed by proliferating cells, but required by these to thrive.
癌基因诱导的衰老（OIS）是一种肿瘤抑制机制。然而，衰老细胞仍然存活，并表现出独特的分泌组（也称为衰老相关分泌表型[SASP]或衰老信息传递分泌组[SMS]），矛盾的是，其中包括促肿瘤发生的因素。HER2 是一种受体酪氨酸激酶，也是人类乳腺癌的一种亚型的驱动致癌基因，其异位过表达可触发 OIS。然而，HER2 阳性肿瘤中尚未对细胞衰老进行表征。
我们采用基于其无法增殖的方法，从多种肿瘤模型（包括 HER2 阳性细胞、转基因小鼠（每组 3 只）和患者来源的异种移植瘤（PDX））中分离出自然发生的衰老细胞（从一个源自一个患者的 PDX 中获得的每组 6 只小鼠）。我们使用不同的生化和细胞生物学技术对这些衰老细胞的分泌组进行了表征。所有统计检验均为双侧检验。
我们发现，HER2 过表达的不同晚期乳腺癌模型中不断出现衰老细胞，约占肿瘤细胞的 5%。在这些模型中，IL-6 和其他细胞因子主要由自然发生的衰老细胞表达（HCC1954 细胞和表达衰老标志物的 HER2 阳性 PDX 细胞中分别有 95.1%和 45.0%表达 IL-6）。此外，抑制 IL-6 会损害 HER2 阳性 PDX 的生长（第 101 天的平均肿瘤体积，对照组与抗人 IL-6 治疗组相比，332.2mm3[95%置信区间{CI} = 216.6 至 449.8]与 114.4mm3[95%CI = 12.79 至 216.0]，P =.005）。
衰老细胞通过提供增殖细胞不表达但这些细胞生长所需的细胞因子，从而有助于肿瘤的生长。
