URBC, NAmur Research Institute for LIfe Science (NARILIS), University of Namur, Namur, Belgium.
Department of Dermatology and Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom.
Int J Biochem Cell Biol. 2018 May;98:113-126. doi: 10.1016/j.biocel.2018.03.005. Epub 2018 Mar 14.
Cutaneous Squamous Cell Carcinoma (cSCC) is the second most common type of non-melanoma skin cancer in white-skinned populations. cSCC is associated with sun exposure and aging, which is concomitant with an accumulation of senescent cells in the skin. The involvement of senescent cells in carcinogenesis has been highlighted in several cancer types and an interaction between cSCC cells and senescent cells is proposed, but still little explored. Tumor-associated effects are mostly attributed to the senescence-associated secretory phenotype (SASP). Here, we compared two in vitro models of senescence, namely replicative senescence and UVB-stress induced premature senescence (UVB-SIPS), in human dermal fibroblasts and screened for expression of SASP-related genes in our models. Next, the impact of senescent fibroblasts on three cSCC isogenic cell lines, representing different stages of keratinocyte malignant transformation, was studied. Only a limited impact on cSCC cell lines' growth and migration has been detected with conditioned media collected from senescent fibroblasts and indirect co-cultures. We then investigated the opposite interaction and found that cSCC cell lines maintained in indirect co-cultures with fibroblasts induced and reinforced their senescence state as shown by an increased proportion of cells positive for the senescence-associated β-galactosidase activity and an increased expression of several SASP-related genes. Moreover, these effects were modulated according to the stage of tumorigenesis of the different cSCC cell lines used. Finally, cSCC cell lines-co-cultures are associated with NF-κB activation in HDFs. Understanding the interplay between tumor cells and their microenvironment may have important influences in cancer research and therapeutic strategies.
皮肤鳞状细胞癌（cSCC）是白种人群中第二常见的非黑色素瘤皮肤癌。cSCC 与阳光照射和衰老有关，这伴随着皮肤中衰老细胞的积累。衰老细胞在几种癌症类型中的致癌作用已被强调，并且提出了 cSCC 细胞与衰老细胞之间的相互作用，但仍很少被探索。肿瘤相关效应主要归因于衰老相关分泌表型（SASP）。在这里，我们比较了两种体外衰老模型，即复制性衰老和 UVB 应激诱导的过早衰老（UVB-SIPS），在人真皮成纤维细胞中，并筛选了我们模型中 SASP 相关基因的表达。接下来，研究了衰老成纤维细胞对三种 cSCC 同基因细胞系的影响，这些细胞系代表了角质形成细胞恶性转化的不同阶段。仅从衰老成纤维细胞收集的条件培养基和间接共培养检测到对 cSCC 细胞系生长和迁移的有限影响。然后，我们研究了相反的相互作用，发现与成纤维细胞间接共培养的 cSCC 细胞系诱导并加强了它们的衰老状态，表现为衰老相关β-半乳糖苷酶活性阳性细胞的比例增加和几个 SASP 相关基因的表达增加。此外，这些效应根据使用的不同 cSCC 细胞系的肿瘤发生阶段而有所调节。最后，cSCC 细胞系-共培养与 HDFs 中的 NF-κB 激活有关。了解肿瘤细胞与其微环境之间的相互作用可能对癌症研究和治疗策略有重要影响。
