Background: Remarkable differences exist in the outcome of systemic cancer therapies. Lymphomas and leukemias generally respond well to systemic chemotherapies, while solid cancers often fail. We engineered different human cancer cells lines to uniformly express a modified herpes simplex virus thymidine kinase TK.007 as a suicide gene when ganciclovir (GCV) is applied, thus in theory achieving a similar response in all cell lines. Methods: Fifteen different cell lines were engineered to express theTK.007gene. XTT-cell proliferation assays were performed and the IC50-values were calculated. Functional kinome profiling, mRNA sequencing, and bottom-up proteomics analysis with Ingenuity pathway analysis were performed. Results: GCV potency varied among cell lines, with lymphoma and leukemia cells showing higher susceptibility than solid cancer cells. Functional kinome profiling implies a contribution of the SRC family kinases and decreased overall kinase activity. mRNA sequencing highlighted alterations in the MAPK pathways and bottom-up proteomics showed differences in apoptotic and epithelial junction signaling proteins. Conclusions: The histogenetic origin of cells influenced the susceptibility of human malignant cells towards cytotoxic agents with leukemias and lymphomas being more sensitive than solid cancer cells.
背景：系统性癌症疗法的疗效存在显著差异。淋巴瘤和白血病通常对系统性化疗反应良好，而实体瘤则往往疗效不佳。我们通过基因工程改造了不同的人类癌细胞系，使其在应用更昔洛韦（GCV）时能稳定表达经修饰的单纯疱疹病毒胸苷激酶TK.007作为自杀基因，理论上可在所有细胞系中实现相似的应答反应。 方法：对十五种不同细胞系进行基因工程改造以表达TK.007基因。通过XTT细胞增殖实验测定并计算IC50值。同时进行了功能性激酶组谱分析、mRNA测序、自下而上的蛋白质组学分析及Ingenuity通路分析。 结果：GCV的效力在不同细胞系间存在差异，淋巴瘤和白血病细胞比实体瘤细胞表现出更高的敏感性。功能性激酶组谱分析提示SRC家族激酶的参与及整体激酶活性降低。mRNA测序显示MAPK通路发生改变，蛋白质组学分析则发现凋亡相关蛋白和上皮连接信号蛋白存在差异。 结论：细胞的组织发生起源影响人类恶性细胞对细胞毒性药物的敏感性，白血病和淋巴瘤细胞比实体瘤细胞更为敏感。
肿瘤(癌症)患者之家