Pallasch Fabian Bernhard, Freytag Vera, Kriegs Malte, Gatzemeier Dennis, Mair Thomas, Voss Hannah, Riecken Kristoffer, Dawood Mona, Fehse Boris, Efferth Thomas, Schlüter Hartmut, Schumacher Udo
Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Department of Diagnostic and Interventional Radiology, Faculty of Medicine, Medical Center-University of Freiburg, 79106 Freiburg Im Breisgau, Germany.
Cancers (Basel). 2024 Jun 19;16(12):2278. doi: 10.3390/cancers16122278.
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.
Fifteen different cell lines were engineered to express the gene. XTT-cell proliferation assays were performed and the IC-values were calculated. Functional kinome profiling, mRNA sequencing, and bottom-up proteomics analysis with Ingenuity pathway analysis were performed.
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.
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.
系统性癌症治疗的结果存在显著差异。淋巴瘤和白血病通常对全身化疗反应良好，而实体癌往往治疗失败。我们构建了不同的人类癌细胞系，使其在应用更昔洛韦（GCV）时一致表达一种修饰的单纯疱疹病毒胸苷激酶TK.007作为自杀基因，从而在理论上使所有细胞系产生相似的反应。
构建15种不同的细胞系以表达该基因。进行XTT细胞增殖试验并计算IC值。进行了功能激酶组分析、mRNA测序以及采用Ingenuity通路分析的自下而上蛋白质组学分析。
GCV的效力在不同细胞系中有所不同，淋巴瘤和白血病细胞比实体癌细胞表现出更高的敏感性。功能激酶组分析表明SRC家族激酶起作用且总体激酶活性降低。mRNA测序突出了丝裂原活化蛋白激酶（MAPK）通路的改变，自下而上蛋白质组学显示凋亡和上皮连接信号蛋白存在差异。
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，白血病和淋巴瘤比实体癌细胞更敏感。
