GSK-3α/β and MEK inhibitors assist the microenvironment of tumor initiation.

IF 2 4区生物学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Cytotechnology Pub Date : 2023-06-01 Epub Date: 2023-04-01 DOI:10.1007/s10616-023-00575-1

Ghmkin Hassan, Said M Afify, Maram H Zahra, Hend M Nawara, Kazuki Kumon, Yoshiaki Iwasaki, David S Salomon, Akimasa Seno, Masaharu Seno

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Abstract

Induced pluripotent stem cells (iPSCs) are useful tools for modeling diseases and developing personalized medicine. We have been developing cancer stem cells (CSCs) from iPSCs with conditioned medium (CM) of cancer-derived cells as the mimicry of the microenvironment of tumor initiation. However, the conversion of human iPSCs has not always been efficient with only CM. In this study, human iPSCs reprogrammed from monocytes of healthy volunteers were cultured in a media containing 50% of the CM from human pancreatic cancer derived BxPC3 cells supplemented with a MEK inhibitor (AZD6244) and a GSK-3α/β inhibitor (CHIR99021). The survived cells were assessed for the characteristics of CSCs in vitro and in vivo. As a result, they exhibited CSC phenotypes of self-renewal, differentiation, and malignant tumorigenicity. Primary culture of the malignant tumors of the converted cells exhibited the elevated expression of CSC related genes CD44, CD24 and EPCAM maintaining the expression of stemness genes. In conclusion, the inhibition of GSK-3α/β and MEK and the microenvironment of tumor initiation mimicked by the CM can convert human normal stem cells into CSCs. This study could provide insights into establishing potentially novel personalized cancer models which could help investigate the tumor initiation and screening of personalized therapies on CSCs.

Supplementary information: The online version contains supplementary material available at 10.1007/s10616-023-00575-1.

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GSK-3α/β和MEK抑制剂有助于肿瘤发生的微环境。

诱导多能干细胞（iPSC）是建模疾病和开发个性化药物的有用工具。我们一直在用癌症衍生细胞的条件培养基（CM）从iPSC中开发癌症干细胞（CSC），以模仿肿瘤发生的微环境。然而，仅使用CM对人iPSC的转化并不总是有效的。在本研究中，从健康志愿者的单核细胞重编程的人iPSC在含有50%来自补充有MEK抑制剂（AZD6244）和GSK-3α/β抑制剂（CHIR99021）的人胰腺癌症衍生的BxPC3细胞的CM的培养基中培养。对存活的细胞在体外和体内评估CSCs的特征。结果，它们表现出自我更新、分化和恶性致瘤性的CSC表型。转化细胞的恶性肿瘤的原代培养显示CSC相关基因CD44、CD24和EPCAM的表达升高，维持干性基因的表达。总之，GSK-3α/β和MEK的抑制作用以及CM模拟的肿瘤起始微环境可以将人类正常干细胞转化为CSCs。这项研究可以为建立潜在的新型个性化癌症模型提供见解，这有助于研究CSC的肿瘤起始和个性化治疗的筛选。补充信息：在线版本包含补充材料，可在10.1007/s10616-023-00575-1上获得。

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来源期刊

Cytotechnology 生物-生物工程与应用微生物

CiteScore

4.10

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： The scope of the Journal includes: 1. The derivation, genetic modification and characterization of cell lines, genetic and phenotypic regulation, control of cellular metabolism, cell physiology and biochemistry related to cell function, performance and expression of cell products. 2. Cell culture techniques, substrates, environmental requirements and optimization, cloning, hybridization and molecular biology, including genomic and proteomic tools. 3. Cell culture systems, processes, reactors, scale-up, and industrial production. Descriptions of the design or construction of equipment, media or quality control procedures, that are ancillary to cellular research. 4. The application of animal/human cells in research in the field of stem cell research including maintenance of stemness, differentiation, genetics, and senescence, cancer research, research in immunology, as well as applications in tissue engineering and gene therapy. 5. The use of cell cultures as a substrate for bioassays, biomedical applications and in particular as a replacement for animal models.