CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：The inhibition of pancreatic cancer progression by K-Ras-overexpressing mesenchymal stem cell-derived secretomes.
The inhibition of pancreatic cancer progression by K-Ras-overexpressing mesenchymal stem cell-derived secretomes.
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胰腺导管腺癌（PDAC）侵袭性强，患者生存率低。为探索K-Ras原癌基因尚未明确的功能，研究人员在间充质干细胞（MSC）中激活K-Ras，并考察MSC条件培养液（CM）对PDAC的作用。K-Ras过表达增强了MSC中的PI3K信号；由K-Ras/PI3K激活的MSC产生的CM可降低肿瘤细胞增殖和迁移，并抑制新鲜分离的人PDAC离体培养物生长。CM与PDAC常用化疗药物吉西他滨联用时具有叠加抗肿瘤作用。在小鼠模型中，全身给予CM可抑制PDAC在肺部定植。MSC-CM富含莫埃辛（MSN），该蛋白可通过与CD44相互作用发挥细胞外肿瘤抑制作用。通过激活PKA的外周血单个核细胞也可产生具有肿瘤抑制作用的CM。总之，本研究显示，激活K-Ras和PI3K可将MSC-CM工程化为肿瘤抑制剂；MSN-CD44调控轴可能部分介导这一潜在的新型PDAC治疗策略。
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor survival. To explore an uncharted function of K-Ras proto-oncogene, K-Ras was activated in mesenchymal stem cells (MSCs) and the effects of MSC conditioned medium (CM) on PDAC were examined. Overexpression of K-Ras elevated PI3K signaling in MSCs, and K-Ras/PI3K-activated MSC-derived CM reduced the proliferation and migration of tumor cells, as well as the growth of ex vivo freshly isolated human PDAC cultures. CM's anti-tumor capability was additive with Gemcitabine, a commonly used chemotherapeutic drug in the treatment of PDAC.
The systemic administration of CM in a mouse model suppressed the colonization of PDAC in the lung. MSC CM was enriched with Moesin (MSN), which acted as an extracellular tumor-suppressing protein by interacting with CD44. Tumor-suppressive CM was also generated by PKA-activated peripheral blood mononuclear cells.
Collectively, this study demonstrated that MSC CM can be engineered to act as a tumor-suppressive agent by activating K-Ras and PI3K, and the MSN-CD44 regulatory axis is in part responsible for this potential unconventional option in the treatment of PDAC.
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