Sarazin Thomas, Collin Guillaume, Buache Emilie, Van Gulick Laurence, Charpentier Céline, Terryn Christine, Morjani Hamid, Saby Charles
Université de Reims Champagne-Ardenne, Unité BioSpecT, EA7506, SFR CAP-Santé, UFR de Pharmacie, Reims, France.
Université de Reims Champagne Ardenne, Plate-forme Imagerie Cellulaire et Tissulaire (PICT), Reims, France.
Front Oncol. 2020 Sep 10;10:1593. doi: 10.3389/fonc.2020.01593. eCollection 2020.
Type I collagen is the major structural component of lung stroma. Because of its long half-life, type I collagen undergoes post-translational modifications such as glycation during aging process. These modifications have been shown to impact the structural organization of type I collagen fibers. In the present work we evaluated the impact of collagen aging on lung carcinoma cells response to erlotinib-induced cytotoxicity and apoptosis, and on Epidermal Growth Factor Receptor (EGFR) expression and phosphorylation. To this end, experiments were performed in 2D and 3D matrix models established from type I collagen extracted from adult (10 weeks-old) and old (100 weeks-old) rat's tail tendons. Our results show that old collagen induces a significant increase in EGFR expression and phosphorylation when compared to adult collagen in 3D matrix but not in 2D coating. Such modification was associated to an increase in the IC of erlotinib in the presence of old collagen and a lower sensitivity to drug-induced apoptosis. These data suggest that collagen aging confers resistance to the cytotoxic and apoptotic effects of therapies targeting EGFR kinase function in lung carcinoma. Moreover, our data underline the importance of the 3D matrix environment in this process.
I型胶原蛋白是肺基质的主要结构成分。由于其半衰期长，I型胶原蛋白在衰老过程中会经历翻译后修饰，如糖基化。这些修饰已被证明会影响I型胶原纤维的结构组织。在本研究中，我们评估了胶原蛋白老化对肺癌细胞对厄洛替尼诱导的细胞毒性和凋亡的反应，以及对表皮生长因子受体（EGFR）表达和磷酸化的影响。为此，我们在从成年（10周龄）和老年（100周龄）大鼠尾腱中提取的I型胶原蛋白建立的二维和三维基质模型中进行了实验。我们的结果表明，与二维包被相比，在三维基质中，与成年胶原蛋白相比，老化胶原蛋白会导致EGFR表达和磷酸化显著增加。这种修饰与在老化胶原蛋白存在下厄洛替尼的IC增加以及对药物诱导的凋亡敏感性降低有关。这些数据表明，胶原蛋白老化赋予肺癌对靶向EGFR激酶功能的治疗的细胞毒性和凋亡作用的抗性。此外，我们的数据强调了三维基质环境在这一过程中的重要性。
