Wu Jin-Long, Xu Cheng-Feng, Yang Xu-Hui, Wang Ming-Song
Department of Thoracic Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai City, 200011, China.
Department of Pharmacy, Shidong Hospital of Shanghai Yangpu District, Shanghai City, 200438, China.
Heliyon. 2023 Sep 14;9(9):e20185. doi: 10.1016/j.heliyon.2023.e20185. eCollection 2023 Sep.
The tumor microenvironment, especially the extracellular matrix (ECM), is strongly associated with tumor cell proliferation and metastasis. Numerous studies have provided evidence suggesting that fibronectin (FN) in ECM supports cancer cell escape and contributes to cell migration, resulting in distant cancer metastasis and poor outcomes in patients. In our study, it was demonstrated that FN expression was elevated in tumor tissues from highly malignant NSCLC patients, compared to those with low malignancy (p = 0.0076). Importantly, FN promoted proliferative phenotypes and strengthened tumorigenesis capabilities in NSCLC cells, including A549 and Lewis cells, leading to sustained tumor growth . Mechanistically, it was identified that FN facilitated the activation of the integrin αvβ3/PI3K/AKT signaling pathway, which subsequently upregulated tumor stemness through the downstream transcription factor SOX2. Blockade of integrin αvβ3 signal efficiently suppressed NSCLC proliferation and tumorigenesis both and . In conclusion, our study demonstrated that extracellular FN could facilitate NSCLC development through the integrin αvβ3/PI3K/AKT/SOX2 signaling pathway. Blockade of integrin αvβ3 could efficiently enhance the anticancer effects of chemotherapy, offering an innovative approach for clinical NSCLC therapy.
肿瘤微环境，尤其是细胞外基质（ECM），与肿瘤细胞的增殖和转移密切相关。大量研究表明，ECM中的纤连蛋白（FN）支持癌细胞逃逸并促进细胞迁移，导致癌症远处转移和患者预后不良。在我们的研究中，结果显示与低恶性度的非小细胞肺癌（NSCLC）患者相比，高恶性度患者肿瘤组织中的FN表达升高（p = 0.0076）。重要的是，FN促进了NSCLC细胞（包括A549和Lewis细胞）的增殖表型并增强了其肿瘤发生能力，导致肿瘤持续生长。从机制上来说，已确定FN促进整合素αvβ3/PI3K/AKT信号通路的激活，随后通过下游转录因子SOX2上调肿瘤干性。整合素αvβ3信号的阻断有效地抑制了NSCLC的增殖和肿瘤发生。总之，我们的研究表明细胞外FN可通过整合素αvβ3/PI3K/AKT/SOX2信号通路促进NSCLC的发展。整合素αvβ3的阻断可有效增强化疗的抗癌效果，为临床NSCLC治疗提供了一种创新方法。
