Department of Oral and Maxillofacial Surgery, Kochi Medical School, Kochi University, Nankoku, Japan.
Cancer Sci. 2022 Feb;113(2):609-621. doi: 10.1111/cas.15225. Epub 2021 Dec 15.
Various cell types secrete exosomes into their surrounding extracellular space, which consequently affect the function and activity of recipient cells. Numerous studies have showed that tumor cell-derived exosomes play important roles in tumor growth and progression. Although a variety of endocytic pathways are reportedly involved in the cellular uptake of exosomes, detailed mechanisms remain unknown. The present study demonstrated that treatment with recombinant epidermal growth factor (EGF) time- and dose-dependently promoted cellular uptake of oral squamous cell carcinoma (OSCC) cell-derived exosomes into OSCC cells themselves. Conversely, EGF receptor (EGFR) knockdown and treatment with EGFR inhibitors, including erlotinib and cetuximab, abrogated OSCC cell uptake of exosomes. The macropinocytosis inhibitor 5-(N-ethyl-N-isopropyl) amiloride (EIPA) blocked the effects of active EGF/EGFR signaling on uptake of OSCC cell-derived exosomes. These EGFR inhibitors also suppressed OSCC cell-derived exosome-induced proliferation, migration, invasion, stemness, and chemoresistance of OSCC cells. Taken together, the data presented herein suggest that EGFR inhibitors might inhibit the malignant potential of OSCC cells through direct inhibition of not only EGFR downstream signaling pathway but also cellular uptake of OSCC cell-derived exosomes through macropinocytosis.
各种细胞类型将外泌体分泌到其周围的细胞外空间，从而影响受体细胞的功能和活性。大量研究表明，肿瘤细胞来源的外泌体在肿瘤生长和进展中发挥重要作用。尽管据报道有多种内吞途径参与外泌体的细胞摄取，但详细的机制仍不清楚。本研究表明，用重组表皮生长因子（EGF）处理可时间和剂量依赖性地促进口腔鳞状细胞癌（OSCC）细胞来源的外泌体进入 OSCC 细胞本身。相反，EGF 受体（EGFR）敲低和 EGFR 抑制剂（包括厄洛替尼和西妥昔单抗）处理则消除了 OSCC 细胞对外泌体的摄取。巨胞饮抑制剂 5-（N-乙基-N-异丙基）amiloride（EIPA）阻断了活性 EGF/EGFR 信号对 OSCC 细胞来源的外泌体摄取的影响。这些 EGFR 抑制剂还抑制了 OSCC 细胞来源的外泌体诱导的 OSCC 细胞增殖、迁移、侵袭、干性和化疗耐药性。综上所述，本文的数据表明，EGFR 抑制剂可能通过直接抑制 EGFR 下游信号通路以及通过巨胞饮作用抑制 OSCC 细胞来源的外泌体的细胞摄取，从而抑制 OSCC 细胞的恶性潜能。
