Setúbal Destro Rodrigues Maria Fernanda, Gammon Luke, Rahman Muhammad M, Biddle Adrian, Nunes Fabio Daumas, Mackenzie Ian C
Oral Pathology Department, School of Dentistry, University of São Paulo, São Paulo, Brazil.
Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Oncotarget. 2018 Feb 5;9(17):13488-13500. doi: 10.18632/oncotarget.24416. eCollection 2018 Mar 2.
The therapeutic responses of many solid tumours to chemo- and radio-therapies are far from fully effective but therapies targeting malignancy-related cellular changes show promise for further control. In head and neck squamous cell carcinoma, the epidermal growth factor receptor (EGFR) is commonly overexpressed and investigation of agents that block this receptor indicate a limited response when used alone but an ability to enhance the actions of other drugs. The hierarchical stem cell patterns present in tumours generate cellular heterogeneity and this is further complicated by cancer stem cells (CSC) shifting between epithelial (Epi-CSC) and mesenchymal (EMT-CSC) states. To clarify how such heterogeneity influences responses to EGFR blocking, we examined the effects of Cetuximab and Erlotinib on the cell sub-populations in HNSCC cell lines. These agents reduced cell proliferation for all subpopulations but induced little cell death. They did however induce large shifts of cells between the EMT-CSC, Epi-CSC and differentiating cell compartments. Loss of EMT-CSCs reduced cell motility and is expected to reduce invasion and metastasis. EGFR blocking also induced shifts of Epi-CSCs into the differentiating cell compartment which typically has greater sensitivity to chemo/radiation, an effect expected to enhance the overall response of tumour cell populations to adjunctive therapies.
许多实体瘤对化疗和放疗的治疗反应远未达到完全有效，但针对与恶性肿瘤相关的细胞变化的疗法显示出进一步控制肿瘤的前景。在头颈部鳞状细胞癌中，表皮生长因子受体（EGFR）通常过度表达，对阻断该受体的药物进行研究表明，单独使用时反应有限，但具有增强其他药物作用的能力。肿瘤中存在的分层干细胞模式会产生细胞异质性，而癌症干细胞（CSC）在上皮（Epi-CSC）和间充质（EMT-CSC）状态之间转换会使这种异质性更加复杂。为了阐明这种异质性如何影响对EGFR阻断的反应，我们研究了西妥昔单抗和厄洛替尼对HNSCC细胞系中细胞亚群的影响。这些药物降低了所有亚群的细胞增殖，但几乎没有诱导细胞死亡。然而，它们确实诱导了EMT-CSC、Epi-CSC和分化细胞区室之间的大量细胞转移。EMT-CSCs的减少降低了细胞运动性，预计会减少侵袭和转移。EGFR阻断还诱导Epi-CSCs向分化细胞区室转移，分化细胞区室通常对化疗/放疗更敏感，这一效应预计会增强肿瘤细胞群体对辅助治疗的总体反应。
