Genenger Benjamin, Perry Jay R, Ashford Bruce, Ranson Marie
School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia.
Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.
Discov Oncol. 2022 Jun 6;13(1):42. doi: 10.1007/s12672-022-00510-4.
Cutaneous squamous cell carcinoma (cSCC) is a disease with globally rising incidence and poor prognosis for patients with advanced or metastatic disease. Epithelial-mesenchymal transition (EMT) is a driver of metastasis in many carcinomas, and cSCC is no exception. We aimed to provide a systematic overview of the clinical and experimental evidence for EMT in cSCC, with critical appraisal of type and quality of the methodology used. We then used this information as rationale for potential drug targets against advanced and metastatic cSCC. All primary literature encompassing clinical and cell-based or xenograft experimental studies reporting on the role of EMT markers or related signalling pathways in the progression of cSCC were considered. A screen of 3443 search results yielded 86 eligible studies comprising 44 experimental studies, 22 clinical studies, and 20 studies integrating both. From the clinical studies a timeline illustrating the alteration of EMT markers and related signalling was evident based on clinical progression of the disease. The experimental studies reveal connections of EMT with a multitude of factors such as genetic disorders, cancer-associated fibroblasts, and matrix remodelling via matrix metalloproteinases and urokinase plasminogen activator. Additionally, EMT was found to be closely tied to environmental factors as well as to stemness in cSCC via NFκB and β-catenin. We conclude that the canonical EGFR, canonical TGF-βR, PI3K/AKT and NFκB signalling are the four signalling pillars that induce EMT in cSCC and could be valuable therapeutic targets. Despite the complexity, EMT markers and pathways are desirable biomarkers and drug targets for the treatment of advanced or metastatic cSCC.
皮肤鳞状细胞癌（cSCC）是一种全球发病率不断上升的疾病，对于晚期或转移性疾病患者预后较差。上皮-间质转化（EMT）是许多癌症转移的驱动因素，cSCC也不例外。我们旨在系统概述cSCC中EMT的临床和实验证据，并对所用方法的类型和质量进行批判性评估。然后，我们将这些信息作为针对晚期和转移性cSCC潜在药物靶点的理论依据。所有涵盖临床以及基于细胞或异种移植实验研究的原始文献，只要报告了EMT标志物或相关信号通路在cSCC进展中的作用，均在考虑范围内。对3443条搜索结果进行筛选后，得到86项符合条件的研究，包括44项实验研究、22项临床研究以及20项综合两者的研究。从临床研究中可以明显看出，根据疾病的临床进展，有一个展示EMT标志物和相关信号变化的时间线。实验研究揭示了EMT与多种因素的联系，如基因紊乱、癌症相关成纤维细胞，以及通过基质金属蛋白酶和尿激酶型纤溶酶原激活剂进行的基质重塑。此外，发现EMT在cSCC中还通过NFκB和β-连环蛋白与环境因素以及干性密切相关。我们得出结论，经典的表皮生长因子受体（EGFR）、经典的转化生长因子-β受体（TGF-βR）、磷脂酰肌醇-3激酶/蛋白激酶B（PI3K/AKT）和NFκB信号通路是诱导cSCC中EMT的四个信号支柱，可能是有价值的治疗靶点。尽管情况复杂，但EMT标志物和信号通路仍是治疗晚期或转移性cSCC的理想生物标志物和药物靶点。
