腺鳞癌转化在肺癌耐药中的功能和机制研究

Functional and mechanistic studies on the transition from adenocarcinoma to squamous cell carcinoma in lung cancer drug resistance

摘要:

肺癌是一种高致死率的疾病，具有高度的异质性和可塑性。基于病理学分型，肺癌可分为小细胞肺癌和非小细胞肺癌，后者又可细分为腺癌，鳞癌和大细胞癌。临床上可观察到同一个肿瘤内部混合腺癌和鳞癌(腺鳞癌)，或小细胞肺癌混合腺癌或鳞癌(混合型小细胞肺癌)。其中，腺鳞癌在临床上占非小细胞肺癌的 4%~10%。近几年越来越多的临床案例报道，肺腺癌患者经过化疗、靶向治疗或免疫治疗，肿瘤类型会从腺癌转变成鳞癌，并表现出耐药性。动物模型的研究发现， 肝激酶 B1(Lkb1)缺失会促进小鼠肺腺癌向鳞癌转化，而腺鳞癌是转化过程的中间态。从细胞起源来看，Club 细胞和 AT2 (Alveolar Epithelial Type 2)来源的肺腺癌可以转化成鳞癌。从分子机制来看，肺腺癌向鳞癌转化的过程中，胞外基质重塑以及代谢重编程会导致细胞氧化应激异常，使得活性氧(Reactive Oxygen Species，ROS)水平急剧上升并诱导 p63 上调，最终导致腺鳞癌转化并伴随肿瘤耐药。本综述将总结近年来肺腺鳞癌转化领域的进展并阐述其与耐药的关系，以期为深入理解临床肺癌的可塑性奠定理论基础。

Abstract:

Lung cancer, featured with strong heterogeneity and plasticity, is the most devastating disease worldwide. Based on histological classification, lung cancer can be categorized as small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), among which the latter could be further classified into lung adenocarcinoma (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC). Mixed pathologies of ADC and SCC (Adenosquamous Cell Carcinoma, Ad-SCC) or mixed SCLC with ADC and/or SCC pathology (mixed SCLC) have been consistently observed in clinic. Lung Ad-SCC is about 4%~10% of NSCLC. Recent clinical studies have shown that epidermal growth factor receptor (EGFR) mutant lung ADC could transition to SCC in relapsed patients failed from chemotherapy, targeted therapy or immunotherapy. Studies of liver kinase B1 (Lkb1)-defi cient mouse model have provided convincing evidence in supporting that lung ADC derived from club cells or AT2 cells (Alveolar Epithelial Type 2 Cells) is prone to squamous transition, and the mixed AdSCC is identified as the intermediate stage. Mechanistic studies demonstrate that uncontrolled accumulation of excessive oxidative stress resulted from extracellular matrix depletion and metabolic reprogramming somehow triggers the up-regulation of SCC-lineage specific transcription factor, p63, which eventually promotes the squamous transition. Such transition confers lung tumors with drug resistance in mouse models. This review will summarize current research progress of the transition from lung ADC to SCC as well as its correlation with drug resistance acquisition, which hopefully provides novel insights into lung cancer plasticity and drug resistance.