摘要
巨胞饮是一个在真核生物中高度保守的、依赖肌动蛋白和溶酶体的内吞途径,通过形成巨胞饮小体非选择性地摄取细胞外可溶性物质.这一过程在多种生物学功能中发挥重要作用,包括抗原递呈、细胞代谢调控以及药物递送等.近年来,巨胞饮因其在胰腺导管腺癌等恶性肿瘤发展和转移中的关键作用而受到广泛关注,阻断巨胞饮能显著抑制肿瘤发展,靶向巨胞饮治疗肿瘤具有重要的临床转化价值,有关肿瘤巨胞饮发生的分子调控机制研究取得了许多重要研究进展.本文在简要概述巨胞饮发生过程的基础上,综述并讨论了最近关于巨胞饮在肿瘤细胞或肿瘤相关成纤维细胞响应营养压力时的信号转导途径,其中包括EGFR-PAK途径、mTOR、Ca^(2+)-CaMKK2-AMPK-RAC1途径、Ca^(2+)-ARHGEF2-RAC1和DDR1-NF-κB-p62/SQSTM1-NRF2途径,抗氧化因子NRF2介导的巨胞饮转录调控机制,巨胞饮与另一营养获取途径细胞自噬的相互调控关系,以及新发现的巨胞饮相关蛋白,包括VATPase、SDC1、LYSET、TPC、TMEM206和Slc15A调控巨胞饮发生的作用和机制.此外,本文还讨论了未来巨胞饮在发生机制研究和抑制剂开发方面所面临的问题及可能的解决策略.理解肿瘤巨胞饮发生的分子调控机制对于建立靶向巨胞饮途径的抗肿瘤策略具有十分重要的意义.
Macropinocytosis is a highly conserved,actin-dependent endocytic pathway in eukaryotic cells that facilitates the non-selective engulfment of extracellular soluble substances by macropinosomes.These macropinosomes can either fuse with lysosomes for degradation or recycle back to the plasma membrane,to replenish membrane receptors.As a vital cellular process,macropinocytosis is important in various biological functions,including immune responses,cellular metabolism,and the progression of several types of advanced cancers.The function of macropinocytosis in the progression of malignant tumors,such as pancreatic ductal adenocarcinoma(PDAC),has been a focus of research.An intriguing aspect of PDAC is how tumor cells exploit macropinocytosis to scavenge nutrients from the surrounding tumor microenvironment.Specifically,collagen,a major component of the extracellular matrix,is an important source of nutrients.Tumor cells internalize collagen via macropinocytosis,followed by its degradation into amino acids and intermediates of the tricarboxylic acid(TCA)cycle.These metabolites facilitate tumor growth and metastasis,particularly to the liver.Inhibitors of macropinocytosis,alone or in combination with other antitumor therapies such as autophagy inhibitors,chemotherapy,or immune checkpoint inhibitors,significantly reduce tumor growth and metastasis.These findings suggest that targeting the macropinocytosis pathway is a promising therapeutic approach.Understanding the molecular regulatory mechanisms that underlie macropinocytosis in tumors is thus essential for the development of novel treatments for cancer.There has been considerable progress in understanding the molecular regulatory mechanisms that control macropinocytosis,particularly in the context of tumor biology.This review first focuses on macropinocytosis to provide readers with insight into this physiological pathway,followed by a discussion of recent findings related to its molecular regulation.Tumor cells often experience nutrient stress due to their rapid growth and the abnormal vascularization of solid tumors.The activation of macropinocytosis in response to this stress promotes the acquisition of extracellular nutrients,such as amino acids and glucose,to meet the metabolic demands of the tumor.Several key signaling pathways regulate macropinocytosis in tumors under nutrient stress.One important pathway is the EGFRPAK axis,which activates macropinocytosis in tumor cells,in response to glutamine deprivation.Unlike cancer cells,in cancerassociated fibroblasts(CAFs),macropinocytosis is initiated by calcium ion(Ca 2+)-dependent pathways,such as Ca 2+-CaMKK2-AMPKRAC1 and Ca 2+-ARHGEF2-RAC1 under glutamine starvation.Furthermore,the DDR1-NF-κB-p62/SQSTM1-NRF2 pathway mediates macropinocytosis under both glutamine-deprivation and glucose-depletion conditions.Notably,NRF2 is a critical regulator of the transcription of macropinocytosis-related genes,which promote the survival of cancer cells when autophagy,another nutrient-scavenging pathway,is inhibited.By contrast,when macropinocytosis is downregulated,the resulting low ATP level activates autophagy,suggesting a compensatory relationship between these two pathways.In addition to these pathways,several novel macropinocytosis-related proteins have been identified,including V-ATPase,SDC1,LYSET,TPC,TMEM206,and Slc15A.These proteins are involved in several aspects of macropinocytosis,such as cholesterol trafficking,RAC1 activation,lysosomal enzyme trafficking,macropinosome resolution,and macropinocytosis activation in Dictyostelium discoideum.Despite the above-mentioned advancements,our understanding of macropinocytosis is incomplete.More research is needed to identify the proteins localized to macropinosomes,the mechanisms of macropinosome acidification,and the molecular machinery that connects macropinocytosis and autophagy.Additionally,the identification of highly specific and effective inhibitors of macropinocytosis would enable the development of novel therapeutics.Future research will benefit from the integration of high-resolution mass spectrometry,ultra-high-resolution confocal microscopy,and structural biology techniques.These advanced tools will enable a detailed examination of the membrane composition of macropinosomes and identification of the mechanisms by which macropinocytosis inhibitors exert their effects.Further exploration of these issues will not only provide a more comprehensive understanding of the formation and molecular regulatory mechanisms of macropinocytosis but also accelerate the translation of these pathways from basic biology to clinical applications.
作者
王春岚
袁子航
林博
孟姿汝
金喆
杨非
苏华
Chunlan Wang;Zihang Yuan;Bo Lin;Ziru Meng;Zhe Jin;Fei Yang;Hua Su(Institutes of Biomedical Sciences,Fudan University,Shanghai 200032,China;Department of Hepatobiliary Surgery,The First Affiliated Hospital of Anhui Medical University,Hefei 230022,China;Liver Cancer Institute,Zhongshan Hospital,Fudan University,Shanghai 200032,China)
出处
《科学通报》
北大核心
2025年第15期2235-2248,共14页
Chinese Science Bulletin
基金
上海市科学技术委员会(23ZR1413600)
国家自然科学基金(82372884,82372644,2022hwyq29)
复旦大学曹娥江基础研究基金(24FCA02)
安徽省高校杰出青年科研项目(2024AH020007)资助。
作者简介
王春岚,同等贡献;袁子航,同等贡献;林博,同等贡献;联系人:杨非,E-mail:fightingforever77@126.com;联系人:苏华,E-mail:suhua@fudan.edu.cn。
