外科理论与实践

外科理论与实践 >

2023 , Vol. 28 >Issue 01: 7 - 16

DOI: https://doi.org/10.16139/j.1007-9610.2023.01.02

专家论坛

胃癌基础与转化研究的热点问题

展开
  • 上海交通大学医学院附属瑞金医院普外科 上海消化外科研究所 上海市胃肿瘤重点实验室，上海 200025

收稿日期: 2023-01-16

  网络出版日期: 2023-08-02

收起

Hotspots in basic and translational research of gastric cancer

Expand
  • Department of General Surgery, Shanghai Institute of Digestive Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

Received date: 2023-01-16

  Online published: 2023-08-02

Fold

摘要

胃癌的发病率、死亡率均较高，而胃癌的总体疗效不满意。临床上面临的早期诊断率低、肿瘤异质性、缺乏精确分型和精准治疗方案、治疗抵抗、复发与转移等问题是胃癌总体疗效不高的关键所在。为根本解决上述临床问题，需加强胃癌的基础研究，包括肿瘤基因组学、基因编辑、肿瘤微环境、炎症和衰老与肿瘤的关系、细胞分化障碍、细胞自噬与死亡、代谢紊乱、免疫治疗和药物开发等核心命题。本文将概述临床上胃癌治疗所面临的问题，并阐述针对这些临床问题的基础研究重点领域，为胃癌基础及转化研究提供思路。

关键词： 胃癌; 转化医学; 基因组学; 免疫治疗

本文引用格式

李建芳, 余俊贤, 严超, 朱正纲, 刘炳亚 . 胃癌基础与转化研究的热点问题[J]. 外科理论与实践, 2023 , 28(01) : 7 -16 . DOI: 10.16139/j.1007-9610.2023.01.02

Abstract

The morbidity and mortality of gastric cancer are high, while the overall therapeutic effect is poor without satisfactory. Clinical obstacles, such as low early-diagnosis rate, tumor heterogeneity, lack of accurate classification and precise treatment, therapeutic resistance, recurrence and metastasis, are the key point issues to the lower efficacy in treatment of gastric cancer. In order to solve these clinical problems, it is necessary to devote more energy to the basic research of gastric cancer, including tumor genomics; gene editing; tumor microenvironment; inflammation, aging and tumor; cell differentiation disorders; autophagy and cell death; metabolic disorders; immunotherapy and drug development. This paper will summarize the clinical obstacles in the treatment of gastric cancer, and describe the directions of basic research on these clinical problems in future, so as to provide notions for the translational research of gastric cancer.

Key words： Gastric cancer; Translational medicine; Genomics; Immunotherapy

参考文献

[1] EISENSTEIN M. Reading cancer's blueprint[J]. Nat Biotechnol, 2012, 30(7):581-584.
[2] GILBERTSON R J. Mapping cancer origins[J]. Cell, 2011, 145(1):25-29.
[3] ZENG D, LI M, ZHOU R, et al. Tumor microenvironment characterization in gastric cancer identifies prognostic and immunotherapeutically relevant gene signatures[J]. Cancer Immunol Res, 2019, 7(5):737-750.
[4] CHIA N Y, TAN P. Molecular classification of gastric cancer[J]. Ann Oncol, 2016, 27(5):763-769.
[5] Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma[J]. Nature, 2014, 513(7517):202-209.
[6] CRISTESCU R, LEE J, NEBOZHYN M, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes[J]. Nat Med, 2015, 21(5):449-456.
[7] PLANA D, PALMER A C, SORGER P K. Independent drug action in combination therapy: implications for precision oncology[J]. Cancer Discov, 2022, 12(3):606-624.
[8] JIN H, WANG L, BERNARDS R. Rational combinations of targeted cancer therapies: background, advances and challenges[J]. Nat Rev Drug Discov, 2022. Online ahead of print.
[9] HANAHAN D, WEINBERG R A. The hallmarks of cancer[J]. Cell, 2000, 100(1):57-70.
[10] HANAHAN D, WEINBERG R A. Hallmarks of cancer: the next generation[J]. Cell, 2011, 144(5):646-674.
[11] HANAHAN D. Hallmarks of cancer: new dimensions[J]. Cancer Discov, 2022, 12(1):31-46.
[12] HUANG K K, RAMNARAYANAN K, ZHU F, et al. Genomic and epigenomic profiling of high-risk intestinal metaplasia reveals molecular determinants of progression to gastric cancer[J]. Cancer Cell, 2018, 33(1):137-150.
[13] YEOH K G, TAN P. Mapping the genomic diaspora of gastric cancer[J]. Nat Rev Cancer, 2022, 22(2):71-84.
[14] CHEN K, YANG D, LI X, et al. Mutational landscape of gastric adenocarcinoma in Chinese: implications for prognosis and therapy[J]. Proc Natl Acad Sci U S A, 2015, 112(4):1107-1112.
[15] WANG K, YUEN S T, XU J, et al. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer[J]. Nat Genet, 2014, 46(6):573-582.
[16] MANGHWAR H, LINDSEY K, ZHANG X, et al. CRISPR/Cas system: recent advances and future prospects for genome editing[J]. Trends Plant Sci, 2019, 24(12):1102-1125.
[17] ROSENBLUM D, GUTKIN A, KEDMI R, et al. CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy[J]. Sci Adv, 2020, 6(47):eabc9450.
[18] FOY S P, JACOBY K, BOTA D A, et al. Non-viral precision T cell receptor replacement for personalized cell therapy[J]. Nature, 2022:1-10.
[19] SAHA K, SONTHEIMER E J, BROOKS P J, et al. The NIH somatic cell genome editing program[J]. Nature, 2021, 592(7853):195-204.
[20] GRADY W M, YU M, MARKOWITZ S D. Epigenetic alterations in the gastrointestinal tract: current and emerging use for biomarkers of cancer[J]. Gastroentero-logy, 2021, 160(3):690-709.
[21] HUANG T, SONG C, ZHENG L, et al. The roles of extracellular vesicles in gastric cancer development, microenvironment, anti-cancer drug resistance, and therapy[J]. Mol Cancer, 2019, 18(1):62.
[22] EISENSTEIN M. Seven technologies to watch in 2022[J]. Nature, 2022, 601(7894):658-661.
[23] KUMAR V, RAMNARAYANAN K, SUNDAR R, et al. Single-cell atlas of lineage states, tumor microenvironment, and subtype-specific expression programs in gastric cancer[J]. Cancer Discov, 2022, 12(3):670-691.
[24] COUSSENS L M, WERB Z. Inflammation and cancer[J]. Nature, 2002, 420(6917):860-867.
[25] DIAKOS C I, CHARLES K A, MCMILLAN D C, et al. Cancer-related inflammation and treatment effectiveness[J]. Lancet Oncol, 2014, 15(11):e493-e503.
[26] SCHMITT C A, WANG B, DEMARIA M. Senescence and cancer-role and therapeutic opportunities[J]. Nat Rev Clin Oncol, 2022, 19(10):619-636.
[27] BLAGOSKLONNY M V. Hallmarks of cancer and hallmarks of aging[J]. Aging (Albany NY), 2022, 14(9):4176-4187.
[28] PRASETYANTI P R, MEDEMA J P. Intra-tumor heterogeneity from a cancer stem cell perspective[J]. Mol Cancer, 2017, 16(1):41.
[29] FATEHULLAH A, TERAKADO Y, SAGIRAJU S, et al. A tumour-resident Lgr5(+) stem-cell-like pool drives the establishment and progression of advanced gastric cancers[J]. Nat Cell Biol, 2021, 23(12):1299-1313.
[30] WILLET S G, LEWIS M A, MIAO Z F, et al. Regenerative proliferation of differentiated cells by mTORC1-dependent paligenosis[J]. EMBO J, 2018, 37(7):e98311.
[31] MIAO Z F, LEWIS M A, CHO C J, et al. A dedicated evolutionarily conserved molecular network licenses differentiated cells to return to the cell cycle[J]. Dev Cell, 2020, 55(2):178-194.
[32] WHITE E, MEHNERT J M, CHAN C S. Autophagy, metabolism, and cancer[J]. Clin Cancer Res, 2015, 21(22):5037-5046.
[33] LI X, HE S, MA B. Autophagy and autophagy-related proteins in cancer[J]. Mol Cancer, 2020, 19(1):12.
[34] WU Q, MA J, WEI J, et al. lncRNA SNHG11 promotes gastric cancer progression by activating the Wnt/beta-catenin pathway and oncogenic autophagy[J]. Mol Ther, 2021, 29(3):1258-1278.
[35] STRASSER A, VAUX D L. Cell death in the origin and treatment of cancer[J]. Mol Cell, 2020, 78(6):1045-1054.
[36] MOU Y, WANG J, WU J, et al. Ferroptosis, a new form of cell death: opportunities and challenges in cancer[J]. J Hematol Oncol, 2019, 12(1):34.
[37] JIANG X, STOCKWELL B R, CONRAD M. Ferroptosis: mechanisms, biology and role in disease[J]. Nat Rev Mol Cell Biol, 2021, 22(4):266-282.
[38] WANG Y, ZHENG L, SHANG W, et al. Wnt/beta-catenin signaling confers ferroptosis resistance by targeting GPX4 in gastric cancer[J]. Cell Death Differ, 2022, 29(11):2190-2202.
[39] O'NEIL N J, BAILEY M L, HIETER P. Synthetic letha-lity and cancer[J]. Nat Rev Genet, 2017, 18(10):613-623.
[40] SETTON J, ZINDA M, RIAZ N, et al. Synthetic lethality in cancer therapeutics: the next generation[J]. Cancer Discov, 2021, 11(7):1626-1635.
[41] AN L, CAO Z, NIE P, et al. Combinatorial targeting of Hippo-STRIPAK and PARP elicits synthetic lethality in gastrointestinal cancers[J]. J Clin Invest, 2022, 132(9):e155468.
[42] SLETTENAAR V I, WILSON J L. The chemokine network: a target in cancer biology?[J]. Adv Drug Deliv Rev, 2006, 58(8):962-974.
[43] YANG D, ZHANG W, ZHANG H, et al. Progress, opportunity, and perspective on exosome isolation-efforts for efficient exosome-based theranostics[J]. Theranostics, 2020, 10(8):3684-3707.
[44] MATHEWS J C, NADEEM S, POURYAHYA M, et al. Functional network analysis reveals an immune tolerance mechanism in cancer[J]. Proc Natl Acad Sci U S A, 2020, 117(28):16339-16345.
[45] SHEN D D, PANG J R, BI Y P, et al. LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in gastric cancer[J]. Mol Cancer, 2022, 21(1):75.
[46] GDOVIN M J, KADRI N, RIOS L, et al. Focal photodynamic intracellular acidification as a cancer therapeutic[J]. Semin Cancer Biol, 2017, 43:147-156.
[47] PAVLOVA N N, ZHU J, THOMPSON C B. The hallmarks of cancer metabolism: still emerging[J]. Cell Metab, 2022, 34(3):355-377.
[48] LU Y X, JU H Q, LIU Z X, et al. ME1 regulates NADPH homeostasis to promote gastric cancer growth and metastasis[J]. Cancer Res, 2018, 78(8):1972-1985.
[49] THOMAS A, TEICHER B A, HASSAN R. Antibody-drug conjugates for cancer therapy[J]. Lancet Oncol, 2016, 17(6):e254-e262.
[50] CHEN W, YUAN Y, JIANG X. Antibody and antibody fragments for cancer immunotherapy[J]. J Control Release, 2020, 328:395-406.
[51] FU Z, LI S, HAN S, et al. Antibody drug conjugate: the "biological missile" for targeted cancer therapy[J]. Signal Transduct Target Ther, 2022, 7(1):93.
[52] OGITANI Y, AIDA T, HAGIHARA K, et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoiso-merase Ⅰ inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1[J]. Clin Cancer Res, 2016, 22(20):5097-5108.
[53] XIONG W, GAO Y, WEI W, et al. Extracellular and nuclear PD-L1 in modulating cancer immunotherapy[J]. Trends Cancer, 2021, 7(9):837-846.
[54] DEPIL S, DUCHATEAU P, GRUPP S A, et al. ‘Off-the-shelf’ allogeneic CAR T cells: development and challenges[J]. Nat Rev Drug Discov, 2020, 19(3):185-199.
[55] NEWICK K, O'BRIEN S, MOON E, et al. CAR T cell therapy for solid tumors[J]. Annu Rev Med, 2017, 68:139-152.
[56] SELLARS M C, WU C J, FRITSCH E F. Cancer vaccines: building a bridge over troubled waters[J]. Cell, 2022, 185(15):2770-2788.
[57] BASELGA J, ARRIBAS J. Treating cancer’s kinase ‘addiction’[J]. Nat Med, 2004, 10(8):786-787.
[58] PATWARDHAN A, CHENG N, TREJO J. Post-translational modifications of G protein-coupled receptors control cellular signaling dynamics in space and time[J]. Pharmacol Rev, 2021, 73(1):120-151.
[59] CZUBA L C, HILLGREN K M, SWAAN P W. Post-translational modifications of transporters[J]. Pharmacol Ther, 2018, 192:88-99.
[60] BéKéS M, LANGLEY D R, CREWS C M. PROTAC targeted protein degraders: the past is prologue[J]. Nat Rev Drug Discov, 2022, 21(3):181-200.
[61] SALAMI J, CREWS C M. Waste disposal-an attractive strategy for cancer therapy[J]. Science, 2017, 355(6330):1163-1167.
[62] KWONG L N, HEFFERNAN T P, CHIN L. A systems biology approach to personalizing therapeutic combinations[J]. Cancer Discov, 2013, 3(12):1339-1344.
[63] GLASER P, BOONE C. Beyond the genome: from geno-mics to systems biology[J]. Curr Opin Microbiol, 2004, 7(5):489-491.
Options
文章导航

/

〈 〉