Login Register Cart 0
Generic placeholder image

Current Molecular Medicine

Editor-in-Chief

ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Research Article

Autophagy-related Prognostic Signature in HER2 Positive Gastric Carcinomas

Author(s): Antonio Ieni*, Cristina Pizzimenti, Giuseppe Giuffrè, Rosario Alberto Caruso and Giovanni Tuccari

Volume 22, Issue 9, 2022

Published on: 11 January, 2022

Page: [809 - 818] Pages: 10

DOI: 10.2174/1566524021666211123093532

Price: $65

Abstract

Background: The immunohistochemical analysis of autophagy-related proteins (ATGs) has been recently applied in human pathology to study differentiation and cancer progression. The aim of the present study is to analyze a cohort of gastric carcinomas (GC) by five ATG antisera (Beclin-1, LC3A/B, p62, ULK-1 and AMBRA-1), also evaluating their possible relationship with clinicopathological parameters, HER2 status and final outcome of patients.

Methods: A cohort of 123 GCs has been studied by ATG antisera utilizing Masuda's criteria that define positive cases in which at least two out of five protein expressions were documented.

Results: The immunohistochemical signature for autophagy (A-IHC) was 49.59% as a whole. The percentage of A-IHC ranged from 31% for poorly cohesive carcinomas to 56% for adenocarcinomas. The performance of each ATG immunomarker documented high values for sensitivity, specificity and efficiency for LC3A/B, Beclin-1 and p62. In univariate analysis of GC, grade, stage, Ki67 expression, HER2 status as well as A-IHC appeared as emerged as relevant parameters with a high p-value (p < 0.001). Finally, in multivariate analysis, HER2 status, stage and A-IHC emerged as independent prognostic variables. In the comparison of survival curves, GC cases immunoreactive for A-IHC exhibited a shorter survival with a worse outcome.

Conclusions: We have hypothesized that A-IHC could represent an additional morphological tool to provide prognostic elements in order to identify patients affected by aggressive with shorter survival and worse outcome.

Keywords: Autophagy, immunohistochemistry, gastric cancer, HER2 status, prognosis, cancer treatment.

« Previous Next »
[1]
Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell 2011; 147(4): 728-41.
[http://dx.doi.org/10.1016/j.cell.2011.10.026] [PMID: 22078875]
[2]
Yu L, Chen Y, Tooze SA. Autophagy pathway: Cellular and molecular mechanisms. Autophagy 2018; 14(2): 207-15.
[http://dx.doi.org/10.1080/15548627.2017.1378838] [PMID: 28933638]
[3]
Chen Y, Yu L. Recent progress in autophagic lysosome reformation. Traffic 2017; 18(6): 358-61.
[http://dx.doi.org/10.1111/tra.12484] [PMID: 28371052]
[4]
Klionsky DJ, Abdelmohsen K, Abe A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. 3rd edition. Autophagy. 2016; 12: p. (2)443.
[5]
Dikic I, Elazar Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol 2018; 19(6): 349-64.
[http://dx.doi.org/10.1038/s41580-018-0003-4] [PMID: 29618831]
[6]
Xiang H, Zhang J, Lin C, Zhang L, Liu B, Ouyang L. Targeting autophagy-related protein kinases for potential therapeutic purpose. Acta Pharm Sin B 2020; 10(4): 569-81.
[http://dx.doi.org/10.1016/j.apsb.2019.10.003] [PMID: 32322463]
[7]
Barton LA, Ren J. Pancreatic Neoplasms and Autophagy. Curr Drug Targets 2018; 19(9): 1018-23.
[http://dx.doi.org/10.2174/1389450117666160622220915] [PMID: 27358060]
[8]
Meschini S, Condello M, Lista P, Arancia G. Autophagy: Molecular mechanisms and their implications for anticancer therapies. Curr Cancer Drug Targets 2011; 11(3): 357-79.
[http://dx.doi.org/10.2174/156800911794519707] [PMID: 21247381]
[9]
Lorin S, Hamaï A, Mehrpour M, Codogno P. Autophagy regulation and its role in cancer. Semin Cancer Biol 2013; 23(5): 361-79.
[http://dx.doi.org/10.1016/j.semcancer.2013.06.007] [PMID: 23811268]
[10]
Qian HR, Yang Y. Functional role of autophagy in gastric cancer. Oncotarget 2016; 7(14): 17641-51.
[http://dx.doi.org/10.18632/oncotarget.7508] [PMID: 26910278]
[11]
Amaravadi R, Kimmelman AC, White E. Recent insights into the function of autophagy in cancer. Genes Dev 2016; 30(17): 1913-30.
[http://dx.doi.org/10.1101/gad.287524.116] [PMID: 27664235]
[12]
Galluzzi L, Bravo-San Pedro JM, Kroemer G. Autophagy Mediates Tumor Suppression via Cellular Senescence. Trends Cell Biol 2016; 26(1): 1-3.
[http://dx.doi.org/10.1016/j.tcb.2015.11.001] [PMID: 26612212]
[13]
Caruso RA, Angelico G, Irato E, de Sarro R, Tuccari G, Ieni A. Autophagy in advanced low- and high-grade tubular adenocarcinomas of the stomach: An ultrastructural investigation. Ultrastruct Pathol 2018; 42(1): 10-7.
[http://dx.doi.org/10.1080/01913123.2017.1388322] [PMID: 29192807]
[14]
Görgülü K, Diakopoulos KN, Kaya-Aksoy E, et al. The Role of Autophagy in Pancreatic Cancer: From Bench to the Dark Bedside. Cells 2020; 9(4): 1063.
[http://dx.doi.org/10.3390/cells9041063] [PMID: 32344698]
[15]
Kiruthiga C, Devi KP, Nabavi SM, Bishayee A. Autophagy: A Potential Therapeutic Target of Polyphenols in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12(3): 562.
[http://dx.doi.org/10.3390/cancers12030562] [PMID: 32121322]
[16]
Liu L, Yan L, Liao N, Wu WQ, Shi JL. A Review of ULK1-Mediated Autophagy in Drug Resistance of Cancer. Cancers (Basel) 2020; 12(2): 352.
[http://dx.doi.org/10.3390/cancers12020352] [PMID: 32033142]
[17]
Li X, He S, Ma B. Autophagy and autophagy-related proteins in cancer. Mol Cancer 2020; 19(1): 12.
[http://dx.doi.org/10.1186/s12943-020-1138-4] [PMID: 31969156]
[18]
Yun CW, Lee SH. The Roles of Autophagy in Cancer. Int J Mol Sci 2018; 19(11): 3466.
[http://dx.doi.org/10.3390/ijms19113466] [PMID: 30400561]
[19]
Milne AN, Sitarz R, Carvalho R, Carneiro F, Offerhaus GJ. Early onset gastric cancer: on the road to unraveling gastric carcinogenesis. Curr Mol Med 2007; 7(1): 15-28.
[http://dx.doi.org/10.2174/156652407779940503] [PMID: 17311530]
[20]
Waldum HL, Fossmark R. Types of Gastric Carcinomas. Int J Mol Sci 2018; 19(12): 4109.
[http://dx.doi.org/10.3390/ijms19124109] [PMID: 30567376]
[21]
Ieni A, Barresi V, Rigoli L, Fedele F, Tuccari G, Caruso RA. Morphological and Cellular Features of Innate Immune Reaction in Helicobacter pylori Gastritis: A Brief Review. Int J Mol Sci 2016; 17(1): 109.
[http://dx.doi.org/10.3390/ijms17010109] [PMID: 26784180]
[22]
Sukri A, Hanafiah A, Mohamad Zin N, Kosai NR. Epidemiology and role of Helicobacter pylori virulence factors in gastric cancer carcinogenesis. APMIS 2020; 128(2): 150-61.
[http://dx.doi.org/10.1111/apm.13034] [PMID: 32352605]
[23]
Baj J. Korona-Głowniak I, Forma A, et al. Mechanisms of the Epithelial-Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric. Cancer Cells 2020; 9(4): 1055.
[http://dx.doi.org/10.3390/cells9041055] [PMID: 32340207]
[24]
Giuffrè G, Ieni A, Barresi V, Caruso RA, Tuccari G. HER2 status in unusual histological variants of gastric adenocarcinomas. J Clin Pathol 2012; 65(3): 237-41.
[http://dx.doi.org/10.1136/jclinpath-2011-200345] [PMID: 22067088]
[25]
Ieni A, Barresi V, Giuffrè G, et al. HER2 status in advanced gastric carcinoma: A retrospective multicentric analysis from Sicily. Oncol Lett 2013; 6(6): 1591-4.
[http://dx.doi.org/10.3892/ol.2013.1611] [PMID: 24260051]
[26]
Ieni A, Barresi V, Caltabiano R, et al. Discordance rate of HER2 status in primary gastric carcinomas and synchronous lymph node metastases: a multicenter retrospective analysis. Int J Mol Sci 2014; 15(12): 22331-41.
[http://dx.doi.org/10.3390/ijms151222331] [PMID: 25479078]
[27]
Ieni A, Barresi V, Rigoli L, Caruso RA, Tuccari G. HER2 Status in Premalignant, Early, and Advanced Neoplastic Lesions of the Stomach. Dis Markers 2015; 2015234851
[http://dx.doi.org/10.1155/2015/234851] [PMID: 26494937]
[28]
Ieni A, Angelico G, Barresi V, et al. Human Epidermal Growth Factor Receptor 2 Status in Gastric Carcinomas with Distinctive Prevalent Cribriform Component. Dis Markers 2018; 20181505428
[http://dx.doi.org/10.1155/2018/1505428] [PMID: 29670669]
[29]
Ieni A, Cardia R, Pizzimenti C, Zeppa P, Tuccari G. HER2 Heterogeneity in Personalized Therapy of Gastro-Oesophageal Malignancies: An Overview by Different Methodologies. J Pers Med 2020; 10(1): 10.
[http://dx.doi.org/10.3390/jpm10010010] [PMID: 32098203]
[30]
Garrett JT, Arteaga CL. Resistance to HER2-directed antibodies and tyrosine kinase inhibitors: mechanisms and clinical implications. Cancer Biol Ther 2011; 11(9): 793-800.
[http://dx.doi.org/10.4161/cbt.11.9.15045] [PMID: 21307659]
[31]
Asić K. Dominant mechanisms of primary resistance differ from dominant mechanisms of secondary resistance to targeted therapies. Crit Rev Oncol Hematol 2016; 97: 178-96.
[http://dx.doi.org/10.1016/j.critrevonc.2015.08.004] [PMID: 26364890]
[32]
Janser FA, Tschan MP, Langer R. The role of autophagy in HER2-targeted therapy. Swiss Med Wkly 2019; 149w20138
[http://dx.doi.org/10.4414/smw.2019.20138] [PMID: 31656036]
[33]
Zhou S, Zhao L, Kuang M, et al. Autophagy in tumorigenesis and cancer therapy: Dr. Jekyll or Mr. Hyde? Cancer Lett 2012; 323(2): 115-27.
[http://dx.doi.org/10.1016/j.canlet.2012.02.017] [PMID: 22542808]
[34]
Cao QH, Liu F, Yang ZL, et al. Prognostic value of autophagy related proteins ULK1, Beclin 1, ATG3, ATG5, ATG7, ATG9, ATG10, ATG12, LC3B and p62/SQSTM1 in gastric cancer. Am J Transl Res 2016; 8(9): 3831-47.
[PMID: 27725863]
[35]
Martinet W, Roth L, De Meyer GRY. Standard Immuno-histochemical Assays to Assess Autophagy in Mammalian Tissue. Cells 2017; 6(3): 17.
[http://dx.doi.org/10.3390/cells6030017] [PMID: 28665306]
[36]
Ieni A, Cardia R, Giuffrè G, Rigoli L, Caruso RA, Tuccari G. Immunohistochemical expression of autophagy-related proteins in advanced tubular gastric adenocarcinomas and its implications. Cancers 2019; 11: p. (3)389.
[37]
Schläfli AM, Berezowska S, Adams O, Langer R, Tschan MP. Reliable LC3 and p62 autophagy marker detection in formalin fixed paraffin embedded human tissue by immunohistochemistry. Eur J Histochem 2015; 59(2): 2481.
[http://dx.doi.org/10.4081/ejh.2015.2481] [PMID: 26150155]
[38]
Liu JL, Chen FF, Lung J, et al. Prognostic significance of p62/SQSTM1 subcellular localization and LC3B in oral squamous cell carcinoma. Br J Cancer 2014; 111(5): 944-54.
[http://dx.doi.org/10.1038/bjc.2014.355] [PMID: 24983366]
[39]
Wu W, Wang X, Berleth N, et al. The Autophagy-Initiating Kinase ULK1 Controls RIPK1-Mediated Cell Death. Cell Rep 2020; 31(3)107547
[http://dx.doi.org/10.1016/j.celrep.2020.107547] [PMID: 32320653]
[40]
Masuda GO, Yashiro M, Kitayama K, et al. Clinico-pathological Correlations of Autophagy-related Proteins LC3, Beclin 1 and p62 in Gastric Cancer. Anticancer Res 2016; 36(1): 129-36.
[PMID: 26722036]
[41]
Romero MA, Bayraktar Ekmekcigil O, Bagca BG, et al. Role of Autophagy in Breast Cancer Development and Progression: Opposite Sides of the Same Coin. Adv Exp Med Biol 2019; 1152: 65-73.
[http://dx.doi.org/10.1007/978-3-030-20301-6_5] [PMID: 31456180]
[42]
Liu T, Zhang J, Li K, Deng L, Wang H. Combination of an Autophagy Inducer and an Autophagy Inhibitor: A Smarter Strategy Emerging in Cancer Therapy. Front Pharmacol 2020; 11: 408.
[http://dx.doi.org/10.3389/fphar.2020.00408] [PMID: 32322202]
[43]
Ye J, Huang Q, Xu J, et al. Targeting of glutamine transporter ASCT2 and glutamine synthetase suppresses gastric cancer cell growth. J Cancer Res Clin Oncol 2018; 144(5): 821-33.
[http://dx.doi.org/10.1007/s00432-018-2605-9] [PMID: 29435734]
[44]
He Y, Zhao X, Subahan NR, Fan L, Gao J, Chen H. The prognostic value of autophagy-related markers beclin-1 and microtubule-associated protein light chain 3B in cancers: a systematic review and meta-analysis. Tumour Biol 2014; 35(8): 7317-26.
[http://dx.doi.org/10.1007/s13277-014-2060-4] [PMID: 24838948]
[45]
Won KY, Kim GY, Lim SJ, et al. Autophagy is related to the hedgehog signaling pathway in human gastric adenocarcinoma: prognostic significance of Beclin-1 and Gli2 expression in human gastric adenocarcinoma. Pathol Res Pract 2015; 211(4): 308-15.
[http://dx.doi.org/10.1016/j.prp.2014.11.005] [PMID: 25512258]
[46]
Yu S, Li G, Wang Z, et al. Low expression of MAP1LC3B, associated with low Beclin-1, predicts lymph node metastasis and poor prognosis of gastric cancer. Tumour Biol 2016; 37(11): 15007-17.
[http://dx.doi.org/10.1007/s13277-016-5383-5] [PMID: 27655288]
[47]
Huang X, Wang C, Sun J, et al. Clinical value of CagA, c-Met, PI3K and Beclin-1 expressed in gastric cancer and their association with prognosis. Oncol Lett 2018; 15(1): 947-55.
[PMID: 29422968]
[48]
Chen Y, Henson ES, Xiao W, et al. Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia. Autophagy 2016; 12(6): 1029-46.
[http://dx.doi.org/10.1080/15548627.2016.1164357] [PMID: 27166522]
[49]
Vega-Rubín-de-Celis S, Zou Z, Fernández ÁF, et al. Increased autophagy blocks HER2-mediated breast tumorigenesis. Proc Natl Acad Sci USA 2018; 115(16): 4176-81.
[http://dx.doi.org/10.1073/pnas.1717800115] [PMID: 29610308]
[50]
Janser FA, Adams O, Bütler V, et al. Her2-Targeted Therapy Induces Autophagy in Esophageal Adenocarcinoma Cells. Int J Mol Sci 2018; 19(10): 3069.
[http://dx.doi.org/10.3390/ijms19103069] [PMID: 30297650]
[51]
Díaz-Serrano A, Angulo B, Dominguez C, et al. Genomic Profiling of HER2-Positive Gastric Cancer: PI3K/Akt/mTOR Pathway as Predictor of Outcomes in HER2-Positive Advanced Gastric Cancer Treated with Trastuzumab. Oncologist 2018; 23(9): 1092-102.
[http://dx.doi.org/10.1634/theoncologist.2017-0379] [PMID: 29700210]
[52]
Sampera A, Sánchez-Martín FJ, Arpí O, et al. HER-Family Ligands Promote Acquired Resistance to Trastuzumab in Gastric Cancer. Mol Cancer Ther 2019; 18(11): 2135-45.
[http://dx.doi.org/10.1158/1535-7163.MCT-19-0455] [PMID: 31484705]

Rights & Permissions Print Cite
Article Metrics
21
1
© 2024 Bentham Science Publishers | Privacy Policy