sibmedСибирский научный медицинский журналСибирский научный медицинский журнал2410-25122410-2520ИЦиГ СО РАН10.18699/SSMJ20250304sibmed-2230Research ArticleОБЗОРЫREVIEWSЗначение ангиогенеза и лимфангиогенеза при раке желудкаThe importance of angiogenesis and lymphangiogenesis in gastric cancerhttps://orcid.org/0000-0002-8182-5084МайбородинИ. В.MaiborodinI. V.

Игорь Валентинович Майбородин, д. м. н., проф.

630090; пр. Академика Лаврентьева, 8; Новосибирск

Igor V. Maiborodin, doctor of medical sciences, professor

630090; Academician Lavrentiev ave., 8; Novosibirsk

imai@mail.ruhttps://orcid.org/0009-0003-9325-8800ИвлеваТ. Г.IvlevaT. G.

Татьяна Геннадьевна Ивлева

630090; пр. Академика Лаврентьева, 8; Новосибирск

Tatyana G. Ivleva

630090; Academician Lavrentiev ave., 8; Novosibirsk

doctorivleva@gmail.comhttps://orcid.org/0009-0008-4140-3531ШеплевБ. В.SheplevB. V.

Борис Валентинович Шеплев, д. м. н.

630090; пр. Академика Лаврентьева, 8; ул. Николаева, 12/3; Новосибирск

Boris V. Sheplev, doctor of medical sciences

630090; Academician Lavrentiev ave., 8; Nikolaeva st., 12/3; Novosibirsk

shepa@icloud.comhttps://orcid.org/0000-0002-3164-9377ШевелаА. И.ShevelaA. I.

Андрей Иванович Шевела, д. м. н., проф.

630090; пр. Академика Лаврентьева, 8; Новосибирск

Andrei I. Shevela, doctor of medical sciences, professor

630090; Academician Lavrentiev ave., 8; Novosibirsk

ashevela@mail.ruИнститут химической биологии и фундаментальной медицины СО РАНРоссияInstitute of Chemical Biology and Fundamental Medicine SB RASRussian FederationИнститут химической биологии и фундаментальной медицины СО РАН; Новосибирский медико-стоматологический институт ДентмастерРоссияInstitute of Chemical Biology and Fundamental Medicine SB RAS; Novosibirsk Medical and Dental Institute DentmasterRussian Federation2025130720254534352Copyright © Майбородин И.В., Ивлева Т.Г., Шеплев Б.В., Шевела А.И., 20252025Майбородин И.В., Ивлева Т.Г., Шеплев Б.В., Шевела А.И.Maiborodin I.V., Ivleva T.G., Sheplev B.V., Shevela A.I.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://sibmed.elpub.ru/jour/article/view/2230

   Проведен литературный поиск в базе данных PubMed для изучения работ, посвященных результатам исследований особенностей кровеносной и лимфатической васкуляризации рака желудка (РЖ). Гемангиогенез и лимфангиогенез в любой опухоли, в том числе и при РЖ, абсолютно необходимы для роста, инвазии и метастатического распространения. Опухолевый ангиогенез активируется гипоксией клеточных элементов, соответственно, в тканях РЖ возрастает содержание факторов, как индуцируемых гипоксией, так и связанных с ростом сосудов. Кроме того, некоторые лейкоциты, инфильтрирующие опухоль, принимают активное участие в ангиогенезе, также способствуя развитию и прогрессированию РЖ. Рост сосудов запускается не только в опухоли, но и в других отделах желудка. Ингибиторы ангиогенеза и роста лимфатических сосудов способствуют замедлению роста опухоли и подавляют метастазирование. К сожалению, остается неисследованным состояние сосудистого русла близлежащих органов, тогда как проангиогенные факторы распространяются по уже имеющимся кровеносным и лимфатическим сосудам и должны влиять на ангиогенез, как минимум, в печени и регионарных лимфатических узлах.

   A literature search was made in the PubMed database to study articles devoted to the results of studies of the features of blood and lymphatic vascularization of gastric cancer (GC). Hemangiogenesis and lymphangiogenesis in any tumor, including GC, are absolutely necessary for growth, invasion and metastatic spread. Tumor angiogenesis is activated via hypoxia of cells, accordingly, the content of factors both induced by hypoxia and associated with vascular growth increases in the GC tissues. In addition, some leukocytes infiltrating the tumor take an active part in angiogenesis, also contributing to the development and progression of GC. Vessel growth is triggered not only in the tumor, but also in other parts of the stomach. Inhibitors of angiogenesis and lymphatic vessel growth contribute to slowing down tumor growth and suppress metastasis. Unfortunately, the state of the vascular network of adjacent organs remains unexplored, while proangiogenic factors spread through existing blood and lymphatic vessels and should affect angiogenesis, at least, in liver and regional lymph nodes.

рак желудкаангиогенезлимфангиогенезваскуляризацияпрогрессирование рака желудкаgastric cancerangiogenesislymphangiogenesisvascularizationprogression of gastric cancerИсследование выполнено в рамках государственного задания ФГБУН ИХБФМ СО РАН «Фундаментальные основы сохранения здоровья нации», № FWGN-2025-0019The study was carried out within the framework of a State assignment for ICBFM SB RAS (grant number FWGN-2025-0019)ReferencesBray F., Laversanne M., Sung H., Ferlay J., Siegel R.L., Soerjomataram I., Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2024;74(3):229–263. doi: 10.3322/caac.21834Bray F., Laversanne M., Sung H., Ferlay J., Siegel R.L., Soerjomataram I., Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2024;74(3):229–263. doi: 10.3322/caac.21834Злокачественные новообразования в России в 2023 году (заболеваемость и смертность). Ред. А.Д. Каприн, В.В. Старинский, А.О. Шахзадова. М.: МНИОИ им. П.А. Герцена, 2024. 276 с.Malignant neoplasms in Russia in 2023 (incidence and mortality). Eds. A.D. Kaprin, V.V. Starinsky, A.O. Shakhzadova. Moscow: P.A. Herzen Moscow Oncology Research Institute, 2024. 276 p. [In Russian].van Cutsem E., Sagaert X., Topal B., Haustermans K., Prenen H. Gastric cancer. Lancet. 2016;388(10060):2654–2664. doi: 10.1016/S0140-6736(16)30354-3van Cutsem E., Sagaert X., Topal B., Haustermans K., Prenen H. Gastric cancer. Lancet. 2016;388(10060):2654–2664. doi: 10.1016/S0140-6736(16)30354-3Lott P.C., Carvajal-Carmona L.G. Resolving gastric cancer aetiology: an update in genetic predisposition. Lancet Gastroenterol. Hepatol. 2018;3(12):874–883. doi: 10.1016/S2468-1253(18)30237-1Lott P.C., Carvajal-Carmona L.G. Resolving gastric cancer aetiology: an update in genetic predisposition. Lancet Gastroenterol. Hepatol. 2018;3(12):874–883. doi: 10.1016/S2468-1253(18)30237-1Russo A.E., Strong V.E. Gastric cancer etiology and management in Asia and the West. Annu. Rev. Med. 2019;70:353–367. doi: 10.1146/annurev-med-081117-043436Russo A.E., Strong V.E. Gastric cancer etiology and management in Asia and the West. Annu. Rev. Med. 2019;70:353–367. doi: 10.1146/annurev-med-081117-043436Shi D.B., Ma R.R., Zhang H., Hou F., Guo X.Y., Gao P. GAGE7B promotes tumor metastasis and growth via activating the p38δ/pMAPKAPK2/pHSP27 pathway in gastric cancer. J. Exp. Clin. Cancer Res. 2019;38(1):124. doi: 10.1186/s13046-019-1125-zShi D.B., Ma R.R., Zhang H., Hou F., Guo X.Y., Gao P. GAGE7B promotes tumor metastasis and growth via activating the p38δ/pMAPKAPK2/pHSP27 pathway in gastric cancer. J. Exp. Clin. Cancer Res. 2019;38(1):124. doi: 10.1186/s13046-019-1125-zXue L., Chu W., Wan F., Wu P., Zhao X., Ma L., She Y., Li C., Li Y. YKL-39 is an independent prognostic factor in gastric adenocarcinoma and is associated with tumor-associated macrophage infiltration and angiogenesis. World J. Surg. Oncol. 2022;20(1):362. doi: 10.1186/s12957-022-02830-9Xue L., Chu W., Wan F., Wu P., Zhao X., Ma L., She Y., Li C., Li Y. YKL-39 is an independent prognostic factor in gastric adenocarcinoma and is associated with tumor-associated macrophage infiltration and angiogenesis. World J. Surg. Oncol. 2022;20(1):362. doi: 10.1186/s12957-022-02830-9Qiu Y., Lu G., Li N., Hu Y., Tan H., Jiang C. Exosome-mediated communication between gastric cancer cells and macrophages: implications for tumor microenvironment. Front. Immunol. 2024;15:1327281. doi: 10.3389/fimmu.2024.1327281Qiu Y., Lu G., Li N., Hu Y., Tan H., Jiang C. Exosome-mediated communication between gastric cancer cells and macrophages: implications for tumor microenvironment. Front. Immunol. 2024;15:1327281. doi: 10.3389/fimmu.2024.1327281Майбородин И.В., Гончаров М.А., Шевела А.И., Красильников С.Э., Шумейкина А.О., Майбородина В.И. Ангиогенез при раке эндометрия: клиническое и биологическое значение. Сиб. онкол. ж. 2024;23(4):172–185. doi: 10.21294/1814-4861-2024-23-4-172-185Maiborodin I.V., Goncharov M.A., Shevela A.I., Krasilnikov S.E., Shumeikina AO., Maiborodina V.I. Angiogenesis in endometrial cancer: clinical and biological significance. Sibirskiy onkologicheskiy zhurnal = Siberian Journal of Oncology. 2024;23(4):172–185. [In Russian]. doi: 10.21294/1814-4861-2024-23-4-172-185Macedo F., Ladeira K., Longatto-Filho A., Martins S.F. Gastric cancer and angiogenesis: is VEGF a useful biomarker to assess progression and remission? J. Gastric Cancer. 2017;17(1):1–10. doi: 10.5230/jgc.2017.17.e1Macedo F., Ladeira K., Longatto-Filho A., Martins S.F. Gastric cancer and angiogenesis: is VEGF a useful biomarker to assess progression and remission? J. Gastric Cancer. 2017;17(1):1–10. doi: 10.5230/jgc.2017.17.e1Li N., Wang H.X., Qin C., Wang X.H., Han F.Y. Relationship between clinicopathological features and HIF-2α in gastric adenocarcinoma. Genet. Mol. Res. 2015;14(1):1404–1413. doi: 10.4238/2015.February.13.19Li N., Wang H.X., Qin C., Wang X.H., Han F.Y. Relationship between clinicopathological features and HIF-2α in gastric adenocarcinoma. Genet. Mol. Res. 2015;14(1):1404–1413. doi: 10.4238/2015.February.13.19Ozmen M.M., Ozmen F., Zulfikaroglu B. Lymph nodes in gastric cancer. J. Surg. Oncol. 2008;98(6):476–481. doi: 10.1002/jso.21134Ozmen M.M., Ozmen F., Zulfikaroglu B. Lymph nodes in gastric cancer. J. Surg. Oncol. 2008;98(6):476–481. doi: 10.1002/jso.21134Mantovani A., Allavena P., Sica A., Balkwill F. Cancer-related inflammation. Nature. 2008; 454(7203):436–444. doi: 10.1038/nature07205Mantovani A., Allavena P., Sica A., Balkwill F. Cancer-related inflammation. Nature. 2008; 454(7203):436–444. doi: 10.1038/nature07205Hanahan D., Coussens L.M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21(3):309–322. doi: 10.1016/j.ccr.2012.02.022Hanahan D., Coussens L.M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21(3):309–322. doi: 10.1016/j.ccr.2012.02.022Galdiero M.R., Garlanda C., Jaillon S., Marone G., Mantovani A. Tumor associated macrophages and neutrophils in tumor progression. J. Cell. Physiol. 2013;228(7):1404–1412. doi: 10.1002/jcp.24260Galdiero M.R., Garlanda C., Jaillon S., Marone G., Mantovani A. Tumor associated macrophages and neutrophils in tumor progression. J. Cell. Physiol. 2013;228(7):1404–1412. doi: 10.1002/jcp.24260Varricchi G., Galdiero M.R., Marone G., Granata F., Borriello F., Marone G. Controversial role of mast cells in skin cancers. Exp. Dermatol. 2017;26(1):11–17. doi: 10.1111/exd.13107Varricchi G., Galdiero M.R., Marone G., Granata F., Borriello F., Marone G. Controversial role of mast cells in skin cancers. Exp. Dermatol. 2017;26(1):11–17. doi: 10.1111/exd.13107Zhang L.X., Wei Z.J., Xu A.M., Zang J.H. Can the neutrophil-lymphocyte ratio and platelet-lymphocyte ratio be beneficial in predicting lymph node metastasis and promising prognostic markers of gastric cancer patients? Tumor maker retrospective study. Int. J. Surg. 2018;56:320–327. doi: 10.1016/j.ijsu.2018.06.037Zhang L.X., Wei Z.J., Xu A.M., Zang J.H. Can the neutrophil-lymphocyte ratio and platelet-lymphocyte ratio be beneficial in predicting lymph node metastasis and promising prognostic markers of gastric cancer patients? Tumor maker retrospective study. Int. J. Surg. 2018;56:320–327. doi: 10.1016/j.ijsu.2018.06.037Стадников А.А., Сеньчукова М.А., Шевлюк Н.Н., Боков Д.А. Морфологическая характеристика сосудов подслизистой основы желудка на участках, прилежащих к опухоли. Морфология. 2011;140(4):18–22.Stadnikov A.A., Sen’chukova M.A., Shevliuk N.N., Bokov D.A. Morphological characteristic of gastric submucosal vessels in the peritumoral areas. Morfologiya = Morphology. 2011;140(4):18–22. [In Russian].Hafez N.H., Tahoun N.S. Expression of cyclooxygenase 2 and vascular endothelial growth factor in gastric carcinoma: Relationship with clinico-pathological parameters. J. Egypt. Natl. Canc. Inst. 2016;28(3):149–156. doi: 10.1016/j.jnci.2016.05.005Hafez N.H., Tahoun N.S. Expression of cyclooxygenase 2 and vascular endothelial growth factor in gastric carcinoma: Relationship with clinico-pathological parameters. J. Egypt. Natl. Canc. Inst. 2016;28(3):149–156. doi: 10.1016/j.jnci.2016.05.005Ikeda K., Oki E., Saeki H., Ando K., Morita M., Oda Y., Imamura M., Kakeji Y., Maehara Y. Intratumoral lymphangiogenesis and prognostic significance of VEGFC expression in gastric cancer. Anticancer Res. 2014;34(8):3911–3915.Ikeda K., Oki E., Saeki H., Ando K., Morita M., Oda Y., Imamura M., Kakeji Y., Maehara Y. Intratumoral lymphangiogenesis and prognostic significance of VEGFC expression in gastric cancer. Anticancer Res. 2014;34(8):3911–3915.Li F., Meng G., Tan B., Chen Z., Ji Q., Wang X., Liu C., Niu S., Li Y., Liu Y. Relationship between HER2 expression and tumor interstitial angiogenesis in primary gastric cancer and its effect on prognosis. Pathol. Res. Pract. 2021;217:153280. doi: 10.1016/j.prp.2020.153280Li F., Meng G., Tan B., Chen Z., Ji Q., Wang X., Liu C., Niu S., Li Y., Liu Y. Relationship between HER2 expression and tumor interstitial angiogenesis in primary gastric cancer and its effect on prognosis. Pathol. Res. Pract. 2021;217:153280. doi: 10.1016/j.prp.2020.153280Fan Z., Li Y., Zhao Q., Fan L., Tan B., Zuo J., Hua K., Ji Q. Highly expressed granulocyte colony-stimulating factor (G-CSF) and granulocyte colony-stimulating factor receptor (G-CSFR) in human gastric cancer leads to poor survival. Med. Sci. Monit. 2018;24:1701–1711. doi: 10.12659/msm.909128Fan Z., Li Y., Zhao Q., Fan L., Tan B., Zuo J., Hua K., Ji Q. Highly expressed granulocyte colony-stimulating factor (G-CSF) and granulocyte colony-stimulating factor receptor (G-CSFR) in human gastric cancer leads to poor survival. Med. Sci. Monit. 2018;24:1701–1711. doi: 10.12659/msm.909128Gao L.M., Wang F., Zheng Y., Fu Z.Z., Zheng L., Chen L.L. Roles of fibroblast activation protein and hepatocyte growth factor expressions in angiogenesis and metastasis of gastric cancer. Pathol. Oncol. Res. 2019;25(1):369–376. doi: 10.1007/s12253-017-0359-3Gao L.M., Wang F., Zheng Y., Fu Z.Z., Zheng L., Chen L.L. Roles of fibroblast activation protein and hepatocyte growth factor expressions in angiogenesis and metastasis of gastric cancer. Pathol. Oncol. Res. 2019;25(1):369–376. doi: 10.1007/s12253-017-0359-3Yan Z., Yan Q., Song Y., Wang L. TMSB10, a potential prognosis prediction biomarker, promotes the invasion and angiogenesis of gastric cancer. J. Gastroenterol. Hepatol. 2021;36(11):3102–3112. doi: 10.1111/jgh.15576Yan Z., Yan Q., Song Y., Wang L. TMSB10, a potential prognosis prediction biomarker, promotes the invasion and angiogenesis of gastric cancer. J. Gastroenterol. Hepatol. 2021;36(11):3102–3112. doi: 10.1111/jgh.15576Cao H., Li Y., Huang L., Bai B., Xu Z. Clinicopathological significance of neuropilin 1 expression in gastric cancer: a meta-analysis. Dis. Markers. 2020;2020:4763492. doi: 10.1155/2020/4763492Cao H., Li Y., Huang L., Bai B., Xu Z. Clinicopathological significance of neuropilin 1 expression in gastric cancer: a meta-analysis. Dis. Markers. 2020;2020:4763492. doi: 10.1155/2020/4763492Tao X., Cheng L., Li Y., Ci H., Xu J., Wu S., Tao Y. Expression of CRYAB with the angiogenesis and poor prognosis for human gastric cancer. Medicine (Baltimore). 2019;98(45):e17799. doi: 10.1097/MD.0000000000017799Tao X., Cheng L., Li Y., Ci H., Xu J., Wu S., Tao Y. Expression of CRYAB with the angiogenesis and poor prognosis for human gastric cancer. Medicine (Baltimore). 2019;98(45):e17799. doi: 10.1097/MD.0000000000017799Liu W., Zhang Q., Zhang Y., Sun L., Xiao H., Luo B. Epstein–Barr virus regulates endothelin-1 expression through the ERK/FOXO1 pathway in EBV-associated gastric cancer. Microbiol. Spectr. 2023;11(1):e0089822. doi: 10.1128/spectrum.00898-22Liu W., Zhang Q., Zhang Y., Sun L., Xiao H., Luo B. Epstein–Barr virus regulates endothelin-1 expression through the ERK/FOXO1 pathway in EBV-associated gastric cancer. Microbiol. Spectr. 2023;11(1):e0089822. doi: 10.1128/spectrum.00898-22Pak K.H., Park K.C., Cheong J.H. VEGF-C induced by TGF- β1 signaling in gastric cancer enhances tumor-induced lymphangiogenesis. BMC Cancer. 2019;19(1):799. doi: 10.1186/s12885-019-5972-yPak K.H., Park K.C., Cheong J.H. VEGF-C induced by TGF- β1 signaling in gastric cancer enhances tumor-induced lymphangiogenesis. BMC Cancer. 2019;19(1):799. doi: 10.1186/s12885-019-5972-yXia Y.J., Jiang X.T., Jiang S.B., He X.J., Luo J.G., Liu Z.C., Wang L., Tao H.Q., Chen J.Z. PHD3 affects gastric cancer progression by negatively regulating HIF1A. Mol. Med. Rep. 2017;16(5):6882–6889. doi: 10.3892/mmr.2017.7455Xia Y.J., Jiang X.T., Jiang S.B., He X.J., Luo J.G., Liu Z.C., Wang L., Tao H.Q., Chen J.Z. PHD3 affects gastric cancer progression by negatively regulating HIF1A. Mol. Med. Rep. 2017;16(5):6882–6889. doi: 10.3892/mmr.2017.7455Ma C., Luo C., Yin H., Zhang Y., Xiong W., Zhang T., Gao T., Wang X., Che D., Fang Z., … Yang X. Kallistatin inhibits lymphangiogenesis and lymphatic metastasis of gastric cancer by downregulating VEGF-C expression and secretion. Gastric Cancer. 2018;21(4):617–631. doi: 10.1007/s10120-017-0787-5Ma C., Luo C., Yin H., Zhang Y., Xiong W., Zhang T., Gao T., Wang X., Che D., Fang Z., … Yang X. Kallistatin inhibits lymphangiogenesis and lymphatic metastasis of gastric cancer by downregulating VEGF-C expression and secretion. Gastric Cancer. 2018;21(4):617–631. doi: 10.1007/s10120-017-0787-5Park J.Y., Sung J.Y., Lee J., Park Y.K., Kim Y.W., Kim G.Y., Won K.Y., Lim S.J. Polarized CD163+ tumor-associated macrophages are associated with increased angiogenesis and CXCL12 expression in gastric cancer. Clin. Res. Hepatol. Gastroenterol. 2016;40(3):357–365. doi: 10.1016/j.clinre.2015.09.005Park J.Y., Sung J.Y., Lee J., Park Y.K., Kim Y.W., Kim G.Y., Won K.Y., Lim S.J. Polarized CD163+ tumor-associated macrophages are associated with increased angiogenesis and CXCL12 expression in gastric cancer. Clin. Res. Hepatol. Gastroenterol. 2016;40(3):357–365. doi: 10.1016/j.clinre.2015.09.005Wu H., Xu J.B., He Y.L., Peng J.J., Zhang X.H., Chen C.Q., Li W., Cai S.R. Tumor-associated macrophages promote angiogenesis and lymphangiogenesis of gastric cancer. J. Surg. Oncol. 2012;106(4):462–468. doi: 10.1002/jso.23110Wu H., Xu J.B., He Y.L., Peng J.J., Zhang X.H., Chen C.Q., Li W., Cai S.R. Tumor-associated macrophages promote angiogenesis and lymphangiogenesis of gastric cancer. J. Surg. Oncol. 2012;106(4):462–468. doi: 10.1002/jso.23110Hiramatsu S., Tanaka H., Nishimura J., Sakimura C., Tamura T., Toyokawa T., Muguruma K., Yashiro M., Hirakawa K., Ohira M. Neutrophils in primary gastric tumors are correlated with neutrophil infiltration in tumor-draining lymph nodes and the systemic inflammatory response. BMC Immunol. 2018;19(1):13. doi: 10.1186/s12865-018-0251-2Hiramatsu S., Tanaka H., Nishimura J., Sakimura C., Tamura T., Toyokawa T., Muguruma K., Yashiro M., Hirakawa K., Ohira M. Neutrophils in primary gastric tumors are correlated with neutrophil infiltration in tumor-draining lymph nodes and the systemic inflammatory response. BMC Immunol. 2018;19(1):13. doi: 10.1186/s12865-018-0251-2Ammendola M., Sacco R., Donato G., Zuccalà V., Russo E., Luposella M., Vescio G., Rizzuto A., Patruno R., de Sarro G., … Ranieri G. Mast cell positivity to tryptase correlates with metastatic lymph nodes in gastrointestinal cancer patients treated surgically. Oncology. 2013;85(2):111–116. doi: 10.1159/000351145Ammendola M., Sacco R., Donato G., Zuccalà V., Russo E., Luposella M., Vescio G., Rizzuto A., Patruno R., de Sarro G., … Ranieri G. Mast cell positivity to tryptase correlates with metastatic lymph nodes in gastrointestinal cancer patients treated surgically. Oncology. 2013;85(2):111–116. doi: 10.1159/000351145Ammendola M., Sacco R., Zuccalà V., Luposella M., Patruno R., Gadaleta P., Zizzo N., Gadaleta C.D., de Sarro G., Sammarco G., Oltean M., Ranieri G. Mast cells density positive to tryptase correlate with microvascular density in both primary gastric cancer tissue and loco-regional lymph node metastases from patients that have undergone radical surgery. Int. J. Mol. Sci. 2016;17(11):1905. doi: 10.3390/ijms17111905Ammendola M., Sacco R., Zuccalà V., Luposella M., Patruno R., Gadaleta P., Zizzo N., Gadaleta C.D., de Sarro G., Sammarco G., Oltean M., Ranieri G. Mast cells density positive to tryptase correlate with microvascular density in both primary gastric cancer tissue and loco-regional lymph node metastases from patients that have undergone radical surgery. Int. J. Mol. Sci. 2016;17(11):1905. doi: 10.3390/ijms17111905Lotfi-Emran S., Ward B.R., Le Q.T., Pozez A.L., Manjili M.H., Woodfolk J.A., Schwartz L.B. Human mast cells present antigen to autologous CD4+ T cells. J. Allergy Clin. Immunol. 2018;141(1):311–321.e10. doi: 10.1016/j.jaci.2017.02.048Lotfi-Emran S., Ward B.R., Le Q.T., Pozez A.L., Manjili M.H., Woodfolk J.A., Schwartz L.B. Human mast cells present antigen to autologous CD4+ T cells. J. Allergy Clin. Immunol. 2018;141(1):311–321.e10. doi: 10.1016/j.jaci.2017.02.048Kritikou E., van der Heijden T., Swart M., van Duijn J., Slütter B., Wezel A., Smeets H.J., Maffia P., Kuiper J., Bot I. Hypercholesterolemia induces a mast Cell-CD4+ T cell interaction in atherosclerosis. J. Immunol. 2019;202(5):1531–1539. doi: 10.4049/jimmunol.1800648Kritikou E., van der Heijden T., Swart M., van Duijn J., Slütter B., Wezel A., Smeets H.J., Maffia P., Kuiper J., Bot I. Hypercholesterolemia induces a mast Cell-CD4+ T cell interaction in atherosclerosis. J. Immunol. 2019;202(5):1531–1539. doi: 10.4049/jimmunol.1800648Dawson M.A., Kouzarides T., Huntly B.J. Targeting epigenetic readers in cancer. N. Engl. J. Med. 2012;367(7):647–657. doi: 10.1056/NEJMra1112635Dawson M.A., Kouzarides T., Huntly B.J. Targeting epigenetic readers in cancer. N. Engl. J. Med. 2012;367(7):647–657. doi: 10.1056/NEJMra1112635Yao J., Da M., Guo T., Duan Y., Zhang Y. RNAi-mediated gene silencing of vascular endothelial growth factor-C inhibits tumor lymphangiogenesis and growth of gastric cancer in vivo in mice. Tumour Biol. 2013;34(3):1493–1501. doi: 10.1007/s13277-013-0674-6Yao J., Da M., Guo T., Duan Y., Zhang Y. RNAi-mediated gene silencing of vascular endothelial growth factor-C inhibits tumor lymphangiogenesis and growth of gastric cancer in vivo in mice. Tumour Biol. 2013;34(3):1493–1501. doi: 10.1007/s13277-013-0674-6Liu P., Ding P., Yang J., Wu H., Wu J., Guo H., Yang P., Tian Y., Meng L., Zhao Q. MicroRNA-431-5p inhibits angiogenesis, lymphangiogenesis, and lymph node metastasis by affecting TGF-β1/SMAD2/3 signaling via ZEB1 in gastric cancer. Mol. Carcinog. 2024;63(7):1378–1391. doi: 10.1002/mc.23731Liu P., Ding P., Yang J., Wu H., Wu J., Guo H., Yang P., Tian Y., Meng L., Zhao Q. MicroRNA-431-5p inhibits angiogenesis, lymphangiogenesis, and lymph node metastasis by affecting TGF-β1/SMAD2/3 signaling via ZEB1 in gastric cancer. Mol. Carcinog. 2024;63(7):1378–1391. doi: 10.1002/mc.23731Liu H.T., Ma R.R., Lv B.B., Zhang H., Shi D.B., Guo X.Y., Zhang G.H., Gao P. LncRNA-HNF1A-AS1 functions as a competing endogenous RNA to activate PI3K/AKT signalling pathway by sponging miR-30b-3p in gastric cancer. Br. J. Cancer. 2020;122(12):1825–1836. doi: 10.1038/s41416-020-0836-4Liu H.T., Ma R.R., Lv B.B., Zhang H., Shi D.B., Guo X.Y., Zhang G.H., Gao P. LncRNA-HNF1A-AS1 functions as a competing endogenous RNA to activate PI3K/AKT signalling pathway by sponging miR-30b-3p in gastric cancer. Br. J. Cancer. 2020;122(12):1825–1836. doi: 10.1038/s41416-020-0836-4Sammarco G., Varricchi G., Ferraro V., Ammendola M., de Fazio M., Altomare D.F., Luposella M., Maltese L., Currò G., Marone G., Ranieri G., Memeo R. Mast cells, angiogenesis and lymphangiogenesis in human gastric cancer. Int. J. Mol. Sci. 2019;20(9):2106. doi: 10.3390/ijms20092106Sammarco G., Varricchi G., Ferraro V., Ammendola M., de Fazio M., Altomare D.F., Luposella M., Maltese L., Currò G., Marone G., Ranieri G., Memeo R. Mast cells, angiogenesis and lymphangiogenesis in human gastric cancer. Int. J. Mol. Sci. 2019;20(9):2106. doi: 10.3390/ijms20092106Tapia O., Riquelme I., Leal P., Sandoval A., Aedo S., Weber H., Letelier P., Bellolio E., Villaseca M., Garcia P., Roa J.C. The PI3K/AKT/mTOR pathway is activated in gastric cancer with potential prognostic and predictive significance. Virchows Arch. 2014;465(1):25–33. doi: 10.1007/s00428-014-1588-4Tapia O., Riquelme I., Leal P., Sandoval A., Aedo S., Weber H., Letelier P., Bellolio E., Villaseca M., Garcia P., Roa J.C. The PI3K/AKT/mTOR pathway is activated in gastric cancer with potential prognostic and predictive significance. Virchows Arch. 2014;465(1):25–33. doi: 10.1007/s00428-014-1588-4Xing X., Zhang L., Wen X., Wang X., Cheng X., Du H., Hu Y., Li L., Dong B., Li Z., Ji J. PP242 suppresses cell proliferation, metastasis, and angiogenesis of gastric cancer through inhibition of the PI3K/AKT/mTOR pathway. Anticancer Drugs. 2014;25(10):1129–1140. doi: 10.1097/CAD.0000000000000148Xing X., Zhang L., Wen X., Wang X., Cheng X., Du H., Hu Y., Li L., Dong B., Li Z., Ji J. PP242 suppresses cell proliferation, metastasis, and angiogenesis of gastric cancer through inhibition of the PI3K/AKT/mTOR pathway. Anticancer Drugs. 2014;25(10):1129–1140. doi: 10.1097/CAD.0000000000000148Ma J., Yao S., Li X.S., Kang H.R., Yao F.F., Du N. Neoadjuvant therapy of DOF regimen plus bevacizumab can increase surgical resection ratein locally advanced gastric cancer: a randomized, controlled study. Medicine (Baltimore). 2015;94(42):e1489. doi: 10.1097/MD.0000000000001489Ma J., Yao S., Li X.S., Kang H.R., Yao F.F., Du N. Neoadjuvant therapy of DOF regimen plus bevacizumab can increase surgical resection ratein locally advanced gastric cancer: a randomized, controlled study. Medicine (Baltimore). 2015;94(42):e1489. doi: 10.1097/MD.0000000000001489Takeuchi T., Yuasa Y., Okitsu H., Maki H., Tsuneki T., Matsuo Y., Edagawa H., Mori O., Miyamoto N., Eto S. … Ishikura H. Effectiveness of ramucirumab therapy for advanced gastric cancer after stent placement for esophagogastric junction carcinoma obstruction-a case report. Gan To Kagaku Ryoho. 2019;46(6):1057–1059.Takeuchi T., Yuasa Y., Okitsu H., Maki H., Tsuneki T., Matsuo Y., Edagawa H., Mori O., Miyamoto N., Eto S. … Ishikura H. Effectiveness of ramucirumab therapy for advanced gastric cancer after stent placement for esophagogastric junction carcinoma obstruction-a case report. Gan To Kagaku Ryoho. 2019;46(6):1057–1059.Mori K., Aoyama T., Morita J., Maezawa Y., Amano S., Sawazaki S., Numata M., Tamagawa H., Sato T., Oshima T., … Rino Y. Gastrectomy for bleeding gastric cancer during ramucirumab plus paclitaxel therapy – a case report. Gan To Kagaku Ryoho. 2019;46(3):586–588.Mori K., Aoyama T., Morita J., Maezawa Y., Amano S., Sawazaki S., Numata M., Tamagawa H., Sato T., Oshima T., … Rino Y. Gastrectomy for bleeding gastric cancer during ramucirumab plus paclitaxel therapy – a case report. Gan To Kagaku Ryoho. 2019;46(3):586–588.Kurihara M., Sawazaki S., Kawabe T., Minowa K., Akimoto N., Tsuchiya K., Kato A., Higuchi A., Rino Y., Matsukawa H., Saeki H. A case of perforation of the diverticulum of the appendix during chemotherapy with ramucirumab plus nab-paclitaxel for gastric cancer. Gan To Kagaku Ryoho. 2021;48(10):1293–1295.Kurihara M., Sawazaki S., Kawabe T., Minowa K., Akimoto N., Tsuchiya K., Kato A., Higuchi A., Rino Y., Matsukawa H., Saeki H. A case of perforation of the diverticulum of the appendix during chemotherapy with ramucirumab plus nab-paclitaxel for gastric cancer. Gan To Kagaku Ryoho. 2021;48(10):1293–1295.Wang J., Dong X., Li D., Fang Z., Wan X, Liu J. Fucoxanthin inhibits gastric cancer lymphangiogenesis and metastasis by regulating Ran expression. Phytomedicine. 2023;118:154926. doi: 10.1016/j.phymed.2023.154926Wang J., Dong X., Li D., Fang Z., Wan X, Liu J. Fucoxanthin inhibits gastric cancer lymphangiogenesis and metastasis by regulating Ran expression. Phytomedicine. 2023;118:154926. doi: 10.1016/j.phymed.2023.154926

The authors declare that there are no conflicts of interest present.