oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2026-25-2-165-174oncotomsk-4209Research ArticleОБЗОРЫREVIEWSРак толстой кишки: ангиогенез и матриксные протеиназыColorectal cancer: angiogenesis and matrix metalloproteinaseshttps://orcid.org/0000-0002-8182-5084МайбородинИ. В.MaiborodinI. V.

Майбородин Игорь Валентинович - доктор медицинских наук, профессор, главный научный сотрудник лаборатории инвазивных медицинских технологий, ФГБУН «ИХЮФМ СО РАН»; проректор по науке, ЧОУ ВО «Новосибирский медико-стоматологический институт Дентмастер».

SPIN-код: 8626-5394

Author ID (Scopus): 6701369984

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

Igor V. Maiborodin - MD, DSc, Professor, Chief Researcher, Laboratory of Invasive Medical Technologies, Institute of Chemical Biology and Fundamental Medicine, RAS, Siberian Branch; Vice-Rector for Science, Novosibirsk Medical and Dental Institute “Dentmaster”.  

Author ID (Scopus): 6701369984

8, Akademika lavrenteva St., Novosibirsk, 630090; 12/3, Nikolaeva St., Novosibirsk, 630090

imai@mail.ruhttps://orcid.org/0009-0004-1637-256XФурсовС. А.FursovS. A.

Фурсов Сергей Александрович - доктор медицинских наук, профессор, заведующий кафедрой онкологии лечебного факультета, ФГБОУ ВО «Новосибирский ГМУ» Минздрава России; главный врач, ГБУЗ «Новосибирский ООД».

SPIN-код: 9714-0875

Author ID (Scopus): 55801107200

630091, Новосибирск, Красный пр-т, 52; 630108, Новосибирск, ул. Плахотного, 2

Sergey A. Fursov - MD, DSc, Professor, Head of the Department of Oncology of the Faculty of Medicine, Novosibirsk SMU, Ministry of Health of Russia; Chief medical officer, State Budgetary Healthcare Institution of the Novosibirsk Region, Novosibirsk ROC.

Author ID (Scopus): 55801107200

52, Krasny Prospect, Novosibirsk, 630091; 2, Plakhotnogo St., Novosibirsk, 630108

https://orcid.org/0009-0000-6543-0368СоловенчукЛ. Л.SolovenchukL. L.

Соловенчук Леонид Леонидович - старший лаборант, кафедра онкологии лечебного факультета, ФГБОУ ВО «Новосибирский ГМУ» Минздрава России; онколог, онкологическое отделение № 1, ГБУЗ «Новосибирский ООД».

630091, Новосибирск, Красный пр-т, 52; 630108, Новосибирск, ул. Плахотного, 2

Leonid L. Solovenchuk - MD, Senior Laboratory Assistant, Department of Oncology, Faculty of Medicine, Novosibirsk SMU, Ministry of Health of Russia; Oncologist, Oncology Department No. 1, Novosibirsk Regional Oncology Center.

52, Krasny Prospect, Novosibirsk, 630091; 2, Plakhotnogo St., Novosibirsk, 630108

https://orcid.org/0009-0007-0618-3556ГерусП. А.GerusP. A.

Герус Павел Александрович - старший лаборант, кафедра онкологии лечебного факультета, ФГБОУ ВО «Новосибирский ГМУ» Минздрава России; онколог, онкологическое отделение № 3, ГБУЗ «Новосибирский ООД».

630091, Новосибирск, Красный пр-т, 52; 630108, Новосибирск, ул. Плахотного, 2

Pavel A. Gerus - MD, Senior Laboratory Assistant, Department of Oncology, Faculty of Medicine, Novosibirsk SMU, Ministry of Health of Russia; Oncologist, Oncology Department No. 3, Novosibirsk ROC.

52, Krasny Prospect, Novosibirsk, 630091; 2, Plakhotnogo St., Novosibirsk, 630108

https://orcid.org/0009-0008-4140-3531ШеплевБ. В.SheplevB. V.

Шеплев Борис Валентинович - доктор медицинских наук, ректор

SPIN-код: 9905-4138

Author ID (Scopus): 6504160928

630090, Новосибирск, ул. Николаева, 12/3

Boris V. Sheplev - MD, DSc, Rector.

Author ID (Scopus): 6504160928

12/3, Nikolaeva St., Novosibirsk, 630090

https://orcid.org/0000-0002-8194-2811ЧернышоваА. Л.ChernyshovaA. L.

Чернышова Алена Леонидовна - доктор медицинских наук, профессор РАН, профессор кафедры онкологии лечебного факультета, ФГБОУ ВО «Новосибирский ГМУ» Минздрава России; директор Института онкологии и нейрохирургии, ФГБУ «Национальный медицинский центр им. академика Е.Н. Мешалкина» Минздрава России; профессор кафедры хирургических болезней, Институт медицины и медицинских технологий, ФГАОУ ВО «Новосибирский НИГУ»

SPIN-код: 2522-7513

Author ID (Scopus): 55220758100

630091, Новосибирск, Красный пр-т, 52; 630055, г. Новосибирск, ул. Речкуновская, 15; 630090, Новосибирск, ул. Пирогова, 1

Alena L. Chernyshova - MD, DSc, Professor, Department of Oncology, Faculty of Medicine, Novosibirsk SMU, Ministry of Health of Russia; Director, Institute of Oncology and Neurosurgery, Meshalkin National Medical Research Center, Ministry of Health of Russia; Professor, Department of Surgical Diseases, Institute of Medicine and Medical Technologies, Novosibirsk NRSU.

Author ID (Scopus): 55220758100

52, Krasny Prospect, Novosibirsk, 630091; 15, Rechkunovskaya St., Novosibirsk, 630055; 1, Pirogov St., Novosibirsk, 630090

ФГБУН «Институт химической биологии и фундаментальной медицины СО РАН»; ЧОУ ВО «Новосибирский медико-стоматологический институт Дентмастер»РоссияInstitute of Chemical Biology and Fundamental Medicine, Russian Academy of Sciences, Siberian Branch; Novosibirsk Medical and Dental institute “Dentmaster”Russian FederationФГБОУ ВО «Новосибирский государственный медицинский университет» Минздрава России; ГБУЗ «Новосибирский областной онкологический диспансер»РоссияNovosibirsk State Medical University, Ministry of Health of Russia; Novosibirsk Regional Oncology CenterRussian FederationЧОУ ВО «Новосибирский медико-стоматологический институт Дентмастер»РоссияNovosibirsk Medical and Dental institute “Dentmaster”Russian FederationФГБОУ ВО «Новосибирский государственный медицинский университет» Минздрава России; Институт онкологии и нейрохирургии, ФГБУ «Национальный медицинский центр имени академика Е. Н. Мешалкина» Минздрава России; Институт медицины и медицинских технологий, ФГАОУ ВО «Новосибирский национальный исследовательский государственный университет»РоссияNovosibirsk State Medical University, Ministry of Health of Russia; Institute of Oncology and Neurosurgery, Meshalkin National Medical Research Center, Ministry of Health of Russia; Novosibirsk National Research State UniversityRussian Federation202617052026252165174Copyright © Майбородин И.В., Фурсов С.А., Соловенчук Л.Л., Герус П.А., Шеплев Б.В., Чернышова А.Л., 20262026Майбородин И.В., Фурсов С.А., Соловенчук Л.Л., Герус П.А., Шеплев Б.В., Чернышова А.Л.Maiborodin I.V., Fursov S.A., Solovenchuk L.L., Gerus P.A., Sheplev B.V., Chernyshova A.L.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/4209

Цель исследования – обобщить данные о роли матриксных металлопротеиназ (ММП) в ангиогенезе, развитии и прогрессировании рака толстой кишки (РТК).

Материал и методы

Материал и методы. Проведен поиск публикаций в базах данных Medline и eliBRARY.RU с 1999 г. по настоящее время по ключевым словам «angiogenesis + cancer + colon + MMP».

Результаты

Результаты. Наиболее распространенным свойством злокачественных опухолей является их способность формировать новые сосуды, проникать в соседние ткани и метастазировать, и эта агрессивность зависит от экспрессии протеолитических ферментов, в том числе ММП. При возникновении РТК в тканях и плазме крови возрастает содержание ММП, которые необходимы для ремоделирования внеклеточного матрикса в процессе ангиогенеза, инвазии и метастазирования опухоли. Степень повышенной экспрессии некоторых ММП коррелирует со стадией РТК, васкуляризацией, экспрессией VEGF и/или прогнозом, но с этим согласны не все исследователи. ММП синтезируются как клеточными элементами опухоли, так и клетками, расположенными в строме, в первую очередь туморассоциированными макрофагами. Изменение функций иммунокомпетентных и стромальных клеток, экспрессирующих и продуцирующих ММП, играет решающую роль как в инициации, так и прогрессировании РТК, в том числе через вновь образованные сосуды. Воздействие на туморассоциированные иммунокомпетентные и стромальные клетки, их перепрограммирование, нейтрализация и/или ингибиция трафика способны задержать васкуляризацию, рост и инвазию РТК. Ингибирование ММП может стать одним из этапов антиангиогенной терапии. Кроме супрессии ангиогенеза, некоторые ингибиторы ММП стимулируют апоптоз, подавляют пролиферацию клеток, индуцируют остановку клеточного цикла и снижают экспрессию антиапоптотических генов семейства Bcl. В качестве ингибиторов ММП предложено использование большого количества различных методик, искусственных и естественных соединений. Однако несмотря на многообещающие экспериментальные результаты, клинические испытания с ингибиторами ММП не оправдали ожиданий. Имеются данные об антиопухолевом эффекте некоторых ММП, блокада которых сопровождается прогрессированием рака.

Заключение

Заключение. Такое значительное число способов воздействия на ММП и определенная противоречивость данных могут служить свидетельством неудовлетворенности исследователей и клиницистов решением проблемы ангиогенеза с участием ММП в тканях опухолей, целесообразности продолжения изучения как эффектов ММП при РТК опухоли, так и методов контроля активности этой группы ферментов, средств управления ими.

Aim

Aim: to summarize the available literature data on the role of matrix metalloproteinases (MMPs) in angiogenesis, as well as in the development and progression of colorectal cancer (CRC).

Material and Methods

Material and Methods. A literature search was conducted in the Medline and eliBRARY.RU databases from 1999 to the present using the keywords “angiogenesis + cancer + colon + MMP”.

Results

Results. Malignant tumors are characterized by the ability to form new vessels, invade surrounding tissues, and metastasize to distant organs, and this aggressiveness depends on the expression of proteolytic enzymes, including MMPs. in CRC, the levels of MMPs are increased in both tumor tissues and blood plasma; these enzymes are required for extracellular matrix remodelling during angiogenesis, tumor invasion and metastasis. The degree of overexpression of certain MMPs correlates with the stage of CRC, vascularization, VEGF expression and/or prognosis; however, not all researchers agree with these findings. MMPs are synthesized both by tumor cells and, more prominently, stromal cells like tumor-associated macrophages. Alterations in the function of immunocompetent and stromal cells that express and produce MMPs play a key role in both the initiation and progression of CRC. Targeting tumor-associated immunocompetent and stromal cells, their reprogramming, neutralization and/or inhibition of their trafficking may delay the growth and invasion of CRC. inhibition of MMPs may represent one of the stages of antiangiogenic therapy. in addition to suppressing angiogenesis, certain MMP inhibitors stimulate apoptosis, suppress cell proliferation, induce cell cycle arrest, and reduce the expression of antiapoptotic genes of the Bcl family. A wide range of artificial and natural compounds and methods has been proposed as MMP inhibitors. However, despite promising experimental results, clinical trials of MMP inhibitors have been largely disappointing. There is evidence that some MMPs exert antitumor effects, and their blockade may be accompanied by tumor progression.

Conclusion

Conclusion. A wide variety of approaches to targeting MMPs, together with the certain inconsistency of available data, may indicate the persisting dissatisfaction of researchers and clinicians with the current solutions to the problem of MMP-mediated angiogenesis in tumor tissues. This also highlights the need for continued investigation into both the effects of MMPs in CRC and the methods for controlling the activity of this enzyme group.

рак толстой кишкиматриксные металлопротеиназыопухолевый ангиогенезваскуляризация опухолитуморассоциированные макрофагиингибиторы матриксных металлопротеиназфакторы прогнозаcolorectal cancermatrix metalloproteinasestumor angiogenesistumor vascularizationtumor-associated macrophagesinhibitors of matrix metalloproteinasesprognostic factorsИсследование поддержано в рамках государственного задания ИХБФМ СО РАН № 125012300674-9 «Фундаментальные основы сохранения здоровья нации»This work was supported by the Russian state-funded project for ICBFM SB RAS (grant number 125012300674-9). The authors did not receive financial support from the drug manufacturersReferencesМайбородин 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. Сибирский онкологический журнал. 2024; 23(4): 172–85. doi: 10.21294/1814-4861-2024-23-4-172-185. EDN: XPLFZD.Maiborodin I.V., Goncharov M.A., Shevela A.I., Krasilnikov S.E., Shumeikina A.O., Maiborodina V.I. Angiogenesis in endometrial cancer: clinical and biological significance. Siberian Journal of Oncology. 2024; 23(4): 172–85. (in Russian). doi: 10.21294/1814-4861-2024-23-4-172-185. EDN: XPLFZD.Ghanghas P., Jain S., Rana C., Sanyal S.N. Chemoprevention of Colon Cancer through Inhibition of Angiogenesis and Induction of Apoptosis by Nonsteroidal Anti-Inflammatory Drugs. J Environ Pathol Toxicol Oncol. 2016; 35(3): 273–89. doi: 10.1615/JEnvironPatholToxicolOncol.2016015704.Ghanghas P., Jain S., Rana C., Sanyal S.N. Chemoprevention of Colon Cancer through Inhibition of Angiogenesis and Induction of Apoptosis by Nonsteroidal Anti-Inflammatory Drugs. J Environ Pathol Toxicol Oncol. 2016; 35(3): 273–89. doi: 10.1615/JEnvironPatholToxicolOncol.2016015704.Майбородин И.В., Гончаров М.А., Шеплев Б.В., Шумейкина А.О., Красильников С.Э., Черноморцева Е.С. Васкуляризация эндометрия при гиперплазии без атипии. Архив патологии. 2025; 87(6): 28–33 doi: 10.17116/patol20258706128. EDN: AEDJUZ.Maiborodin I.V., Goncharov M.A., Sheplev B.V., Shumeikina A.O., Krasilnikov S.E., Chernomortseva E.S. Endometrial vascularization in hyperplasia without atypia. Russian Journal of Archive of Pathology. 2025; 87(6): 28–33. (in Russian). doi: 10.17116/patol20258706128. EDN: AEDJUZ.Esteban S., Clemente C., Koziol A., Gonzalo P., Rius C., Martínez F., Linares PM., Chaparro M., Urzainqui A., Andrés V., Seiki M., Gisbert J.P., Arroyo A.G. Endothelial MT1-MMP targeting limits intussusceptive angiogenesis and colitis via TSP1/nitric oxide axis. EMBO Mol Med. 2020; 12(2): e10862. doi: 10.15252/emmm.201910862.Esteban S., Clemente C., Koziol A., Gonzalo P., Rius C., Martínez F., Linares PM., Chaparro M., Urzainqui A., Andrés V., Seiki M., Gisbert J.P., Arroyo A.G. Endothelial MT1-MMP targeting limits intussusceptive angiogenesis and colitis via TSP1/nitric oxide axis. EMBO Mol Med. 2020; 12(2): e10862. doi: 10.15252/emmm.201910862.Klupp F., Neumann L., Kahlert C., Diers J., Halama N., Franz C., Schmidt T., Koch M., Weitz J., Schneider M., Ulrich A. Serum MMP7, MMP10 and MMP12 level as negative prognostic markers in colon cancer patients. BMC Cancer. 2016; 16: 494. doi: 10.1186/s12885-016-2515-7.Klupp F., Neumann L., Kahlert C., Diers J., Halama N., Franz C., Schmidt T., Koch M., Weitz J., Schneider M., Ulrich A. Serum MMP7, MMP10 and MMP12 level as negative prognostic markers in colon cancer patients. BMC Cancer. 2016; 16: 494. doi: 10.1186/s12885-016-2515-7.Buttacavoli M., Di Cara G., Roz E., Pucci-Minafra I., Feo S., Cancemi P. Integrated Multi-Omics Investigations of Metalloproteinases in Colon Cancer: Focus on MMP2 and MMP9. Int J Mol Sci. 2021; 22(22): 12389. doi: 10.3390/ijms222212389.Buttacavoli M., Di Cara G., Roz E., Pucci-Minafra I., Feo S., Cancemi P. Integrated Multi-Omics Investigations of Metalloproteinases in Colon Cancer: Focus on MMP2 and MMP9. Int J Mol Sci. 2021; 22(22): 12389. doi: 10.3390/ijms222212389.Shantha Kumara H., Miyagaki H., Herath S.A., Pettke E., Yan X., Cekic V., Whelan R.L. Plasma MMP-2 and MMP-7 levels are elevated first month after surgery and may promote growth of residual metastases. World J Gastrointest Oncol. 2021; 13(8): 879–92. doi: 10.4251/wjgo.v13.i8.879.Shantha Kumara H., Miyagaki H., Herath S.A., Pettke E., Yan X., Cekic V., Whelan R.L. Plasma MMP-2 and MMP-7 levels are elevated first month after surgery and may promote growth of residual metastases. World J Gastrointest Oncol. 2021; 13(8): 879–92. doi: 10.4251/wjgo.v13.i8.879.Boulay A., Masson R., Chenard M.P., El Fahime M., Cassard L., Bellocq J.P., Sautès-Fridman C., Basset P., Rio M.C. High cancer cell death in syngeneic tumors developed in host mice deficient for the stromelysin-3 matrix metalloproteinase. Cancer Res. 2001; 61(5): 2189–93.Boulay A., Masson R., Chenard M.P., El Fahime M., Cassard L., Bellocq J.P., Sautès-Fridman C., Basset P., Rio M.C. High cancer cell death in syngeneic tumors developed in host mice deficient for the stromelysin-3 matrix metalloproteinase. Cancer Res. 2001; 61(5): 2189–93.Mook O.R., Frederiks W.M., van Noorden C.J. The role of gelatinases in colorectal cancer progression and metastasis. Biochim Biophys Acta. 2004; 1705(2): 69–89. doi: 10.1016/j.bbcan.2004.09.006.Mook O.R., Frederiks W.M., van Noorden C.J. The role of gelatinases in colorectal cancer progression and metastasis. Biochim Biophys Acta. 2004; 1705(2): 69–89. doi: 10.1016/j.bbcan.2004.09.006.Sun J. Matrix metalloproteinases and tissue inhibitor of metalloproteinases are essential for the inflammatory response in cancer cells. J Signal Transduct. 2010; 2010: 985132. doi: 10.1155/2010/985132.Sun J. Matrix metalloproteinases and tissue inhibitor of metalloproteinases are essential for the inflammatory response in cancer cells. J Signal Transduct. 2010; 2010: 985132. doi: 10.1155/2010/985132.Bozhenko V.K., Stanojevic U.S., Trotsenko I.D., Zakharenko M.V., Kiseleva Y.Y., Solodkiy V.A. Comparison of matrix proteinase mRNA expression in morphologically normal, neoplastic, and metastatic colon tissue and colon biopsies from healthy donors. Biomed Khim. 2018; 64(1): 46–52. Russian. doi: 10.18097/PBMC20186401046.Bozhenko V.K., Stanojevic U.S., Trotsenko I.D., Zakharenko M.V., Kiseleva Y.Y., Solodkiy V.A. Comparison of matrix proteinase mRNA expression in morphologically normal, neoplastic, and metastatic colon tissue and colon biopsies from healthy donors. Biomed Khim. 2018; 64(1): 46–52. Russian. doi: 10.18097/PBMC20186401046.Xiao Y., Li G., Xie Y., Shao B., Hao J., Zhu Y., Kong D., Qin Y., Qin H., Ren S., Wang H., Sun C., Wang H. High matrix metalloproteinase-2 expression predicts poor prognosis of colon adenocarcinoma and is associated with PD-L1 expression and lymphocyte infiltration. PeerJ. 2025; 13: e19550. doi: 10.7717/peerj.19550.Xiao Y., Li G., Xie Y., Shao B., Hao J., Zhu Y., Kong D., Qin Y., Qin H., Ren S., Wang H., Sun C., Wang H. High matrix metalloproteinase-2 expression predicts poor prognosis of colon adenocarcinoma and is associated with PD-L1 expression and lymphocyte infiltration. PeerJ. 2025; 13: e19550. doi: 10.7717/peerj.19550.Wyganowska-Świątkowska M., Tarnowski M., Murtagh D., Skrzypczak-Jankun E., Jankun J. Proteolysis is the most fundamental property of malignancy and its inhibition may be used therapeutically (Review). Int J Mol Med. 2019; 43(1): 15–25. doi: 10.3892/ijmm.2018.3983.Wyganowska-Świątkowska M., Tarnowski M., Murtagh D., Skrzypczak-Jankun E., Jankun J. Proteolysis is the most fundamental property of malignancy and its inhibition may be used therapeutically (Review). Int J Mol Med. 2019; 43(1): 15–25. doi: 10.3892/ijmm.2018.3983.Zucker S., Vacirca J. Role of matrix metalloproteinases (MMPs) in colorectal cancer. Cancer Metastasis Rev. 2004; 23(1-2): 101–17. doi: 10.1023/a:1025867130437.Zucker S., Vacirca J. Role of matrix metalloproteinases (MMPs) in colorectal cancer. Cancer Metastasis Rev. 2004; 23(1-2): 101–17. doi: 10.1023/a:1025867130437.Mokgautsi N., Kuo Y.C., Huang Y.J., Chen C.H., Mukhopadhyay D., Wu A.T.H., Huang H.S. Preclinical Evaluation of a Novel Small Molecule LCC-21 to Suppress Colorectal Cancer Malignancy by Inhibiting Angiogenic and Metastatic Signatures. Cells. 2023; 12(2): 266. doi: 10.3390/cells12020266.Mokgautsi N., Kuo Y.C., Huang Y.J., Chen C.H., Mukhopadhyay D., Wu A.T.H., Huang H.S. Preclinical Evaluation of a Novel Small Molecule LCC-21 to Suppress Colorectal Cancer Malignancy by Inhibiting Angiogenic and Metastatic Signatures. Cells. 2023; 12(2): 266. doi: 10.3390/cells12020266.Li Y., Kuscu C., Banach A., Zhang Q., Pulkoski-Gross A., Kim D., Liu J., Roth E., Li E., Shroyer K.R., Denoya P.I., Zhu X., Chen L., Cao J. miR-181a-5p Inhibits Cancer Cell Migration and Angiogenesis via Downregulation of Matrix Metalloproteinase-14. Cancer Res. 2015; 75(13): 2674–85. doi: 10.1158/0008-5472.CAN-14-2875.Li Y., Kuscu C., Banach A., Zhang Q., Pulkoski-Gross A., Kim D., Liu J., Roth E., Li E., Shroyer K.R., Denoya P.I., Zhu X., Chen L., Cao J. miR-181a-5p Inhibits Cancer Cell Migration and Angiogenesis via Downregulation of Matrix Metalloproteinase-14. Cancer Res. 2015; 75(13): 2674–85. doi: 10.1158/0008-5472.CAN-14-2875.Zeynali-Moghaddam S., Mohammadian M., Kheradmand F., FathiAzarbayjani A., Rasmi Y., Esna-Ashari O., Malekinejad H. A molecular basis for the synergy between 17-allylamino-17-demethoxy geldanamycin with Capecitabine and Irinotecan in human colorectal cancer cells through VEFG and MMP-9 gene expression. Gene. 2019; 684: 30–38. doi: 10.1016/j.gene.2018.10.016.Zeynali-Moghaddam S., Mohammadian M., Kheradmand F., FathiAzarbayjani A., Rasmi Y., Esna-Ashari O., Malekinejad H. A molecular basis for the synergy between 17-allylamino-17-demethoxy geldanamycin with Capecitabine and Irinotecan in human colorectal cancer cells through VEFG and MMP-9 gene expression. Gene. 2019; 684: 30–38. doi: 10.1016/j.gene.2018.10.016.Gungor H., Ilhan N., Eroksuz H. The effectiveness of cyclooxygenase-2 inhibitors and evaluation of angiogenesis in the model of experimental colorectal cancer. Biomed Pharmacother. 2018; 102: 221–29. doi: 10.1016/j.biopha.2018.03.066.Gungor H., Ilhan N., Eroksuz H. The effectiveness of cyclooxygenase-2 inhibitors and evaluation of angiogenesis in the model of experimental colorectal cancer. Biomed Pharmacother. 2018; 102: 221–29. doi: 10.1016/j.biopha.2018.03.066.Takahashi Y., Ellis L.M., Mai M. The angiogenic switch of human colon cancer occurs simultaneous to initiation of invasion. Oncol Rep. 2003; 10(1): 9–13.Takahashi Y., Ellis L.M., Mai M. The angiogenic switch of human colon cancer occurs simultaneous to initiation of invasion. Oncol Rep. 2003; 10(1): 9–13.Staton C.A., Chetwood A.S., Cameron I.C., Cross S.S., Brown N.J., Reed M.W. The angiogenic switch occurs at the adenoma stage of the adenoma carcinoma sequence in colorectal cancer. Gut. 2007; 56(10): 1426–32. doi: 10.1136/gut.2007.125286.Staton C.A., Chetwood A.S., Cameron I.C., Cross S.S., Brown N.J., Reed M.W. The angiogenic switch occurs at the adenoma stage of the adenoma carcinoma sequence in colorectal cancer. Gut. 2007; 56(10): 1426–32. doi: 10.1136/gut.2007.125286.Setia S., Nehru B., Sanyal S.N. The PI3K/Akt pathway in colitis associated colon cancer and its chemoprevention with celecoxib, a Cox-2 selective inhibitor. Biomed Pharmacother. 2014; 68(6): 721–27. doi: 10.1016/j.biopha.2014.07.006.Setia S., Nehru B., Sanyal S.N. The PI3K/Akt pathway in colitis associated colon cancer and its chemoprevention with celecoxib, a Cox-2 selective inhibitor. Biomed Pharmacother. 2014; 68(6): 721–27. doi: 10.1016/j.biopha.2014.07.006.Chen X., Su Y., Fingleton B., Acuff H., Matrisian L.M., Zent R., Pozzi A. Increased plasma MMP9 in integrin alpha1-null mice enhances lung metastasis of colon carcinoma cells. Int J Cancer. 2005; 116(1): 52–61. doi: 10.1002/ijc.20997.Chen X., Su Y., Fingleton B., Acuff H., Matrisian L.M., Zent R., Pozzi A. Increased plasma MMP9 in integrin alpha1-null mice enhances lung metastasis of colon carcinoma cells. Int J Cancer. 2005; 116(1): 52–61. doi: 10.1002/ijc.20997.Uslukaya O., Yegin Z., Taskesen F., Yildirim I.H. Elevated expression levels of COX-2, IL-8 and VEGF in colon adenocarcinoma. Cell Mol Biol (Noisy-le-grand). 2023; 69(6): 146–50. doi: 10.14715/cmb/2023.69.6.22.Uslukaya O., Yegin Z., Taskesen F., Yildirim I.H. Elevated expression levels of COX-2, IL-8 and VEGF in colon adenocarcinoma. Cell Mol Biol (Noisy-le-grand). 2023; 69(6): 146–50. doi: 10.14715/cmb/2023.69.6.22.Hashemzehi M., Rahmani F., Khoshakhlagh M., Avan A., Asgharzadeh F., Barneh F., Moradi-Marjaneh R., Soleimani A., Fiuji H., Ferns GA., Ryzhikov M., Jafari M., Khazaei M., Hassanian S.M. Angiotensin receptor blocker Losartan inhibits tumor growth of colorectal cancer. EXCLI J. 2021; 20: 506–21. doi: 10.17179/excli2020-3083.Hashemzehi M., Rahmani F., Khoshakhlagh M., Avan A., Asgharzadeh F., Barneh F., Moradi-Marjaneh R., Soleimani A., Fiuji H., Ferns GA., Ryzhikov M., Jafari M., Khazaei M., Hassanian S.M. Angiotensin receptor blocker Losartan inhibits tumor growth of colorectal cancer. EXCLI J. 2021; 20: 506–21. doi: 10.17179/excli2020-3083.Deng Y., Jia X., Liu L., He Q., Liu L. The role of intestinal macrophage polarization in colitis-associated colon cancer. Front Immunol. 2025; 16: 1537631. doi: 10.3389/fimmu.2025.1537631.Deng Y., Jia X., Liu L., He Q., Liu L. The role of intestinal macrophage polarization in colitis-associated colon cancer. Front Immunol. 2025; 16: 1537631. doi: 10.3389/fimmu.2025.1537631.Toledo B., Zhu Chen L., Paniagua-Sancho M., Marchal J.A., Perán M., Giovannetti E. Deciphering the performance of macrophages in tumour microenvironment: a call for precision 25. Deng Y., Jia X., Liu L., He Q., Liu L. The role of intestinal macrophage polarization in colitis-associated colon cancer. Front Immunol. 2025; 16: 1537631. doi: 10.3389/fimmu.2025.1537631.Toledo B., Zhu Chen L., Paniagua-Sancho M., Marchal J.A., Perán M., Giovannetti E. Deciphering the performance of macrophages in tumour microenvironment: a call for precision 25. Deng Y., Jia X., Liu L., He Q., Liu L. The role of intestinal macrophage polarization in colitis-associated colon cancer. Front Immunol. 2025; 16: 1537631. doi: 10.3389/fimmu.2025.1537631.Murray P.J. Macrophage Polarization. Annu Rev Physiol. 2017; 79: 541–66. doi: 10.1146/annurev-physiol-022516-034339.Murray P.J. Macrophage Polarization. Annu Rev Physiol. 2017; 79: 541–66. doi: 10.1146/annurev-physiol-022516-034339.Carrara S.C., Davila-Lezama A., Cabriel C., Berenschot E.J.W., Krol S., Gardeniers J.G.E., Izeddin I., Kolmar H., Susarrey-Arce A. 3D topographies promote macrophage M2d-Subset differentiation. Mater Today Bio. 2023; 24: 100897. doi: 10.1016/j.mtbio.2023.100897.Carrara S.C., Davila-Lezama A., Cabriel C., Berenschot E.J.W., Krol S., Gardeniers J.G.E., Izeddin I., Kolmar H., Susarrey-Arce A. 3D topographies promote macrophage M2d-Subset differentiation. Mater Today Bio. 2023; 24: 100897. doi: 10.1016/j.mtbio.2023.100897.Zhao W., Wu Y., Wang Y., Li T., Liu Q., Hou Z. Exosomal miR-92a3p modulates M2 macrophage polarization in colorectal cancer: implications for tumor migration and angiogenesis. Med Oncol. 2025; 42(4): 96. doi: 10.1007/s12032-025-02635-2. PMID: 40059261.Zhao W., Wu Y., Wang Y., Li T., Liu Q., Hou Z. Exosomal miR-92a3p modulates M2 macrophage polarization in colorectal cancer: implications for tumor migration and angiogenesis. Med Oncol. 2025; 42(4): 96. doi: 10.1007/s12032-025-02635-2. PMID: 40059261.Mezheyeuski A., Micke P., Martín-Bernabé A., Backman M., Hrynchyk I., Hammarström K., Ström S., Ekström J., Edqvist P.H., Sundström M., Ponten F., Leandersson K., Glimelius B., Sjöblom T. The Immune Landscape of Colorectal Cancer. Cancers (Basel). 2021; 13(21): 5545. doi: 10.3390/cancers13215545.Mezheyeuski A., Micke P., Martín-Bernabé A., Backman M., Hrynchyk I., Hammarström K., Ström S., Ekström J., Edqvist P.H., Sundström M., Ponten F., Leandersson K., Glimelius B., Sjöblom T. The Immune Landscape of Colorectal Cancer. Cancers (Basel). 2021; 13(21): 5545. doi: 10.3390/cancers13215545.Aharinejad S., Abraham D., Paulus P., Abri H., Hofmann M., Grossschmidt K., Schäfer R., Stanley E.R., Hofbauer R. Colony-stimulating factor-1 antisense treatment suppresses growth of human tumor xenografts in mice. Cancer Res. 2002; 62(18): 5317–24.Aharinejad S., Abraham D., Paulus P., Abri H., Hofmann M., Grossschmidt K., Schäfer R., Stanley E.R., Hofbauer R. Colony-stimulating factor-1 antisense treatment suppresses growth of human tumor xenografts in mice. Cancer Res. 2002; 62(18): 5317–24.Cardoso A.P., Pinto M.L., Pinto A.T., Pinto M.T., Monteiro C., Oliveira M.I., Santos S.G., Relvas J.B., Seruca R., Mantovani A., Mareel M., Barbosa M.A., Oliveira M.J. Matrix metalloproteases as maestros for the dual role of LPSand IL-10-stimulated macrophages in cancer cell behaviour. BMC Cancer. 2015; 15: 456. doi: 10.1186/s12885015-1466-8.Cardoso A.P., Pinto M.L., Pinto A.T., Pinto M.T., Monteiro C., Oliveira M.I., Santos S.G., Relvas J.B., Seruca R., Mantovani A., Mareel M., Barbosa M.A., Oliveira M.J. Matrix metalloproteases as maestros for the dual role of LPSand IL-10-stimulated macrophages in cancer cell behaviour. BMC Cancer. 2015; 15: 456. doi: 10.1186/s12885015-1466-8.Korbecki J., Bosiacki M., Barczak K., Łagocka R., Chlubek D., Baranowska-Bosiacka I. The Clinical Significance and Role of CXCL1 Chemokine in Gastrointestinal Cancers. Cells. 2023; 12(10): 1406. doi: 10.3390/cells12101406.Korbecki J., Bosiacki M., Barczak K., Łagocka R., Chlubek D., Baranowska-Bosiacka I. The Clinical Significance and Role of CXCL1 Chemokine in Gastrointestinal Cancers. Cells. 2023; 12(10): 1406. doi: 10.3390/cells12101406.Wang L., Ma L., Song Z., Zhou L., Chen K., Wang X., Liu Z., Wang B., Shen C., Guo X., Jia X. Single-cell transcriptome analysis profiling lymphatic invasion-related TME in colorectal cancer. Sci Rep. 2024; 14(1): 8911. doi: 10.1038/s41598-024-59656-6.Wang L., Ma L., Song Z., Zhou L., Chen K., Wang X., Liu Z., Wang B., Shen C., Guo X., Jia X. Single-cell transcriptome analysis profiling lymphatic invasion-related TME in colorectal cancer. Sci Rep. 2024; 14(1): 8911. doi: 10.1038/s41598-024-59656-6.Tacconi C., Ungaro F., Correale C., Arena V., Massimino L., Detmar M., Spinelli A., Carvello M., Mazzone M., Oliveira A.I., Rubbino F., Garlatti V., Spanò S., Lugli E., Colombo F.S., Malesci A., PeyrinBiroulet L., Vetrano S., Danese S., D'Alessio S. Activation of the VEGFC/ VEGFR3 Pathway Induces Tumor Immune Escape in Colorectal Cancer. Cancer Res. 2019; 79(16): 4196–210. doi: 10.1158/0008-5472.CAN-18-3657.Tacconi C., Ungaro F., Correale C., Arena V., Massimino L., Detmar M., Spinelli A., Carvello M., Mazzone M., Oliveira A.I., Rubbino F., Garlatti V., Spanò S., Lugli E., Colombo F.S., Malesci A., PeyrinBiroulet L., Vetrano S., Danese S., D'Alessio S. Activation of the VEGFC/ VEGFR3 Pathway Induces Tumor Immune Escape in Colorectal Cancer. Cancer Res. 2019; 79(16): 4196–210. doi: 10.1158/0008-5472.CAN-18-3657.Bui T.M., Yalom L.K., Ning E., Urbanczyk J.M., Ren X., Herrnreiter C.J., Disario J.A., Wray B., Schipma M.J., Velichko Y.S., Sullivan D.P., Abe K., Lauberth S.M., Yang G.Y., Dulai P.S., Hanauer S.B., Sumagin R. Tissue-specific reprogramming leads to angiogenic neutrophil specialization and tumor vascularization in colorectal cancer. J Clin Invest. 2024; 134(7): e174545. doi: 10.1172/JCI174545.Bui T.M., Yalom L.K., Ning E., Urbanczyk J.M., Ren X., Herrnreiter C.J., Disario J.A., Wray B., Schipma M.J., Velichko Y.S., Sullivan D.P., Abe K., Lauberth S.M., Yang G.Y., Dulai P.S., Hanauer S.B., Sumagin R. Tissue-specific reprogramming leads to angiogenic neutrophil specialization and tumor vascularization in colorectal cancer. J Clin Invest. 2024; 134(7): e174545. doi: 10.1172/JCI174545.Gallazzi M., Baci D., Mortara L., Bosi A., Buono G., Naselli A., Guarneri A., Dehò F., Capogrosso P., Albini A., Noonan D.M., Bruno A. Prostate Cancer Peripheral Blood NK Cells Show Enhanced CD9, CD49a, CXCR4, CXCL8, MMP-9 Production and Secrete Monocyte-Recruiting and Polarizing Factors. Front Immunol. 2021; 11: 586126. doi: 10.3389/fimmu.2020.586126.Gallazzi M., Baci D., Mortara L., Bosi A., Buono G., Naselli A., Guarneri A., Dehò F., Capogrosso P., Albini A., Noonan D.M., Bruno A. Prostate Cancer Peripheral Blood NK Cells Show Enhanced CD9, CD49a, CXCR4, CXCL8, MMP-9 Production and Secrete Monocyte-Recruiting and Polarizing Factors. Front Immunol. 2021; 11: 586126. doi: 10.3389/fimmu.2020.586126.Ying L., Zhu Y., Zhang L., Ji M., Wang M., Dong L., Yun Z., Chen Y., Zhou J., Huang C., Zhang S., Yang X., Yang H., Huang G., Qin S., Xie J., Liu L. Cancer-associated fibroblasts expressing FSTL3 promote vasculogenic mimicry formation and drive colon cancer malignancy. Cell Death Dis. 2025; 16(1): 706. doi: 10.1038/s41419-025-08009-w.Ying L., Zhu Y., Zhang L., Ji M., Wang M., Dong L., Yun Z., Chen Y., Zhou J., Huang C., Zhang S., Yang X., Yang H., Huang G., Qin S., Xie J., Liu L. Cancer-associated fibroblasts expressing FSTL3 promote vasculogenic mimicry formation and drive colon cancer malignancy. Cell Death Dis. 2025; 16(1): 706. doi: 10.1038/s41419-025-08009-w.Harada A., Yasumizu Y., Harada T., Fumoto K., Sato A., Maehara N., Sada R., Matsumoto S., Nishina T., Takeda K., Morii E., Kayama H., Kikuchi A. Hypoxia-induced Wnt5a-secreting fibroblasts promote colon cancer progression. Nat Commun. 2025; 16(1): 3653. doi: 10.1038/s41467-025-58748-9.Harada A., Yasumizu Y., Harada T., Fumoto K., Sato A., Maehara N., Sada R., Matsumoto S., Nishina T., Takeda K., Morii E., Kayama H., Kikuchi A. Hypoxia-induced Wnt5a-secreting fibroblasts promote colon cancer progression. Nat Commun. 2025; 16(1): 3653. doi: 10.1038/s41467-025-58748-9.Li H., Li L., Zheng H., Yao X., Zang W. Regulatory effects of ΔFosB on proliferation and apoptosis of MCF-7 breast cancer cells. Tumour Biol. 2016; 37(5): 6053–63. doi: 10.1007/s13277-015-4356-4.Li H., Li L., Zheng H., Yao X., Zang W. Regulatory effects of ΔFosB on proliferation and apoptosis of MCF-7 breast cancer cells. Tumour Biol. 2016; 37(5): 6053–63. doi: 10.1007/s13277-015-4356-4.Yi T., Wei Y.Q., Tian L., Zhao X., Li J., Deng H.X., Wen Y.J., Zou C.H., Tan G.H., Kan B., Su J.M., Jiang Y., Mao Y.Q., Chen P., Wang Y.S. Humoral and cellular immunity induced by tumor cell vaccine based on the chicken xenogeneic homologous matrix metalloproteinase-2. Cancer Gene Ther. 2007; 14(2): 158–64. doi: 10.1038/sj.cgt.7700994.Yi T., Wei Y.Q., Tian L., Zhao X., Li J., Deng H.X., Wen Y.J., Zou C.H., Tan G.H., Kan B., Su J.M., Jiang Y., Mao Y.Q., Chen P., Wang Y.S. Humoral and cellular immunity induced by tumor cell vaccine based on the chicken xenogeneic homologous matrix metalloproteinase-2. Cancer Gene Ther. 2007; 14(2): 158–64. doi: 10.1038/sj.cgt.7700994.Chen J., Hui X.H., Li H., Cai B.W., Wang W., Zhu B. [An experimental research on tumor metastasis treated by chicken homologous matrix metalloproteinase-2 vaccine combined with low-dose cisplatin]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2007; 38(1): 35–39. Chinese.Chen J., Hui X.H., Li H., Cai B.W., Wang W., Zhu B. [An experimental research on tumor metastasis treated by chicken homologous matrix metalloproteinase-2 vaccine combined with low-dose cisplatin]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2007; 38(1): 35–39. Chinese.Kimura Y., Sumiyoshi M., Baba K. Antitumor activities of synthetic and natural stilbenes through antiangiogenic action. Cancer Sci. 2008; 99(10): 2083–96. doi: 10.1111/j.1349-7006.2008.00948.x.Kimura Y., Sumiyoshi M., Baba K. Antitumor activities of synthetic and natural stilbenes through antiangiogenic action. Cancer Sci. 2008; 99(10): 2083–96. doi: 10.1111/j.1349-7006.2008.00948.x.Li H., Lindenmeyer F., Grenet C., Opolon P., Menashi S., Soria C., Yeh P., Perricaudet M., Lu H. AdTIMP-2 inhibits tumor growth, angiogenesis, and metastasis, and prolongs survival in mice. Hum Gene Ther. 2001; 12(5): 515–26. doi: 10.1089/104303401300042429.Li H., Lindenmeyer F., Grenet C., Opolon P., Menashi S., Soria C., Yeh P., Perricaudet M., Lu H. AdTIMP-2 inhibits tumor growth, angiogenesis, and metastasis, and prolongs survival in mice. Hum Gene Ther. 2001; 12(5): 515–26. doi: 10.1089/104303401300042429.Verma S., Das P., Kumar V.L. Chemoprevention by artesunate in a preclinical model of colorectal cancer involves down regulation of β-catenin, suppression of angiogenesis, cellular proliferation and induction of apoptosis. Chem Biol Interact. 2017; 278: 84–91. doi: 10.1016/j.cbi.2017.10.011.Verma S., Das P., Kumar V.L. Chemoprevention by artesunate in a preclinical model of colorectal cancer involves down regulation of β-catenin, suppression of angiogenesis, cellular proliferation and induction of apoptosis. Chem Biol Interact. 2017; 278: 84–91. doi: 10.1016/j.cbi.2017.10.011.Choi S.H., Lee H.J., Jin Y.B., Jang J., Kang G.Y., Lee M., Kim C.H., Kim J., Yoon S.S., Lee Y.S., Lee Y.J. MMP9 processing of HSPB1 regulates tumor progression. PLoS One. 2014; 9(1): e85509. doi: 10.1371/journal.pone.0085509.Choi S.H., Lee H.J., Jin Y.B., Jang J., Kang G.Y., Lee M., Kim C.H., Kim J., Yoon S.S., Lee Y.S., Lee Y.J. MMP9 processing of HSPB1 regulates tumor progression. PLoS One. 2014; 9(1): e85509. doi: 10.1371/journal.pone.0085509.Pozzi A., LeVine W.F., Gardner H.A. Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesis. Oncogene. 2002; 21(2): 272–81. doi: 10.1038/sj.onc.1205045.Pozzi A., LeVine W.F., Gardner H.A. Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesis. Oncogene. 2002; 21(2): 272–81. doi: 10.1038/sj.onc.1205045.

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