Extracellular matrix, which constitutes the majority of tumor stroma, plays a leading role in the progression of various cancers, including colorectal carcinoma, and, therefore, contributes to the creation of an environment conducive to metastasis. The aim of this work was to study the clinical significance of the immunohistochemical activity of metalloproteinases (MMP-9, MMP-12) and proangiogenic factors (HIFa, VEGF-A, Ang1, Ang2) and to identify their relationship with the clinical and morphological characteristics and prognosis of colorectal cancer (CRC). Material and methods. For the study, histological material was collected from patients with verified colorectal carcinoma (n=263). All patients were divided into two groups: 1st - with metastatic colorectal cancer (n=132); 2nd - with non-metastatic colorectal cancer (n=131). The study material was tumor tissue fragments obtained during surgery for subsequent histological and immunohistochemical studies with markers of metalloproteinases type 9, 12 (MMP12, MMP9), vascular endothelial growth factor (VEGF-A), hypoxia-inducible factor-1Α (HIF1α), angiopoietins type 1 and 2 (Ang1, Ang2). Evaluation of the expression of metalloproteinases and proangiogenic factors confirmed their clinical significance in the progression of neoplastic processes. Results.The obtained data on the close functional relationship between proangiogenic factors and metalloproteinases indicate the promise of their use as prognostic biomarkers. It is assumed that the determination of these markers will identify a subclass of patients with a higher risk of recurrence/progression of colorectal carcinoma. Thus, the use of immunohistochemical diagnostic methods that determine the expression of such markers as: MMP12, MMP9, HIFa, VEGF-A, Ang1, Ang2 with an assessment of the intensity of the reaction and the correlation between them, opens up new prospects in oncodiagnostics. Conclusion. Conducting the recommended diagnostic studies will not only predict the prognosis of the disease, but will also help with the further determination of therapeutic tactics.
colorectal cancer, extracellular matrix, metalloproteinases, proangiogenic factors, immunohistochemistry.
1. Kim M. S., Ha S. E., Wu M., Zogg H., Ronkon C. F., Lee M. Y., Ro S. Extracellular Matrix Biomarkers in Colorectal Cancer. Int J Mol Sci. 2021;22(17):9185. doihttps://doi.org/10.3390/ijms22179185.
2. Asiry S., Kim G., Filippou P. S., Sanchez L. R., Entenberg D., Marks D. K., Oktay M. H., Karagiannis G. S. The Cancer Cell Dissemination Machinery as an Immunosuppressive Niche: A New Obstacle Towards the Era of 3. Karamanos N. K. Extracellular matrix: Key structural and functional meshwork in health and disease. FEBS J 2019;286:2826-29. doi:10.1111/ febs.14992.
3. Yuzhalin A. E., Lim S. Y., Kutikhin A. G., Gordon-Weeks A. N. Dynamic matrisome: ECM remodeling factors licensing cancer progression and metastasis. Biochim. Biophys. Acta Rev. Cancer 2018;1870:207–228.
4. Sanderson R. D., Elkin M., Rapraeger A. C., Ilan N., Vlodavsky I. Heparanase regulation of cancer, autophagy and inflammation: new mechanisms and targets for therapy. FEBS J 2017;284(1):42-55. doihttps://doi.org/10.1111/febs.13932.
5. Stamenkovic I. Extracellular matrix remodelling: The role of matrix metalloproteinases. J. Pathol 2003;200:448-464. doihttps://doi.org/10.1002/path.1400.
6. Petersen E. V., Chudakova D. A., Skorova E. Y., Anikin V., Reshetov I. V., Mynbaev O. A. The Extracellular Matrix-Derived Biomarkers for Diagnosis, Prognosis, and Personalized Therapy of Malignant Tumors. Front. Oncol
7. Henke E., Nandigama R., Ergun S. Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy. Front. Mol. Biosci 2019;6:160. doihttps://doi.org/10.3389/fmolb.2019.00160.
8. Herszényi L., Hritz I., Lakatos G., Varga M. Z., Tulassay Z. The behavior of matrix metalloproteinases and their inhibitors in colorectal cancer. Int J Mol Sci. 2012;13(10):13240-63. doihttps://doi.org/10.3390/ijms131013240.
9. Pezeshkian Z., Nobili S., Peyravian N., Shojaee B., Nazari H., Soleimani H., Asadzadeh-Aghdaei H., Ashrafian Bonab M., Nazemalhosseini-Mojarad E., Mini E. Insights into the Role of Matrix Metalloproteinases in
10. Unsal D., Akyurek N., Uner A., Erpolat O. P., Han U., Akmansu M., Mentes B.B., Dursun A. Gelatinase B expression as a prognostic factor in patients with stage II/III rectal carcinoma treated by postoperative adjuvant therapy.
11. Chu D., Zhao Z., Zhou Y., Li Y., Li J., Zheng J., Zhao Q., Wang W. Matrix metalloproteinase-9 is associated with relapse and prognosis of patients with colorectal cancer. Ann Surg Oncol. 2012;19(1):318325.
12. Buhmeida A., Bendardaf R., Hilska M., Collan Y., Laato M., Syrjänen S., Syrjänen K., Pyrhönen S. Prognostic significance of matrix metalloproteinase-9 (MMP-9) in stage II colorectal carcinoma. J Gastrointest Cancer.
13. Asano T., Tada M., Cheng S., Takemoto N., Kuramae T., Abe M., Takahashi O., Miyamoto M., Hamada J., Moriuchi T., Hamada J., Moriuchi T., Kondo S. Prognostic values of matrix metalloproteinase family expression in
14. Yang W., Arii S., Gorrin-Rivas M. J., Mori A., Onodera H., Imamura M. Human macrophage metalloelastase gene expression in colorectal carcinoma and its clinicopathologic significance. Cancer. 2001;91:1277-1283.
15. 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
16. Wang L., Geng H., Liu Y., Liu L., Chen Y., Wu F., Liu Z., Ling S., Wang Y., Zhou L. Hot and cold tumors: Immunological features and the therapeutic strategies. MedComm. 2023;4(5):e343. doihttps://doi.org/10.1002/mco2.343.
17. Fagiani E, Christofori G. Angiopoietins in angiogenesis. Cancer Lett. 2013;328(1):18-26. doihttps://doi.org/10.1016/j.canlet.2012.08.018.
18. Rundhaug J. E. Matrix metalloproteinases and angiogenesis. J Cell Mol Med. 2005;9(2):26785. doihttps://doi.org/10.1111/j.1582-4934.2005.tb00355.x.
19. Delektorskaya V. V., Perevoshchikov A. G., Golovkov D. A., Kushlinskii N. E. Prognostic significance of expression of matrix metalloproteinase in colorectal adenocarcinomas and their metastases. Bull Exp Biol Med. 2007
20. Cavdar Z., Canda A. E., Terzi C., Sarioglu S., Fuzun M., Oktay G. Role of gelatinases (matrix metalloproteinases 2 and 9), vascular endothelial growth factor and endostatin on clinicopathological behaviour of rectal cancer.
