Expression levels of β1, β3 integrins and MMP2 and features of morphological heterogeneity of pancreatic ductal adenocarcinoma associated with distant metastasis

Background. Pancreatic cancer is characterized by pronounced invasive growth and a high tendency to lymphogenous and hematogenous metastasis. Molecular mechanisms underlying the epithelial-mesenchymal transition, in particular, changes in the expression of β1, β3 integrins and MMP2, contribute to the invasion and metastasis of pancreatic cancer. A phenotypic manifestation of invasive potential of pancreatic cancer may be the heterogeneity of the morphological structure of the parenchymal component of ductal adenocarcinoma.

The aim of the study was to analyze the expression levels of β1 integrin, β3 integrin, MMP2 and the morphological heterogeneity in the tissue of pancreatic ductal adenocarcinoma, as well as to compare the data obtained with distant metastasis.

Material and Methods. The study group included 84 patients with morphologically verifed pancreatic ductal adenocarcinoma (T1–4N0–2M0–1). The median age of the patients was 58.6 ± 9.1 years. All patients underwent surgery, during which an incisional biopsy of the primary tumor tissue was performed. Expression of integrin β1, integrin β3, and MMP2 markers was assessed by immunohistochemistry.

Results. The positive expression of β3 integrin in glandular, trabecular, and solid structures was observed more frequently in patients with hematogenous metastases than in patients without distant metastases (87 vs 12 %, р=0.001; 100 vs 22 %, р=0.004; 100 vs 8 %, р=0.001, respectively). The positive expression of MMP2 in glandular and solid structures was also observed more often in patients with hematogenous metastases than in patients without distant metastases (87 vs 32 %, р=0.001 and 100 vs 27 %, р=0.001, respectively). The positive expression of integrin β1 in glandular, trabecular, solid structures and tumor cells was observed less frequently in patients with hematogenous metastases than in patients without distant metastases (27 vs 86 %, р=0.001; 25 vs 79 %, р=0.007; 0 vs 93 %, р=0.001 and 18 vs 60 %, respectively). The logistic regression model for predicting the risk of hematogenous metastasis of pancreatic ductal adenocarcinoma was developed: Y=(-6.71 + 30.9×X1 – 27.2×X2), where X1 – the presence or absence of β3 integrin expression in the cells of the glandular structures, X2 – the presence or absence of MMP2 in the cells of the glandular structures. The risk of developing hematogenous metastasis was determined by the formula: Р=е^Y/(1+е^Y). Model confdence interval: χ² =34.0; p<0.001, sensitivity: 89 %, specifcity: 87 %. Conclusion. Expression of integrin β1, integrin β3, and MMP2 markers in various structures of the parenchymal component of pancreatic ductal adenocarcinoma is associated with distant metastasis. The localization of the expression of the studied markers in the glandular structures of tumor tissue is of particular importance. The presence of positive expression of integrin β3 and MMP2 in almost all types of tumor structures is associated with the highest frequency of distant dissemination. Key words: ductal pancreatic adenocarcinoma, β1 integrin, β3 integrin, MMP2, tumor morphological heterogeneity, distant metastases> ˂ 0.001, sensitivity: 89 %, specifcity: 87 %.

Conclusion. Expression of integrin β1, integrin β3, and MMP2 markers in various structures of the parenchymal component of pancreatic ductal adenocarcinoma is associated with distant metastasis. The localization of the expression of the studied markers in the glandular structures of tumor tissue is of particular importance. The presence of positive expression of integrin β3 and MMP2 in almost all types of tumor structures is associated with the highest frequency of distant dissemination. 

1. McGuigan A., Kelly P., Turkington R.C., Jones C., Coleman H.G., McCain R.S. Pancreatic cancer: A review of clinical diagnosis, epidemiology, treatment and outcomes. World J Gastroenterol. 2018; 24(43): 4846–61. doi: 10.3748/wjg.v24.i43.4846.

2. Park W., Chawla A., O’Reilly E.M. Pancreatic Cancer: A Review. JAMA. 2021; 326(9): 851–62. doi: 10.1001/jama.2021.13027.

3. Dorman K., Heinemann V., Kobold S., von Bergwelt-Baildon M., Boeck S. Novel systemic treatment approaches for metastatic pancreatic cancer. Expert Opin Investig Drugs. 2022; 31(3): 249–62. doi: 10.1080/13543784.2022.2037552.

4. Ren B., Cui M., Yang G., Wang H., Feng M., You L., Zhao Y. Tumor microenvironment participates in metastasis of pancreatic cancer. Mol Cancer. 2018; 17(1): 108. doi: 10.1186/s12943-018-0858-1.

5. Schaffner F., Ray A.M., Dontenwill M. Integrin α5β1, the Fibronectin Receptor, as a Pertinent Therapeutic Target in Solid Tumors. Cancers (Basel). 2013; 5(1): 27–47. doi: 10.3390/cancers5010027.

6. Pan B., Guo J., Liao Q., Zhao Y. β1 and β3 integrins in breast, prostate and pancreatic cancer: A novel implication. Oncol Lett. 2018; 15(4): 5412–6. doi: 10.3892/ol.2018.8076.

7. Sliker B.H., Goetz B.T., Barnes R., King H., Maurer H.C., Olive K.P., Solheim J.C. HLA-B infuences integrin beta-1 expression and pancreatic cancer cell migration. Exp Cell Res. 2020; 390(2): 111960. doi: 10.1016/j.yexcr.2020.111960.

8. Casari I., Howard J.A., Robless E.E., Falasca M. Exosomal integrins and their infuence on pancreatic cancer progression and metastasis. Cancer Lett. 2021; 507: 124–34. doi: 10.1016/j.canlet.2021.03.010.

9. Zeltz C., Primac I., Erusappan P., Alam J., Noel A., Gullberg D. Cancer-associated fbroblasts in desmoplastic tumors: emerging role of integrins. Semin Cancer Biol. 2020; 62: 166–81. doi: 10.1016/j.semcancer.2019.08.004.

10. Görte J., Danen E., Cordes N. Therapy-Naive and Radioresistant 3-Dimensional Pancreatic Cancer Cell Cultures Are Efectively Radiosensitized by β1 Integrin Targeting. Int J Radiat Oncol Biol Phys. 2022; 112(2): 487–98. doi: 10.1016/j.ijrobp.2021.08.035.

11. Torres C., Grippo P.J. Pancreatic cancer subtypes: a roadmap for precision medicine. Ann Med. 2018; 50(4): 277–87. doi: 10.1080/07853890.2018.1453168.

12. Rakina Yu.Yu., Zavyalova M.V., Krakhmal N.V., Koshel A.P., Afanasyev S.G., Vtorushin S.V. Morphological and expression features of ductal pancreatic adenocarcinoma. Siberian Journal of Oncology. 2017; 16(4): 26–31. (in Russian). doi: 10.21294/1814-4861-2017-16-4-26-31.

13. Krakhmal N.V., Zavyalova M.V., Denisov E.V., Vtorushin S.V., Perelmuter V.M. Cancer Invasion: Patterns and Mechanisms. Acta Naturae. 2015; 7(2): 17–28. doi: 10.32607/20758251-2015-7-2-17-28.

14. Dong S., Wang L., Guo Y.B., Ying H.F., Shen X.H., Meng Z.Q., Chen Hao, Chen Q.W., Li Z.S. Risk factors of liver metastasis from advanced pancreatic adenocarcinoma: a large multicenter cohort study. World J Surg Onc. 2017; 15(1): 120. doi: 10.1186/s12957-017-1175-7.