Immunohistochemical features of gastrointestinal stromal tumors and the role of expression of p16ink4A, Ki-67, VEGF and MMP-9 in their behavior
DOI:
https://doi.org/10.14739/2310-1237.2021.2.233425Keywords:
gastrointestinal stromal tumor, cytoplasmic expression of p16ink4A, MMP-9, Ki-67, VEGF, metastases of gastrointestinal stromal tumors, aggressive behavior of gastrointestinal stromal tumorsAbstract
Aim: to clarify the prognostic value of cytoplasmic p16ink4A, VEGF, MMP-9 and Ki-67 expressions in gastrointestinal stromal tumors (GISTs) and connection of different levels of these markers expression with aggressive transformation of GISTs.
Materials and methods. Our study included 36 samples of primary tumors and 10 relapses of GIST and metastases in liver after primary combined treatment (surgery and chemotherapy with imatinib). The immunohistochemical study was performed with 4 primary antibodies: Ki-67, p16ink4A, VEGF and MMP-9. We used formalin fixed and paraffin embedded (FFPE) tissue samples for immunohistochemical study.
Results. In our study we showed significant connection between levels of cytoplasmic expression of p16ink4A in primary GISTs and such markers of tumor aggressive behaviour as Ki-67, MMP-9 and VEGF (Fisher’s exact P-value = 0.000753; 0.000101 and 0.000048 respectively). Between cytoplasmic expression of p16ink4A and VEGF and also between p16ink4A and MMP-9 strong direct correlation was found (γ = 0.829, P < 0.05 and rs = 0.961, P < 0.05 respectively). The correlation between expression of Ki-67 and p16ink4A was also direct and strong (rs = 0.754, P < 0.05), but with some exclusions, that’s why this correlation needs further investigation in larger groups with preciser molecular analysis. Analysis of metastatic GISTs samples showed prominent levels of MMP-9 and VEGF expression.
Conclusions. Our study has shown very important role of cytoplasmic expression of p16ink4A in GIST as one of the markers of aggressive behavior, which can be used in complex with other markers for more accurate prognosis of GISTs progression. Prominent levels of MMP-9 and VEGF expression in metastatic GISTs can be a marker of resistance to imatinib. So probably evaluation of MMP-9 and VEGF expression can be used as a tool for correct choice of chemotherapy for patients with GISTs.
References
Lokuhetty, D. (2019). Gastrointestinal stromal tumour. In: WHO Classification of Tumours: Digestive System Tumours, (5th ed., pp. 439-443). Lyon.
National Cancer Institute: Surveillance, Epidemiology, and End Result Program. (2011, May 23). SEER Inquiry System – View. https://seer.cancer.gov/seerinquiry/index.php?page=view&id=20100014&type=q
Zhao, W. Y., Xu, J., Wang, M., Zhang, Z. Z., Tu, L., Wang, C. J., Lin, T. L., Shen, Y. Y., Liu, Q., & Cao, H. (2014). Prognostic value of Ki67 index in gastrointestinal stromal tumors. International journal of clinical and experimental pathology, 7(5), 2298-2304.
Xu, D., Su, C., Guo, L., Yan, H., Wang, S., Yuan, C., Chen, G., Pang, L., & Zhang, N. (2019). Predictive Significance of Serum MMP-9 in Papillary Thyroid Carcinoma. Open life sciences, 14, 275-287. https://doi.org/10.1515/biol-2019-0031
Liu, N., Huang, J., Sun, S., Zhou, Z., Zhang, J., Gao, F., & Sun, Q. (2015). Expression of matrix metalloproteinase-9, cyclooxygenase-2 and vascular endothelial growth factor are increased in gastrointestinal stromal tumors. International journal of clinical and experimental medicine, 8(4), 6495-6501.
Inoue, K., & Fry, E. A. (2018). Aberrant expression of p16INK4a in human cancers - a new biomarker?. Cancer reports and reviews, 2(2), 10.15761/CRR.1000145. https://doi.org/10.15761/CRR.1000145
Haller, F., Agaimy, A., Cameron, S., Beyer, M., Gunawan, B., Happel, N., Langer, C., Ramadori, G., von Heydebreck, A., & Füzesi, L. (2010). Expression of p16INK4A in gastrointestinal stromal tumours (GISTs): two different forms exist that independently correlate with poor prognosis. Histopathology, 56(3), 305-318. https://doi.org/10.1111/j.1365-2559.2010.03478.x
Mendaza, S., Fernández-Irigoyen, J., Santamaría, E., Zudaire, T., Guarch, R., Guerrero-Setas, D., Vidal, A., Santos-Salas, J., Matias-Guiu, X., Ausín, K., Díaz de Cerio, M. J., & Martín-Sánchez, E. (2020). Absence of Nuclear p16 Is a Diagnostic and Independent Prognostic Biomarker in Squamous Cell Carcinoma of the Cervix. International journal of molecular sciences, 21(6), 2125. https://doi.org/10.3390/ijms21062125
Ricci, R., Arena, V., Castri, F., Martini, M., Maggiano, N., Murazio, M., Pacelli, F., Potenza, A. E., Vecchio, F. M., & Larocca, L. M. (2004). Role of p16/INK4a in gastrointestinal stromal tumor progression. American journal of clinical pathology, 122(1), 35-43. https://doi.org/10.1309/MJ4X-N2M5-7HNC-8X5H
Schmieder, M., Wolf, S., Danner, B., Stoehr, S., Juchems, M. S., Wuerl, P., Henne-Bruns, D., Knippschild, U., Hasel, C., & Kramer, K. (2008). p16 expression differentiates high-risk gastrointestinal stromal tumor and predicts poor outcome. Neoplasia, 10(10), 1154-1162. https://doi.org/10.1593/neo.08646
Ciesielska, U., Zatonski, T., Nowinska, K., Ratajczak-Wielgomas, K., Grzegrzolka, J., Piotrowska, A., Olbromski, M., Pula, B., Podhorska-Okolow, M., & Dziegiel, P. (2017). Expression of Cell Cycle-related Proteins p16, p27 and Ki-67 Proliferating Marker in Laryngeal Squamous Cell Carcinomas and in Laryngeal Papillomas. Anticancer research, 37(5), 2407-2415. https://doi.org/10.21873/anticanres.11580
Koga, Y., Iwatsuki, M., Yamashita, K., Kiyozumi, Y., Kurashige, J., Masuda, T., Eto, K., Iwagami, S., Harada, K., Ishimoto, T., Baba, Y., Yoshida, N., Miyanari, N., Takamori, H., Ajani, J. A., & Baba, H. (2019). The role of FBXW7, a cell-cycle regulator, as a predictive marker of recurrence of gastrointestinal stromal tumors. Gastric cancer, 22(6), 1100-1108. https://doi.org/10.1007/s10120-019-00950-y
Ihle, M. A., Huss, S., Jeske, W., Hartmann, W., Merkelbach-Bruse, S., Schildhaus, H. U., Büttner, R., Sihto, H., Sundby Hall, K., Eriksson, M., Reichardt, P., Joensuu, H., & Wardelmann, E. (2018). Expression of cell cycle regulators and frequency of TP53 mutations in high risk gastrointestinal stromal tumors prior to adjuvant imatinib treatment. PloS one, 13(2), e0193048. https://doi.org/10.1371/journal.pone.0193048
Schaefer, I. M., Wang, Y., Liang, C. W., Bahri, N., Quattrone, A., Doyle, L., Mariño-Enríquez, A., Lauria, A., Zhu, M., Debiec-Rychter, M., Grunewald, S., Hechtman, J. F., Dufresne, A., Antonescu, C. R., Beadling, C., Sicinska, E. T., van de Rijn, M., Demetri, G. D., Ladanyi, M., Corless, C. L., … Fletcher, J. A. (2017). MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation. Nature communications, 8, 14674. https://doi.org/10.1038/ncomms14674
Song, L.-J., Zhang, X.-M., Wang, T., Yuan, L., Yue, H., Fu, G.-H., & Shen, W.-W. (2018). Cytoplasmic Expression of P16 is Related to Low Infiltration of CD8+ T cell and Poor Prognosis in Digestive Neuroendocrine Carcinoma. Journal of Diagnostic Techniques and Biomedical Analysis, 7(1). https://doi.org/10.4172/2469-5653.1000125
Park, J. W., Kang, J., Lim, K. Y., Kim, H., Kim, S. I., Won, J. K., Park, C. K., & Park, S. H. (2021). The prognostic significance of p16 expression pattern in diffuse gliomas. Journal of pathology and translational medicine, 55(2), 102-111. https://doi.org/10.4132/jptm.2020.10.22
Pinter, M., & Jain, R. K. (2017). Targeting the renin-angiotensin system to improve cancer treatment: Implications for immunotherapy. Science translational medicine, 9(410), eaan5616. https://doi.org/10.1126/scitranslmed.aan5616
Regad T. (2015). Targeting RTK Signaling Pathways in Cancer. Cancers, 7(3), 1758-1784. https://doi.org/10.3390/cancers7030860
Den Hollander, D., Van der Graaf, W., Desar, I., & Le Cesne, A. (2019). Predictive factors for toxicity and survival of second-line sunitinib in advanced gastrointestinal stromal tumours (GIST). Acta oncologica, 58(11), 1648-1654. https://doi.org/10.1080/0284186X.2019.1637017
Basilio-de-Oliveira, R. P., & Pannain, V. L. (2015). Prognostic angiogenic markers (endoglin, VEGF, CD31) and tumor cell proliferation (Ki67) for gastrointestinal stromal tumors. World journal of gastroenterology, 21(22), 6924-6930. https://doi.org/10.3748/wjg.v21.i22.6924
Fudalej, M. M., & Badowska-Kozakiewicz, A. M. (2021). Improved understanding of gastrointestinal stromal tumors biology as a step for developing new diagnostic and therapeutic schemes. Oncology letters, 21(5), 417. https://doi.org/10.3892/ol.2021.12678
Toulmonde, M., Blay, J. Y., Bouche, O., Mir, O., Penel, N., Isambert, N., Duffaud, F., Bompas, E., Esnaud, T., Boidot, R., Geneste, D., Ghiringhelli, F., Lucchesi, C., Bellera, C. A., Le Loarer, F., & Italiano, A. (2019). Activity and Safety of Palbociclib in Patients with Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib: A Biomarker-driven Phase II Study. Clinical cancer research, 25(15), 4611-4615. https://doi.org/10.1158/1078-0432.CCR-18-3127
Downloads
Published
How to Cite
Issue
Section
License
Authors who publish with this journal agree to the following terms:- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (SeeThe Effect of Open Access).