Prostat Kanseri Kök Hücrelerinde Zoledronik Asit Tedavisinin Hücre Adezyon Moleküllerine Etkisi

Öz

Prostat kanserinin tanı ve tedavisine yönelik birçok alanda ilerleme sağlanabilmesine rağmen hastalık bazı vakalar için ölümcül olma niteliğini sürdürmektedir. Hastaların ölümden kurtulması için atılan her adım hedefe yaklaşılmasına yardım etse de halen sonuca ulaşmak için araştırılması gereken pek çok konu bulunmaktadır. Kök hücrenin keşfi ile bu hücrelerin insan sağlığı için önemi anlaşılmış ve tedavide nasıl kullanılacağının belirlenmesine yönelik çalışmalar büyük hız kazanmıştır. İlerleyen yıllarda Kanser Kök Hücresi kavramı ortaya çıkmış ve bu hücrelerin, kök hücre özelliklerini taşıyan ancak tümör dokusu içinde metastazı yapan, tedavi sonrası nükse yol açabilen veya tedaviye direnç̧ geliştiren hücreler oldukları belirlenmiştir. Köklülük özelliğine sahip bu hücreler dışında kalan hücre gurubu kanser kök hücresi olmayan hücre gurubudur ve konvansiyonel kanser tedavisine cevap veren kanser hücrelerdir. Kanserin metastaz yapması ve çevre dokuya invazyonunda adezyon moleküllerinin önemi büyüktür. Yapılan çalışmalar özellikle çoklu ilaç direnci ve epitelial mezenşimal geçişte adezyon moleküllerinin büyük önem kazandığını göstermiştir. Bu çalışmanın amacı prostat kanseri kök hücreleri üzerine zoledronik asit uygulaması sonrası, metastaz geliştirme sürecinde önemli rolü olan adezyon molekülleri üzerine etkisinin incelenmesidir. Bu amaçla DU145 insan prostat kanseri hücre hattından akım sitometri cihazı ile CD133/CD44 yüzey belirteçleri kullanılarak izole edilen kanser kök hücreleri üzerine zoledronik asit tedavisi uygulanmıştır. Kanser kök hücresinde oluşan değişiklikler adezyon molekülleri yönü ile araştırılmıştır. Elde edilen sonuçlar zoledronik asit tedavisi sonrası kanser kök hücresi sayısında önemli bir düşüş olduğunu ve bu uygulamanın CD44, ITGB1, CD29, LAMB1, LAMB3, LAMC1, SPP1, TGFB1, TGFB1, TIMP2, ADAMTS1, ITGB5’de önemli değişimlere yol açtığını göstermiştir. Bu çalışmada in-vitro ortamda zoledronik asit uygulamasının kanser kök hücresi adezyon molekülleri üzerine baskılayıcı etki oluşturduğu ve ilerleyen çalışmalarda bu ilacın klinik kullanımda prostat kanseri tedavisinde uygulanabilme olasılığının olduğunu göstermiştir.

Anahtar Kelimeler

• Prostat kanseri;
• kanser kök hücresi
• zoledronik asit
• hücre adezyon molekülleri
• tedavi

Effect of Zoledronic Acid Treatment on Cell Adhesion Molecules in Prostate Cancer Stem Cells

Öz

Although the diagnosis and treatment of prostate cancer has made a progress, the disease remains fatal for some cases. Every step taken to save patients from death helps to approach the goal but there are still many issues that need to be investigated to reach a result. With the discovery of stem cells, the importance of these cells for human health has been understood and studies on how to use them in treatment have gained great momentum. In the following years, the concept of Cancer Stem Cell has emerged. It has been shown that these cells have stem cell characteristics but metastasize within the tumor tissue. They can cause recurrence after treatment or develop resistance to treatment. The other group of cells with rootedness is the non-cancer stem cell group and are cancer cells that respond to conventional cancer treatment. Adhesion molecules are of great importance in the cancer metastasis and invasion into the surrounding tissue. Studies have shown that adhesion molecules has great importance spesifically in multi-drug resistance and epithelial-mesenchymal transition. The aim of this study is to examine the effect of zoledronic acid application on prostate cancer stem cells on adhesion molecules, which have an important role in the metastasis development process. For this purpose, zoledronic acid treatment was applied to cancer stem cells isolated from DU145 human prostate cancer cell line using a flow cytometry device and CD133/CD44 surface markers. Changes in cancer stem cells have been investigated in terms of adhesion molecules. The results showed that there was a significant decrease in the number of cancer stem cells after zoledronic acid treatment and this application led to significant changes in CD44, ITGB1, CD29, LAMB1, LAMB3, LAMC1, SPP1, TGFB1, TGFB1, TIMP2, ADAMTS1, ITGB5. In this study, it has been shown that zoledronic acid administration in-vitro has a suppressive effect on cancer stem cell adhesion molecules and that this drug may be used in the treatment of prostate cancer in clinical use in further studies.

Anahtar Kelimeler

• prostate cancer
• cancer stem cell
• zoledronic acid
• cell adhesion molecules
• treatment

Kaynakça

1. Referans 1 Rebecca L. Siegel, Kimberly D. Miller, Ahmedin Jemal. Cancer Statistics, 2018, CA Cancer J Clin 2018;68:7–30
2. Referans 2 American Cancer Society. Survival rates for prostate cancer. http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer- survival-rates. Erişim tarihi: Mart 12, 2015
3. Referans 3 Kumar VE, Nambiar R, De Souza C, Nguyen A, Chien J, Lam KS.Targeting Epigenetic Modifiers of Tumor Plasticity and Cancer Stem Cell Behavior. Cells. 2022 Apr 21;11(9):1403. doi: 10.3390/cells11091403.
4. Referans 4 Ju F, Atyah MM, Horstmann N, Gul S, Vago R, Bruns CJ, Zhao Y, Dong QZ, Ren N. Characteristics of the cancer stem cell niche and therapeutic strategies. Stem Cell Res Ther. 2022 Jun 3;13(1):233. doi: 10.1186/s13287-022-02904-1.
5. Referans 5 Alison MR, Murphy G, Leedham S. Stem cells and cancer: a deadly mix. Cell Tissue Res. 2008;331:109–24
6. Referans 6 Oktem G, Bilir A, Uslu R, Inan SV, Demiray SB, Atmaca H, Ayla S, Sercan O, Uysal A. Expression profiling of stem cell signaling alters with spheroid formation in CD133high/CD44high prostate cancer stem cells. Oncol Lett. 2014 Jun;7(6):2103-2109.
7. Referans 7 Majumdar S, Liu ST Cell division symmetry control and cancer stem cells.AIMS Mol Sci. 2020;7(2):82-98. doi: 10.3934/molsci.2020006.
8. Referans 8 Duzagac F, Inan S, Ela Simsek F, Acikgoz E, Guven U, Khan SA, Rouhrazi H, Oltulu F, Aktug H, Erol A, Oktem G. JAK/STAT pathway interacts with intercellular cell adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) while prostate cancer stem cells form tumor spheroids. J BUON. 2015 Sep-Oct;20(5):1250-7. PMID: 26537072.

9. Referans 9 Heinly BE, Grant CN.Cell Adhesion Molecules in Neuroblastoma: Complex Roles, Therapeutic Potential. Front Oncol. 2022 Apr 27; 12:782186.
10. Referans 10 Witte KE, Pfitzenmaier J, Storm J, Lütkemeyer M, Wimmer C, Schulten W, Czaniera N, Geisler M, Förster C, Wilkens L, Knabbe C, Mertzlufft F, Kaltschmidt B, Am Esch JS, Kaltschmidt C. Analysis of Several Pathways for Efficient Killing of Prostate Cancer Stem Cells: A Central Role of NF-κB RELA. Int J Mol Sci. 2021 Aug 18;22(16):8901.
11. Referans 11 Adamowicz J, Pakravan K, Bakhshinejad B, Drewa T, Babashah S. Prostate cancer stem cells: from theory to practice. Scand J Urol. 2017 Apr;51(2):95-106. doi: 10.1080/21681805.2017.1283360
12. Referans 12 Gnant M, Clézardin P Direct and indirect anticancer activity of bisphosphonates: a brief review of published literature. Cancer Treat Rev. 2012 Aug;38(5):407-15. doi: 10.1016/j.ctrv.2011.09.003.
13. Referans 13 Yamada J, Tsuno NH, Kitayama J, Tsuchiya T, Yoneyama S, Asakage M, Okaji Y, Shuno Y, Nishikawa T, Tanaka J, Takahashi K, Nagawa H. Anti-angiogenic property of zoledronic acid by inhibition of endothelial progenitor cell differentiation. J Surg Res. 2009 Jan;151(1):115-20. doi: 10.1016/j.jss.2008.01.031
14. Referans 14 Gallo M, De Luca A, Lamura L, Normanno N.Zoledronic acid blocks the interaction between mesenchymal stem cells and breast cancer cells: implications for adjuvant therapy of breast cancer. Ann Oncol. 2012 Mar;23(3):597-604.
15. Referans 15 Borghese C, Casagrande N, Pivetta E, Colombatti A, Boccellino M, Amler E, Normanno N, Caraglia M, De Rosa G, Aldinucci D.Self-assembling nanoparticles encapsulating zoledronic acid inhibit mesenchymal stromal cells differentiation, migration and secretion of proangiogenic factors and their interactions with prostate cancer cells.Oncotarget. 2017 Jun 27;8(26):42926-38.
16. Referans 16 Tanaka, T., Morimoto, K., & Nakatani, T. (2018). Zoledronic Acid Suppresses Epithelial-to-Mesenchymal Transition and Invasion via Degradation of Ubiquitinated NEDD9 in PC-3 Prostate Cancer Cells. Journal of Cancer Science & Therapy, 10(04),80–4.
17. Referans 17 Yoshiyama A, Morii T, Ohtsuka K, Ohnishi H, Tajima T, Aoyagi T, ve ark. Development of Stemness in Cancer Cell Lines Resistant to the Anticancer Effects of Zoledronic Acid. Anticancer Res. 2016 Feb;36(2):625-31. PMID: 26851017.
18. Referans 18 Giraudo E, Inoue M, Hanahan D. An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J Clin Invest. 2004 Sep;114(5):623-33. doi: 10.1172/JCI22087. PMID: 15343380; PMCID: PMC514591.
19. Referans 19 Santini, D., Zoccoli, A., Gregorj, C., Di Cerbo, M., Iuliani, M., Pantano, F., ... Tonini, G. (2013). Zoledronic acid induces a significant decrease of circulating endothelial cells and circulating endothelial precursor cells in the early prostate cancerneoadjuvant setting. Oncology (Switzerland), 85(6), 342–7.
20. Referans 20 Hasmim, M., Bieler, G., & Rüegg, C. (2007). Zoledronate inhibits endothelial cell adhesion, migration and survival through the suppression of multiple, prenylation-dependent signaling pathways. Journal of Thrombosis and Haemostasis, 5(1), 166173.
21. Referans 21 Rouhrazi, H., Turgan, N., & Oktem, G. (2018). Zoledronic acid overcomes chemoresistance by sensitizing cancer stem cells to apoptosis. Biotechnic and Histochemistry, 93(2), 77–88.
22. Referans 22 Acikgoz E, Soner BC, Ozdil B, Guven M. CD133+/CD44+ prostate cancer stem cells exhibit embryo-like behavior patterns. Acta Histochem. 2021 Jul;123(5):151743. doi: 10.1016/j.acthis.2021.151743. Epub 2021 Jun 20. PMID: 34157581.
23. Referans 23 Maitland NJ, Collins AT: Prostate cancer stem cells: a new target for therapy. J Clin Oncol 2008; 26:2862-70.
24. Referans 24 Dubrovska A, Elliott J, Salamone RJ, Kim S, Aimone LJ, Walker JR, Watson J, Sauveur-Michel M, Garcia-Echeverria C, Cho CY, Reddy VA, Schultz PG: Combination therapy targeting both tumor-initiating and differentiated cell populations in prostate carcinoma. Clin Cancer Res 2010; 16:5692-5702.
25. Referans 25 Castelo-Branco P, Zhang C, Lipman T, Fujitani M, Hansford L, Clarke I, Harley CB, Tressler R, Malkin D, Walker E, Kaplan DR, Dirks P, Tabori U: Neural tumorinitiating cells have distinct telomere maintenance and can be safely targeted for telomerase inhibition. Clin Cancer Res 2011;17:111-2
26. Referans 26 Leão R. Domingos C. Figueiredo A. Hamilton R. Tabori U. Castelo-Branco P. Cancer Stem Cells in Prostate Cancer: Implications for Targeted Therapy. Urol Int 2017;99:125-136
27. Referans 27 Sheikh A, Niazi AK, Ahmed MZ, Iqbal B, Anwer SM, Khan HH: The role of Wnt signaling pathway in carcinogenesis and implications for anticancer therapeutics. Hered Cancer Clin Pract 2014;12:13.
28. Referans 28 Le PN, McDermott JD, Jimeno A. Targeting the Wnt pathway in human cancers: therapeutic targeting with a focus on OMP-54F28. Pharmacol Ther. 2015 Feb;146:1-11. doi: 10.1016/j.pharmthera.2014.08.005. Epub 2014 Aug 27. PMID: 25172549; PMCID: PMC4304994.
29. Referans 29 Takebe N, Harris PJ, Warren RQ, Ivy SP: Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nat Rev Clin Oncol 2011;8:97-106.
30. Referans 30 Gonnissen A, Isebaert S, Haustermans K: Hedgehog signaling in prostate cancer and its therapeutic implication. Int J Mol Sci 2013;14:13979-14007.
31. Referans 31 Gonnissen A, Isebaert S, Haustermans K: Targeting the Hedgehog signaling pathway in cancer: beyond Smoothened. Oncotarget 2015;6:13899-913.