SOX2 expression in the primary tumor of castration-naive metastatic prostate adenocarcinoma in association with metastasis extent
DOI:
https://doi.org/10.13181/mji.oa.247588Keywords:
cancer stem cells, metastasis, prostate cancer, prostate-specific antigen, SOX2Abstract
BACKGROUND Poor prognosis in patients with metastatic prostate adenocarcinoma (mPCa) may be due to the expression of stem cell-related genes. This study aimed to demonstrate the association between the expression of cancer stem cell markers and metastasis in patients with castration-naive mPCa.
METHODS This cross-sectional, analytical study investigated a formalin-fixed paraffin-embedded prostate specimens from patients diagnosed in Cipto Mangunkusumo Hospital. Patients aged ≥50 years old were grouped based on the extent of metastases (high-volume disease [HVD] and low-volume disease [LVD]). In each case, immunohistochemical staining for CD133, CD44, SOX2, and androgen receptor was performed and analyzed using H-score. All data were recorded and analyzed using SPSS software version 20.0.
RESULTS A total of 61 patients were recruited from 2020 to 2023 and divided into the HVD (n = 38) and LVD (n = 23) groups, with a mean age of 67.9 years. 45 of the patients had International Society of Urological Pathology (ISUP) grade 5 disease, while 16 of them had grade <5. A significant difference of ISUP grade and PSA serum level was observed in the HVD versus LVD group (p = 0.017 and <0.001, respectively). Additionally, a significant association was found between SOX2 expression and metastatic extent.
CONCLUSIONS The LVD group showed higher SOX2 expression in the primary tumor compared to the HVD group. Different SOX2 expressions in various sites and stages may be due to the cancer cells’ systemic network.
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References
Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-63. https://doi.org/10.3322/caac.21834
Yuri P, Shigemura K, Kitagawa K, Hadibrata E, Risan M, Zulfiqqar A, et al. Increased tumor-associated macrophages in the prostate cancer microenvironment predicted patients' survival and responses to androgen deprivation therapies in Indonesian patients cohort. Prostate Int. 2020;8(2):62-9. https://doi.org/10.1016/j.prnil.2019.12.001
Guccini I, Revandkar A, D'Ambrosio M, Colucci M, Pasquini E, Mosole S, et al. Senescence reprogramming by TIMP1 deficiency promotes prostate cancer metastasis. Cancer Cell. 2021;39(1):68-82.e9. https://doi.org/10.1016/j.ccell.2020.10.012
Beksisa J, Getinet T, Tanie S, Diribi J, Hassen HY. Survival and prognostic determinants of prostate cancer patients in Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia: a retrospective cohort study. PLoS One. 2020;15(3):e0229854. https://doi.org/10.1371/journal.pone.0229854
Mochtar CA, Atmoko W, Umbas R, Hamid AR. Prostate cancer detection rate in Indonesian men. Asian J Surg. 2018;41(2):163-9. https://doi.org/10.1016/j.asjsur.2017.01.001
Zhang AC, Rasul R, Golden A, Feuerstein MA. Incidence and mortality trends of metastatic prostate cancer: surveillance, epidemiology, and end results database analysis. Can Urol Assoc J. 2021;15(12):E637-43. https://doi.org/10.5489/cuaj.7173
Abida W, Armenia J, Gopalan A, Brennan R, Walsh M, Barron D, et al. Prospective genomic profiling of prostate cancer across disease states reveals germline and somatic alterations that may affect clinical decision making. 2017;2017:PO.17.00029.
Welter L, Zheng S, Setayesh SM, Morikado M, Agrawal A, Nevarez R, et al. Cell state and cell type: deconvoluting circulating tumor cell populations in liquid biopsies by multi-omics. Cancers (Basel). 2023;15(15):3949. https://doi.org/10.3390/cancers15153949
Bocci F, Levine H, Onuchic JN, Jolly MK. Deciphering the dynamics of epithelial-mesenchymal transition and cancer stem cells in tumor progression. arXiv. 2019;5(1):11-21. https://doi.org/10.1007/s40778-019-0150-3
Tewari AK, Gillessen S, Sweeney CJ. Metastatic prostate cancer: in search of more granularity. J Clin Oncol. 2021;39(26):2968-9. https://doi.org/10.1200/JCO.21.00643
Kyriakopoulos CE, Chen YH, Carducci MA, Liu G, Jarrard DF, Hahn NM, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED Trial. J Clin Oncol. 2018;38(11):1080-7. https://doi.org/10.1200/JCO.2017.75.3657
Formaggio N, Rubin MA, Theurillat JP. Loss and revival of androgen receptor signaling in advanced prostate cancer. Oncogene. 2021;40(7):1205-16. https://doi.org/10.1038/s41388-020-01598-0
Thomas E, Thankan RS, Purushottamachar P, Huang W, Kane MA, Zhang Y, et al. Transcriptome profiling reveals that VNPP433-3β, the lead next-generation galeterone analog inhibits prostate cancer stem cells by downregulating epithelial-mesenchymal transition and stem cell markers. Mol Carcinog. 2022;61(7):643-54. https://doi.org/10.1002/mc.23406
Damarsingu PV, Das S, Mh S, Bodapati S. Evaluation of CD44 expression in prostatic adenocarcinoma: an institutional study. Cureus. 2023;15(6):e40510. https://doi.org/10.7759/cureus.40510
Glumac PM, LeBeau AM. The role of CD133 in cancer: a concise review. Clin Transl Med. 2018;7(1):18. https://doi.org/10.1186/s40169-018-0198-1
Mirzaei S, Paskeh MD, Entezari M, Mirmazloomi SR, Hassanpoor A, Aboutalebi M, et al. SOX2 function in cancers: association with growth, invasion, stemness and therapy response. Biomed Pharmacother. 2022;156:113860. https://doi.org/10.1016/j.biopha.2022.113860
Alghezi DA, Aljawher R, Alsaadi E. Increased Sox2 immunostaining in prostate cancer and associated with Gleason score and stage. Bull Natl Inst Health Sci. 2022;140(04):2423−31.
Srinivasan D, Senbanjo L, Majumdar S, Franklin RB, Chellaiah MA. Androgen receptor expression reduces stemness characteristics of prostate cancer cells (PC3) by repression of CD44 and SOX2. J Cell Biochem. 2019;120(2):2413-28. https://doi.org/10.1002/jcb.27573
Castellón EA, Indo S, Contreras HR. Cancer stemness/epithelial-mesenchymal transition axis influences metastasis and castration resistance in prostate cancer: potential therapeutic target. Int J Mol Sci. 2022;23(23):14917. https://doi.org/10.3390/ijms232314917
Metz EP, Wuebben EL, Wilder PJ, Cox JL, Datta K, Coulter D, et al. Tumor quiescence: elevating SOX2 in diverse tumor cell types downregulates a broad spectrum of the cell cycle machinery and inhibits tumor growth. BMC Cancer. 2020;20(1):941. https://doi.org/10.1186/s12885-020-07370-7
Williams A, Gutgesell L, de Wet L, Selman P, Dey A, Avineni M, et al. SOX2 expression in prostate cancer drives resistance to nuclear hormone receptor signaling inhibition through the WEE1/CDK1 signaling axis. Cancer Lett. 2023;565:216209. https://doi.org/10.1016/j.canlet.2023.216209
Li H, Wang L, Li Z, Geng X, Li M, Tang Q, et al. SOX2 has dual functions as a regulator in the progression of neuroendocrine prostate cancer. Lab Invest. 2020;100(4):570-82. https://doi.org/10.1038/s41374-019-0343-5
Russo M, Esposito S, Tupone M, Manzoli L, Airoldi I, Pompa P, et al. SOX2 boosts major tumor progression genes in prostate cancer and is a functional biomarker of lymph node metastasis. Oncotarget. 2016;7(11):12372-85. https://doi.org/10.18632/oncotarget.6029
Mangiola S, Hong MK, Cmero M, Kurganovs N, Ryan A, Costello AJ, et al. Comparing nodal versus bony metastatic spread using tumour phylogenies. Sci Rep. 2016;6:33918. https://doi.org/10.1038/srep33918
Wuebben EL, Rizzino A. The dark side of SOX2: cancer - a comprehensive overview. Oncotarget. 2017;8(27):44917-43. https://doi.org/10.18632/oncotarget.16570
Paul D. The systemic hallmarks of cancer. J Cancer Metastasis Treat. 2020;6:29. https://doi.org/10.20517/2394-4722.2020.63
Zheng Y, Wang L, Yin L, Yao Z, Tong R, Xue J, et al. Lung cancer stem cell markers as therapeutic targets: an update on signaling pathways and therapies. Front Oncol. 2022;12:873994. https://doi.org/10.3389/fonc.2022.873994
Roudi R, Ebrahimi M, Sabet MN, Najafi A, Nourani MR, Fomeshi MR, et al. Comparative gene-expression profiling of CD133 + and CD133 - D10 melanoma cells. Future Oncol. 2015;11(17):2383-93. https://doi.org/10.2217/fon.15.174
Chaves LP, Melo CM, Saggioro FP, Reis RB, Squire JA. Epithelial-mesenchymal transition signaling and prostate cancer stem cells: emerging biomarkers and opportunities for precision therapeutics. Genes (Basel). 2021;12(12):1900. https://doi.org/10.3390/genes12121900
Manna F, Karkampouna S, Zoni E, De Menna M, Hensel J, Thalmann GN, et al. Metastases in prostate cancer. Cold Spring Harb Perspect Med. 2019;9(3):a033688. https://doi.org/10.1101/cshperspect.a033688
Lambert AW, Pattabiraman DR, Weinberg RA. Emerging biological principles of metastasis. Cell. 2017;168(4):670-91. https://doi.org/10.1016/j.cell.2016.11.037
Mei W, Lin X, Kapoor A, Gu Y, Zhao K, Tang D. The contributions of prostate cancer stem cells in prostate cancer initiation and metastasis. Cancers (Basel). 2019;11(4):434. https://doi.org/10.3390/cancers11040434
Zheng Z, Zhou Z, Yan W, Zhou Y, Chen C, Li H, et al. Tumor characteristics, treatments, and survival outcomes in prostate cancer patients with a PSA level <4 ng/ml: a population-based study. BMC Cancer. 2020;20(1):340. https://doi.org/10.1186/s12885-020-06827-z
Lojanapiwat B, Anutrakulchai W, Chongruksut W, Udomphot C. Correlation and diagnostic performance of the prostate-specific antigen level with the diagnosis, aggressiveness, and bone metastasis of prostate cancer in clinical practice. Prostate Int. 2014;2(3):133-9. https://doi.org/10.12954/PI.14054
Spajić B, Nikles S, Grubišić I, Knežević M, Shoipi S, Ulamec M, et al. Histopathological outcomes after radical prostatectomy for prostate cancer based on a new grading system. Acta Clin Croat. 2018;57(Suppl 1):50−5.
Okubo Y, Sato S, Osaka K, Yamamoto Y, Suzuki T, Ida A, et al. Clinicopathological analysis of the ISUP grade group and other parameters in prostate cancer: elucidation of mutual impact of the various parameters. Front Oncol. 2021;11:695251. https://doi.org/10.3389/fonc.2021.695251
Mahal BA, Aizer AA, Efstathiou JA, Nguyen PL. Association of very low prostate-specific antigen levels with increased cancer-specific death in men with high-grade prostate cancer. Cancer. 2016;122(1):78-83. https://doi.org/10.1002/cncr.29691
Grigore AD, Ben-Jacob E, Farach-Carson MC. Prostate cancer and neuroendocrine differentiation: more neuronal, less endocrine? Front Oncol. 2015;5:37. https://doi.org/10.3389/fonc.2015.00037
Atallah C, Toi A, van der Kwast TH. Gleason grade 5 prostate cancer: sub-patterns and prognosis. Pathology. 2021;53(1):3-11. https://doi.org/10.1016/j.pathol.2020.09.016
Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373(8):737-46. https://doi.org/10.1056/NEJMoa1503747
Yamada Y, Sakamoto S, Shimazaki J, Sugiura M, Amiya Y, Sasaki M, et al. Significant prognostic difference between grade group 4 and 5 in the 2014 International Society of Urological Pathology Grading System for high grade prostate cancer with bone metastasis. Prostate Int. 2017;5(4):143−8. https://doi.org/10.1016/j.prnil.2017.03.001
Miyoshi Y, Yasui M, Yoneyama S, Kawahara T, Nakagami Y, Ohno Y, et al. A novel prognostic model for Japanese patients with newly diagnosed bone-metastatic hormone-naïve prostate cancer. BJUI Compass. 2020;2(2):105-14. https://doi.org/10.1002/bco2.46
Kishan AU, Romero T, Alshalalfa M, Liu Y, Tran PT, Nickols NG, et al. Transcriptomic heterogeneity of gleason grade group 5 prostate cancer. Eur Urol. 2020;78(3):327-32. https://doi.org/10.1016/j.eururo.2020.05.009
Lambis-Anaya L, Fernandez-Ruiz M, Liscano Y, Suarez-Causado A. High OCT4 expression might be associated with an aggressive phenotype in rectal cancer. Cancers (Basel). 2023;15(14):3740. https://doi.org/10.3390/cancers15143740
Aurilio G, Cimadamore A, Mazzucchelli R, Lopez-Beltran A, Verri E, Scarpelli M, et al. Androgen receptor signaling pathway in prostate cancer: from genetics to clinical applications. Cells. 2020;9(12):2653. https://doi.org/10.3390/cells9122653
Wolf I, Gratzke C, Wolf P. Prostate cancer stem cells: clinical aspects and targeted therapies. Front Oncol. 2022;12:935715. https://doi.org/10.3389/fonc.2022.935715
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