Prognostic Impact of Coexpressed CXCL12 and CD44v5 on Human Cervical Cancer After Radiotherapy: Stem-Like Hallmark and Radioresistance
Objectives: The aim of this study is to investigate the prognostic impact of CXCL12 and CD44v5 on patients with advanced cervical cancer.
Methods: Paraffin specimens from 130 advanced cervix cancer before radiotherapy were examined using immunohistochemistry to test the expressions of CXCL12 and CD44v5. The correlations between the expressions of CXCL12 and CD44v5 and the five-year survival rate were analyzed. The expression changes of CXCL12 and CD44v5 in residual cancer tissues after a total radiotherapy dose of 50 Gy were tested by Real-Time PCR.
Results: In the 130 patients, a significant correlation was found between CXCL12 and CD44v5 (P=0.028). The coexpression occurred in 34 patients with lower five-year survival rate of 22.9%.There was no correlation between the expression of CXCL12 and CD44v5 and age, tumor stage, size, pelvic lymph node involvement and therapeutic schedule. Log-rank and multi-factor survivals analysis showed that tumor stage, lymph node involvement, CXCL12 expression, CD44v5 expression, CXCL12 and CD44v5 co-expression were independent prognostic factors. The expressions of CXCL12 and CD44 were significant elevated in residual tumor tissues, when compared to pre-radiotherapy, (p<0.05).
Conclusion: A significant positive correlation occurred between the expression of CXCL12 and CD44v5. The coexpression might be informative regarding poor prognosis in patients with radical radiotherapy.
1. Du PL, Wu KS, Fang JY, Zeng Y, Xu ZX, Tang WR, et al. Cervical cancer mortality trends in China, 1991-2013, and predictions for the future. Asian Pac J Cancer Prev 2015;16:6391–6.
2. Chen T, Wei M, Liu Y, Wang H, Zhou W, Bi Y, et al. Rising mortality rate of cervical cancer in younger women in urban China. J Gen Intern Med 2020;35:593.
3. Chargari C, Peignaux K, Escande A, Renard S, Lafond C, Petit A, et al. Radiotherapy of cervical cancer. Cancer Radiother 2022;26:298–308.
4. Hiraoka S, Nakajima A, Kishi N, Takehana K, Hanazawa H, Matsuo Y, et al. Efficacy of local salvage therapy for recurrent uterine cervical cancer after definitive radiotherapy. Int J Clin Oncol 2021;26:1968–76.
5. He S, Wang Y, Lai Y, Cao X, Ren Y, Chen Y. Concurrent chemoradiotherapy with nedaplatin versus cisplatin in patients with stage IIB-IVA cervical cancer: a randomized phase III trial. Front Oncol 2022;11:798617.
6. Kusunoki S, Kato K, Tabu K, Inagaki T, Okabe H, Kaneda H, et al. The inhibitory effect of salinomycin on the proliferation, migration and invasion of human endometrial cancer stem-like cells. Gynecol Oncol 2013;129:598–605.
7. Feng D, Peng C, Li C, Zhou Y, Li M, Ling B, et al. Identification and characterization of cancer stem-like cells from primary carcinoma of the cervix uteri. Oncol Rep 2009;22:1129–34.
8. Raza S, Rajak S, Tewari A, Gupta P, Chattopadhyay N, Sinha RA, et al. Multifaceted role of chemokines in solid tumors: From biology to therapy. Semin Cancer Biol 2022;86:1105–21.
9. Malik S, Westcott JM, Brekken RA, Burrows FJ. CXCL12 in Pancreatic cancer: its function and potential as a therapeutic drug target. Cancers (Basel) 2021;14:86.
10. Ahn S, Saha A, Clark R, Kolonin MG, DiGiovanni J. CXCR4 and CXCR7 signaling promotes tumor progression and obesity-associated epithelial-mesenchymal transition in prostate cancer cells. Oncogene 2022;41:4633–44.
11. Qin F, Pang H, Yu T, Luo Y, Dong Y. Treatment strategies and prognostic factors of 2018 FIGO Stage IIIC Cervical Cancer: A Review. Technol Cancer Res Treat 2022;21:15330338221086403.
12. Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144–53.
13. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumour initiating cells. Nature 2004;432:396–401.
14. Ponti D, Costa A, Zaffaroni N, Pratesi G, Petrangolini G, Coradini D, et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res 2005;65:5506–11.
15. López-Mateo I, Alonso-Merino E, Suarez-Cabrera C, Park JW, Cheng SY, Alemany S, et al. Thyroid hormone receptor β inhibits self-renewal capacity of breast cancer stem cells. Thyroid 2020;30:116–32.
16. Richard V, Kumar TRS, Pillai RM. Transitional dynamics of cancer stem cells in invasion and metastasis. Transl Oncol 2021;14:100909.
17. O'Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007;445:106–10.
18. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, et al. Identification of pancreatic cancer stem cells. Cancer Res 2007;67:1030–7.
19. Gaiteiro C, Soares J, Relvas-Santos M, Peixoto A, Ferreira D, Paulo P, et al. Glycoproteogenomics characterizes the CD44 splicing code associated with bladder cancer invasion. Theranostics 2022;12:3150–77.
20. Kumazawa S, Kajiyama H, Umezu T, Mizuno M, Suzuki S, Yamamoto E, et al. Possible association between stem-like hallmark and radioresistance in human cervical carcinoma cells. J Obstet Gynaecol Res 2014;40:1389–98.
21. Ghanbarnasab Behbahani R, Danyaei A, Shogi H, Tahmasbi MJ, Saki G, Neisi N. Irradiation and conditioned media from human umbilical cord stem cells suppress epithelial-mesenchymal transition biomarkers in breast cancer cells. Iran J Basic Med Sci 2023;26:486–91.
22. Goodison S, Urquidi V, Tarin D. CD44 cell adhesion molecules. Mol Pathol 1999;52:189–96.
23. Sulaiman A, McGarry S, Chambers J, Al-Kadi E, Phan A, Li L, et al. Targeting hypoxia sensitizes TNBC to cisplatin and promotes inhibition of both bulk and cancer stem cells. Int J Mol Sci 2020;21:5788.
24. Boimel PJ, Smirnova T, Zhou ZN, Wyckoff J, Park H, Coniglio SJ, et al. Contribution of CXCL12 secretion to invasion of breast cancer cells. Breast Cancer Res 2012;14:R23.
25. Strickland J, Garrison D, Copple BL. Hypoxia upregulates Cxcl12 in hepatocytes by a complex mechanism involving hypoxia-inducible factors and transforming growth factor-β. Cytokine 2020;127:154986.