Transforming Growth Factor Beta1 Expression in Cancer- Associated Fibroblasts of Urinary Bladder Cancer: Crucial Applications and Deep Insights
DOI:
https://doi.org/10.3889/oamjms.2022.9971Keywords:
Transforming growth factor beta1, Urinary bladder cancer, Cancer-associated fibroblast, Cancer-associated fibroblasts, ImmunohistochemistryAbstract
Background: Urinary bladder carcinoma (UBC) is one of the most common malignancies in Egypt and all over the world. TGFB levels in plasma and urine were proved to connote predictive and prognostic attributes in UBC patients. Furthermore, Cancer associated fibroblasts (CAFs) are now recognized as a key player in carcinogenesis. Yet, TGFΒ1 expression in CAFs of UBC had not been elucidated. Moreover, TGFB1 targeted therapy is now emerging with potential benefits for TGFB1 expressing cancers.
Aim of the study: we dedicated this study to explore potential implications of TGFB1 immunohistochemical expression in CAFs of UBC by correlating it to relevant clinical and pathological data.
Material and methods: This retrospective study included 48 UBC specimens. Different tumor grades were presented in balanced groups. TGFB1 immunohistochemical expression was evaluated, categorized as low or high and compared in CAFs among different UBC grades, statistical analysis of the results was then followed.
Results: TGFB1 expression in CAFs was significantly different among tumor histologic types (P=0.01), high tumor grade (P=<0.01), presence of muscle invasion (P=<0.001), higher tumor stage (P=0.01), presence of preceding bilharziasis (P=0.003), and necrosis (P=0.03). There was a highly significant difference between TGFB1 expression in both tumor cells and CAFs (P=0.002). Intense CAFs TGFB1 staining was also strikingly observed along the muscle invading frontside UBC cells further emphasizing the pivotal role of CAFs expressing TGFB1 in invasion.
Conclusion: This study demonstrates significant predictive implications of TGFB1 in UBC, thus emphasizing its potential benefits in management and therapy.
Downloads
Metrics
Plum Analytics Artifact Widget Block
References
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-49. https://doi.org/10.3322/caac.21660 PMid:33538338 DOI: https://doi.org/10.3322/caac.21660
Humphrey PA, Moch H, Cubilla AL, Ulbright TM, Reuter VE. The 2016 WHO classification of tumours of the urinary system and male genital organs-part B: Prostate and bladder tumours. Eur Urol. 2016;70(1):106-19. https//doi.org/10.1016/j.eururo.2016.02.028 PMid:26996659 DOI: https://doi.org/10.1016/j.eururo.2016.02.028
Kucuk U, Pala EE, Cakır E, Sezer O, Bayol U, Divrik RT, et al. Clinical, demographic and histopathological prognostic factors for urothelial carcinoma of the bladder. Cent Eur J Urol. 2015;68(1):30. https//doi.org/10.5173/ceju.2015.01.465 PMid:25914835 DOI: https://doi.org/10.5173/ceju.2015.01.465
Weber CE, Kuo PC. The tumor microenvironment. Surg Oncol. 2012;21(3):172-7. https//doi.org/10.1016/j.suronc.2011.09.001 PMid:21963199 DOI: https://doi.org/10.1016/j.suronc.2011.09.001
Cirri P, Chiarugi P. Cancer associated fibroblasts: The dark side of the coin. Am J Cancer Res. 2011;1(4):482-97. PMid:21984967
Neuzillet C, Tijeras-Raballand A, Cohen R, Cros J, Faivre S, Raymond E, et al. A. targeting the TGFβ _pathway for cancer therapy. Pharmacol Ther. 2015;147:22-31. https//doi.org/10.1016/j.pharmthera.2014.11.001 PMid:25444759 DOI: https://doi.org/10.1016/j.pharmthera.2014.11.001
Kandori S, Kojima T, Nishiyama H. The updated points of TNM classification of urological cancers in the 8th edition of AJCC and UICC. Jpn J Clin Oncol. 2019;49(5):421-25. https//doi.org/10.1093/jjco/hyz017 PMid:30844068 DOI: https://doi.org/10.1093/jjco/hyz017
Kim JH, Shariat SF, Kim IY, Menesses-Diaz A, Tokunaga H, Wheeler TM, et al. Predictive value of expression of transforming growth factor-β1 and its receptors in transitional cell carcinoma of the urinary bladder. Cancer. 2001;92(6):1475-83. https://doi.org/10.1002/1097-0142(20010915)92:6<1475:AID-CNCR1472>3.0.CO;2-X PMid:11745225 DOI: https://doi.org/10.1002/1097-0142(20010915)92:6<1475::AID-CNCR1472>3.0.CO;2-X
Izadifar V, de Boer WI, Muscatelli-Groux B, Maillé P, van der Kwast TH, Chopin DK. Expression of transforming growth factor β1 and its receptors in normal human urothelium and human transitional cell carcinomas. Hum Pathol. 1999;30(4):372-7. https//doi.org/10.1016/s0046-8177(99)90110-7 PMid:10208456 DOI: https://doi.org/10.1016/S0046-8177(99)90110-7
Zhang J, Wang Y, Li D, Jing S. Notch and TGF-β/Smad3 pathways are involved in the interaction between cancer cells and cancer-associated fibroblasts in papillary thyroid carcinoma. Tumor Biol. 2014;35(1):379-85. https//doi.org/10.1007/s13277-013-1053-z PMid:23918305 DOI: https://doi.org/10.1007/s13277-013-1053-z
Kuzet SE, Gaggioli C. Fibroblast activation in cancer: When seed fertilizes soil. Cell Tissue Res. 2016;365(3):607-19. https//doi.org/10.1007/s00441-016-2467-x PMid:27474009 DOI: https://doi.org/10.1007/s00441-016-2467-x
Erdogan B, Webb DJ. Cancer-associated fibroblasts modulate growth factor signaling and extracellular matrix remodeling to regulate tumor metastasis. Biochem Soc Trans. 2017;45(1):229-36. https//doi.org/10.1042/BST20160387 PMid:28202677 DOI: https://doi.org/10.1042/BST20160387
Kong J, Tian H, Zhang F, Zhang Z, Li J, Liu X, et al. Extracellular vesicles of carcinoma-associated fibroblasts creates a pre-metastatic niche in the lung through activating fibroblasts. Mol Cancer. 2019;18(1):1-6. https://doi.org/10.1186/s12943-019-1101-4 PMid:31796058 DOI: https://doi.org/10.1186/s12943-019-1101-4
Umakoshi M, Takahashi S, Itoh G, Kuriyama S, Sasaki Y, Yanagihara K, et al. Macrophage-mediated transfer of cancer-derived components to stromal cells contributes to establishment of a pro-tumor. Oncogene. 2019;38(12):2162-76. https://doi.org/10.1038/s41388-018-0564-x PMid:30459356 DOI: https://doi.org/10.1038/s41388-018-0564-x
Zigeuner R, Shariat SF, Margulis V, Karakiewicz PI, Roscigno M, Weizer A, et al. Tumour necrosis is an indicator of aggressive biology in patients with urothelial carcinoma of the upper urinary tract. Eur Urol. 2010;57(4):575-81. https://doi.org/10.1016/j.eururo.2009.11.035. PMid:19959276 DOI: https://doi.org/10.1016/j.eururo.2009.11.035
Choudhury A, West CM, Porta N, Hall E, Denley H, Hendron C, et al. The predictive and prognostic value of tumour necrosis in muscle invasive bladder cancer patients receiving radiotherapy with or without chemotherapy in the BC2001 trial (CRUK/01/004). Br J Cancer. 2017;116(5):649-57. https://doi.org/10.1038/bjc.2017.2 PMid:28125821 DOI: https://doi.org/10.1038/bjc.2017.2
Bredholt G, Mannelqvist M, Stefansson IM, Birkeland E, Bø TH, Øyan AM, et al. Tumor necrosis is an important hallmark of aggressive endometrial cancer and associates with hypoxia, angiogenesis and inflammation responses. Oncotarget. 2015;6(37):39676-91. https://doi.org/10.18632/oncotarget.5344 PMid:26485755 DOI: https://doi.org/10.18632/oncotarget.5344
Lamouille S, Connolly E, Smyth JW, Akhurst RJ, Derynck R. TGF-β-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion. J Cell Sci. 2012;125(5):1259-73. https://doi.org/10.1242/jcs.095299 PMid:22399812 DOI: https://doi.org/10.1242/jcs.095299
Zaghloul MS, Zaghloul TM, Bishr MK, Baumann BC. Urinary schistosomiasis and the associated bladder cancer: Update. J Egypt Natl Canc Inst. 2020;32(1):44. https://doi.org/10.1186/s43046-020-00055-z PMid:33252773 DOI: https://doi.org/10.1186/s43046-020-00055-z
Downloads
Published
How to Cite
License
Copyright (c) 2022 Noha Helmy Ghanem, Nafissa El-Badawy, Sahar Saad El Din, Iman Hewedi, Lobna Shash (Author)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
http://creativecommons.org/licenses/by-nc/4.0
