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Endoglin expression in UTUC
In conclusion, upregulation of endoglin was observed in the endothelium of UTUC compared with normal urothelium, and was associated with intravesical recurrence. The endoglin expression in UTUC could be a biomarker to predict intravesical recurrence, as well as a potential therapeutic target.
Acknowledgments This study was funded by the Osaka Foundation for the Prevention of Cancer and Cardiovascular Diseases.
Conflicts of interest None declared.
References 1. Green DA, Rink M, Xylinas E et al. Urothelial Carcinoma of the Bladder and the Upper Tract: Disparate Twins. J. Urol. 2012; 189: 1214–1221. 2. Oya M, Kikuchi E. Evidenced-based clinical practice guideline for upper tract urothelial carcinoma (summary - Japanese Urological Association, 2014 edition). Int. J. Urol. 2015; 22: 3–13. 3. Fujita K, Uemura M, Yamamoto Y et al. Preoperative risk stratification for cancer-specific survival of patients with upper urinary tract urothelial carcinoma treated by nephroureterectomy. Int. J. Clin. Oncol. 2014; doi: 10.1007/ s10147-014-0695-1 4. Fujita K, Tanigawa G, Imamura R et al. Preoperative serum sodium is associated with cancer-specific survival in patients with upper urinary tract urothelial carcinoma treated by nephroureterectomy. Int. J. Urol. 2013; 20: 594–601. 5. Li DY, Sorensen LK, Brooke BS et al. Defective angiogenesis in mice lacking endoglin. Science 1999; 284: 1534–7. 6. Dubinski W, Gabril M, Iakovlev VV et al. Assessment of the prognostic significance of endoglin (CD105) in clear cell renal cell carcinoma using automated image analysis. Hum. Pathol. 2012; 43: 1037–43. 7. Takahashi N, Kawanishi-Tabata R, Haba A et al. Association of serum endoglin with metastasis in patients with colorectal, breast, and other solid tumors, and suppressive effect of chemotherapy on the serum endoglin. Clin. Cancer Res. 2001; 7: 524–32. 8. Fujita K, Ewing CM, Chan DYS et al. Endoglin (CD105) as a urinary and serum marker of prostate cancer. Int. J. Cancer 2009; 124: 664–9.
9. Rosen LS, Hurwitz HI, Wong MK et al. A phase I first-in-human study of TRC105 (Anti-Endoglin Antibody) in patients with advanced cancer. Clin. Cancer Res. 2012; 18: 4820–9. 10. Munari E, Fujita K, Faraj S et al. Dysregulation of mammalian target of rapamycin pathway in upper tract urothelial carcinoma. Hum. Pathol. 2013; 44: 2668–2676. 11. Zijlmans HJ, Fleuren GJ, Hazelbag S et al. Expression of endoglin (CD105) in cervical cancer. Br. J. Cancer 2009; 100: 1617–26. 12. El-Gohary YM, Silverman JF, Olson PR et al. Endoglin (CD105) and vascular endothelial growth factor as prognostic markers in prostatic adenocarcinoma. Am. J. Clin. Pathol. 2007; 127: 572–9. 13. Dales J-P, Garcia S, Bonnier P et al. CD105 expression is a marker of high metastatic risk and poor outcome in breast carcinomas. Correlations between immunohistochemical analysis and long-term follow-up in a series of 929 patients. Am. J. Clin. Pathol. 2003; 119: 374–80. 14. Saad RS, Liu YL, Nathan G, Celebrezze J, Medich D, Silverman JF. Endoglin (CD105) and vascular endothelial growth factor as prognostic markers in colorectal cancer. Mod. Pathol. 2004; 17: 197–203. 15. Kyzas PA, Agnantis NJ, Stefanou D. Endoglin (CD105) as a prognostic factor in head and neck squamous cell carcinoma. Virchows Arch. 2006; 448: 768–75. 16. Sandlund J, Hedberg Y, Bergh A, Grankvist K, Ljungberg B, Rasmuson T. Endoglin (CD105) expression in human renal cell carcinoma. BJU Int. 2006; 97: 706–10. 17. Agrawal U, Mishra AK, Salgia P, Verma S, Mohanty NK, Saxena S. Role of tumor suppressor and angiogenesis markers in prediction of recurrence of non muscle invasive bladder cancer. Pathol. Oncol. Res. 2011; 17: 91–101. 18. Santos L, Costa C, Pereira S et al. Neovascularisation is a prognostic factor of early recurrence in T1/G2 urothelial bladder tumours. Ann. Oncol. 2003; 14: 1419–1424. 19. Inoue K, Kamada M, Slaton JW, Yoshikawa C, Tamboli P. The Prognostic Value of Angiogenesis and Metastasis-related Genes for Progression of Transitional Cell Carcinoma of the Renal Pelvis and Ureter. Clin. Cancer Res. 2002; 8: 1863–1870. 20. Miyazaki Y, Kosaka T, Mikami S et al. The prognostic significance of vasohibin-1 expression in patients with upper urinary tract urothelial carcinoma. Clin. Cancer Res. 2012; 18: 4145–53. 21. Shirotake S, Miyajima A, Kosaka T et al. Angiotensin II type 1 receptor expression and microvessel density in human bladder cancer. Urology 2011; 77: 1009.e19–25. 22. Crew JP, O’Brien T, Bradburn M et al. Vascular endothelial growth factor is a predictor of relapse and stage progression in superficial bladder cancer. Cancer Res. 1997; 57: 5281–5. 23. Jeon SH, Lee SJ, Chang SG. Clinical significance of urinary vascular endothelial growth factor in patients with superficial bladder tumors. Oncol. Rep. 2001; 8: 1265–7.
Original Article: Editorial Comment Clinical Investigation Editorial Comment to Endoglin expression in upper urinary tract urothelial carcinoma is associated with intravesical recurrence after radical nephroureterectomy Upper urinary tract urothelial carcinoma (UTUC) is a rare malignancy. Because of the rarity of this disease, identifying prognostic factors is difficult and also imperative. Besides local relapse and distal organ metastasis, UTUC can also recur in the urinary bladder. Although the incidence of intravesical recurrence of UTUC varies from 20% to 75%, follow up with regular cystoscopy is required.1 Considering the invasiveness of cystoscopy, it is necessary to find a useful biomarker for predicting intravesical recurrence of UTUC. Fujita et al. found that endoglin might be a good candidate for predicting intravesical recurrence in UTUC.2 They reported that UTUC patients with high expression of endoglin in © 2015 The Japanese Urological Association
primary tumor tissue had a 2.67-fold risk of presenting intravesical recurrence than those with low expression of endoglin. These finding was based on the immunohistochemistry results in a cohort of 99 UTUC, which highlighted the association of endoglin expression and intravesical recurrence. In previous studies, factors correlative with intravesical recurrence included previous bladder cancer, tumor stage and multifocality.3 However, in the study by Fujita et al., the authors failed to find a significant association between the aforementioned parameters and intravesical recurrence.2 One explanation for this phenomenon might be that endoglin is such an important prognostic factor that other clinicopathological factors 467
K FUJITA ET AL.
become not statistically significant when endoglin was added to the Cox proportional hazards model. Or we should consider the relatively small sample size and selection bias in the present study. Furthermore, some important clinicopathological factors that might affect the prognosis of UTUC were not included in the final analysis, including sarcomatoid differentiation, neoadjuvant therapy, adjuvant therapy and so on. Hence, before popularizing the finding in the present study, large series studies with rigorously designed methodology are required. Endoglin is a marker for endothelial cells proliferation. More newborn microvessels and lymph vessels can contribute to distal metastasis and/or nodes metastasis. However, in the present study, high expression of endoglin is not associated with local or distal metastasis, which seems to be contradictory to the biological characteristics of endoglin. Furthermore, the intravesical recurrence of UTUC might be caused by seeding of tumor cells in the upper urinary tract or be explained by the multifocal field change of urothelial carcinoma. How can we explain the connection between expression of endoglin and intravesical recurrence of UTUC in theory? It is one question need that needs to be answered by further study. In summary, the present study not only supported that endoglin plays a role as a predictor for intravesical recurrence in UTUC, but also warrants further studies on its underlying molecular mechanism.
468
Zhiling Zhang M.D. and Fangjian Zhou M.D. State Key Laboratory of Oncology in Southern China, and Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China [email protected] DOI: 10.1111/iju.12719
Conflict of interest None declared.
References 1. Wein AJ KR, Novick AC et al. Campbell-Walsh Urology, 10th edition ed. Saunders Elsevier, Philadelphia, 2012. 2. Fujita K, Ujike T, Nagahara A et al. Endoglin expression in upper urinary tract urothelial carcinoma is associated with intravesical recurrence after radical nephroureterectomy. Int. J. Urol. 2015; 22: 463–7. 3. Seisen T, Granger B, Colin P et al. A systematic review and meta-analysis of clinicopathologic factors linked to intravesical recurrence after radical nephroureterectomy to treat upper tract urothelial carcinoma. Eur. Urol. 2014; doi:10.1016/j.eururo.2014.11.035.
© 2015 The Japanese Urological Association
Copyright of International Journal of Urology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Endoglin expression in UTUC
In conclusion, upregulation of endoglin was observed in the endothelium of UTUC compared with normal urothelium, and was associated with intravesical recurrence. The endoglin expression in UTUC could be a biomarker to predict intravesical recurrence, as well as a potential therapeutic target.
Acknowledgments This study was funded by the Osaka Foundation for the Prevention of Cancer and Cardiovascular Diseases.
Conflicts of interest None declared.
References 1. Green DA, Rink M, Xylinas E et al. Urothelial Carcinoma of the Bladder and the Upper Tract: Disparate Twins. J. Urol. 2012; 189: 1214–1221. 2. Oya M, Kikuchi E. Evidenced-based clinical practice guideline for upper tract urothelial carcinoma (summary - Japanese Urological Association, 2014 edition). Int. J. Urol. 2015; 22: 3–13. 3. Fujita K, Uemura M, Yamamoto Y et al. Preoperative risk stratification for cancer-specific survival of patients with upper urinary tract urothelial carcinoma treated by nephroureterectomy. Int. J. Clin. Oncol. 2014; doi: 10.1007/ s10147-014-0695-1 4. Fujita K, Tanigawa G, Imamura R et al. Preoperative serum sodium is associated with cancer-specific survival in patients with upper urinary tract urothelial carcinoma treated by nephroureterectomy. Int. J. Urol. 2013; 20: 594–601. 5. Li DY, Sorensen LK, Brooke BS et al. Defective angiogenesis in mice lacking endoglin. Science 1999; 284: 1534–7. 6. Dubinski W, Gabril M, Iakovlev VV et al. Assessment of the prognostic significance of endoglin (CD105) in clear cell renal cell carcinoma using automated image analysis. Hum. Pathol. 2012; 43: 1037–43. 7. Takahashi N, Kawanishi-Tabata R, Haba A et al. Association of serum endoglin with metastasis in patients with colorectal, breast, and other solid tumors, and suppressive effect of chemotherapy on the serum endoglin. Clin. Cancer Res. 2001; 7: 524–32. 8. Fujita K, Ewing CM, Chan DYS et al. Endoglin (CD105) as a urinary and serum marker of prostate cancer. Int. J. Cancer 2009; 124: 664–9.
9. Rosen LS, Hurwitz HI, Wong MK et al. A phase I first-in-human study of TRC105 (Anti-Endoglin Antibody) in patients with advanced cancer. Clin. Cancer Res. 2012; 18: 4820–9. 10. Munari E, Fujita K, Faraj S et al. Dysregulation of mammalian target of rapamycin pathway in upper tract urothelial carcinoma. Hum. Pathol. 2013; 44: 2668–2676. 11. Zijlmans HJ, Fleuren GJ, Hazelbag S et al. Expression of endoglin (CD105) in cervical cancer. Br. J. Cancer 2009; 100: 1617–26. 12. El-Gohary YM, Silverman JF, Olson PR et al. Endoglin (CD105) and vascular endothelial growth factor as prognostic markers in prostatic adenocarcinoma. Am. J. Clin. Pathol. 2007; 127: 572–9. 13. Dales J-P, Garcia S, Bonnier P et al. CD105 expression is a marker of high metastatic risk and poor outcome in breast carcinomas. Correlations between immunohistochemical analysis and long-term follow-up in a series of 929 patients. Am. J. Clin. Pathol. 2003; 119: 374–80. 14. Saad RS, Liu YL, Nathan G, Celebrezze J, Medich D, Silverman JF. Endoglin (CD105) and vascular endothelial growth factor as prognostic markers in colorectal cancer. Mod. Pathol. 2004; 17: 197–203. 15. Kyzas PA, Agnantis NJ, Stefanou D. Endoglin (CD105) as a prognostic factor in head and neck squamous cell carcinoma. Virchows Arch. 2006; 448: 768–75. 16. Sandlund J, Hedberg Y, Bergh A, Grankvist K, Ljungberg B, Rasmuson T. Endoglin (CD105) expression in human renal cell carcinoma. BJU Int. 2006; 97: 706–10. 17. Agrawal U, Mishra AK, Salgia P, Verma S, Mohanty NK, Saxena S. Role of tumor suppressor and angiogenesis markers in prediction of recurrence of non muscle invasive bladder cancer. Pathol. Oncol. Res. 2011; 17: 91–101. 18. Santos L, Costa C, Pereira S et al. Neovascularisation is a prognostic factor of early recurrence in T1/G2 urothelial bladder tumours. Ann. Oncol. 2003; 14: 1419–1424. 19. Inoue K, Kamada M, Slaton JW, Yoshikawa C, Tamboli P. The Prognostic Value of Angiogenesis and Metastasis-related Genes for Progression of Transitional Cell Carcinoma of the Renal Pelvis and Ureter. Clin. Cancer Res. 2002; 8: 1863–1870. 20. Miyazaki Y, Kosaka T, Mikami S et al. The prognostic significance of vasohibin-1 expression in patients with upper urinary tract urothelial carcinoma. Clin. Cancer Res. 2012; 18: 4145–53. 21. Shirotake S, Miyajima A, Kosaka T et al. Angiotensin II type 1 receptor expression and microvessel density in human bladder cancer. Urology 2011; 77: 1009.e19–25. 22. Crew JP, O’Brien T, Bradburn M et al. Vascular endothelial growth factor is a predictor of relapse and stage progression in superficial bladder cancer. Cancer Res. 1997; 57: 5281–5. 23. Jeon SH, Lee SJ, Chang SG. Clinical significance of urinary vascular endothelial growth factor in patients with superficial bladder tumors. Oncol. Rep. 2001; 8: 1265–7.
Original Article: Editorial Comment Clinical Investigation Editorial Comment to Endoglin expression in upper urinary tract urothelial carcinoma is associated with intravesical recurrence after radical nephroureterectomy Upper urinary tract urothelial carcinoma (UTUC) is a rare malignancy. Because of the rarity of this disease, identifying prognostic factors is difficult and also imperative. Besides local relapse and distal organ metastasis, UTUC can also recur in the urinary bladder. Although the incidence of intravesical recurrence of UTUC varies from 20% to 75%, follow up with regular cystoscopy is required.1 Considering the invasiveness of cystoscopy, it is necessary to find a useful biomarker for predicting intravesical recurrence of UTUC. Fujita et al. found that endoglin might be a good candidate for predicting intravesical recurrence in UTUC.2 They reported that UTUC patients with high expression of endoglin in © 2015 The Japanese Urological Association
primary tumor tissue had a 2.67-fold risk of presenting intravesical recurrence than those with low expression of endoglin. These finding was based on the immunohistochemistry results in a cohort of 99 UTUC, which highlighted the association of endoglin expression and intravesical recurrence. In previous studies, factors correlative with intravesical recurrence included previous bladder cancer, tumor stage and multifocality.3 However, in the study by Fujita et al., the authors failed to find a significant association between the aforementioned parameters and intravesical recurrence.2 One explanation for this phenomenon might be that endoglin is such an important prognostic factor that other clinicopathological factors 467
K FUJITA ET AL.
become not statistically significant when endoglin was added to the Cox proportional hazards model. Or we should consider the relatively small sample size and selection bias in the present study. Furthermore, some important clinicopathological factors that might affect the prognosis of UTUC were not included in the final analysis, including sarcomatoid differentiation, neoadjuvant therapy, adjuvant therapy and so on. Hence, before popularizing the finding in the present study, large series studies with rigorously designed methodology are required. Endoglin is a marker for endothelial cells proliferation. More newborn microvessels and lymph vessels can contribute to distal metastasis and/or nodes metastasis. However, in the present study, high expression of endoglin is not associated with local or distal metastasis, which seems to be contradictory to the biological characteristics of endoglin. Furthermore, the intravesical recurrence of UTUC might be caused by seeding of tumor cells in the upper urinary tract or be explained by the multifocal field change of urothelial carcinoma. How can we explain the connection between expression of endoglin and intravesical recurrence of UTUC in theory? It is one question need that needs to be answered by further study. In summary, the present study not only supported that endoglin plays a role as a predictor for intravesical recurrence in UTUC, but also warrants further studies on its underlying molecular mechanism.
468
Zhiling Zhang M.D. and Fangjian Zhou M.D. State Key Laboratory of Oncology in Southern China, and Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China [email protected] DOI: 10.1111/iju.12719
Conflict of interest None declared.
References 1. Wein AJ KR, Novick AC et al. Campbell-Walsh Urology, 10th edition ed. Saunders Elsevier, Philadelphia, 2012. 2. Fujita K, Ujike T, Nagahara A et al. Endoglin expression in upper urinary tract urothelial carcinoma is associated with intravesical recurrence after radical nephroureterectomy. Int. J. Urol. 2015; 22: 463–7. 3. Seisen T, Granger B, Colin P et al. A systematic review and meta-analysis of clinicopathologic factors linked to intravesical recurrence after radical nephroureterectomy to treat upper tract urothelial carcinoma. Eur. Urol. 2014; doi:10.1016/j.eururo.2014.11.035.
© 2015 The Japanese Urological Association
Copyright of International Journal of Urology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
