Hypoxia‐inducible factor and mammalian target of rapamycin pathway markers in urothelial carcinoma of the bladder: possible therapeutic implications

• Published in: BJU international Vol. 107; no. 5; pp. 844 - 849
• Main Authors: Tickoo, Satish K., Milowsky, Matthew I., Dhar, Nitin, Dudas, Maria E., Gallagher, David J., Al‐Ahmadie, Hikmat, Gopalan, Anuradha, Fine, Samson W., Ishill, Nicole, Bajorin, Dean F., Reuter, Victor E.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.03.2011; Wiley-Blackwell; Wiley Subscription Services, Inc
• Subjects: Antibodies; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Bladder; Bladder cancer; bladder carcinoma; Carcinoma, Transitional Cell - drug therapy; Carcinoma, Transitional Cell - pathology; Cell Hypoxia; Cell Line, Tumor; Clinical trials; Humans; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Hypoxia-inducible factors; hypoxia‐inducible factor; Immunohistochemistry; Immunoreactivity; mammalian target of rapamycin; Medical sciences; Nephrology. Urinary tract diseases; Rapamycin; Signal Transduction; Sirolimus - therapeutic use; Studies; TOR protein; TOR Serine-Threonine Kinases - metabolism; Tumorigenesis; Tumors; Tumors of the urinary system; Urinary bladder; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - pathology; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; Urothelial carcinoma; Vascular endothelial growth factor; Vascular endothelial growth factor receptors; Immunohistochemistry; Oxygen; Nephrology; Urinary system disease; bladdercarcinoma; Biological marker; Biological indicator; Urinary tract disease; Malignant tumor; Bladder cancer; Urology; Anatomic pathology; Treatment; Mammalian target of rapamycin; Hypoxia; Bladder disease; Transcription factor HIF1; hypoxia-induciblefactor; Cancer
• ISSN: 1464-4096; 1464-410X; 1464-410X
• DOI: 10.1111/j.1464-410X.2010.09517.x

What’s known on the subject? and What does the study add? The hypoxia‐inducible factor (HIF) and mammalian target of rapamycin (mTOR) pathways are important in tumorigenesis and novel agents targeting these respective pathways have shown promising activity in several malignancies. The current study demonstrates the expression of HIF and mTOR related pathway markers in urothelial carcinoma providing a rationale for clinical trials evaluating agents targeting these pathways. OBJECTIVE To investigate the rationale for using targeted therapies against hypoxia‐inducible factor (HIF) and mammalian target of rapamycin (mTOR) pathways in urothelial carcinoma of the bladder, by studying the immunohistochemical expression of molecules of these pathways in urothelial carcinoma, as recent pre‐clinical studies and clinical trials have shown the potential utility of such targeted therapies. PATIENTS AND METHODS Immunohistochemical stains were performed on a tissue microarray prepared from 92 cases of ≥ pT2 urothelial (transitional cell) carcinoma of bladder, using antibodies against HIF‐1α and VEGF‐R2, and phospho‐S6 and phospho‐4E BP1, molecules of HIF and activated mTOR pathways, respectively. Immunoreactivity was graded from 0 to 3+ (0, 0–5%; 1+, 6–25%; 2+, 26–50%; 3+, > 50% tumour cells positive). RESULTS In all, 58, 34, 35 and 17% of the tumours showed grade 2–3+ expression of phospho‐4E BP1, phospho‐S6, HIF‐1α and VEGF‐R2, respectively. Moderate correlation for immunoreactivity was observed between molecules within the same pathway [(phospho‐4E BP1 with phospho‐S6 (rho = 0.411), and HIF‐1α with VEGF‐R2 (rho = 0.265)], but not between molecules across pathways. CONCLUSIONS Urothelial carcinomas of the bladder express molecules of the HIF and mTOR pathways, providing a rationale for clinical trials evaluating agents targeting these pathways. Correlation between molecules within the same pathway, and not across pathways, suggests that investigating the usefulness of a specific targeted agent might benefit from pre‐treatment evaluation of pathway marker expression.