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


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.
Tickoo
Satish K
SK
Department of PathologyGenitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer CenterWeill Cornell Medical College of Cornell UniversityDepartment of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer, Center, New York, NY, USA.
Milowsky
Matthew I
MI
Department of PathologyGenitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer CenterWeill Cornell Medical College of Cornell UniversityDepartment of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer, Center, New York, NY, USA.
Dhar
Nitin
N
Department of PathologyGenitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer CenterWeill Cornell Medical College of Cornell UniversityDepartment of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer, Center, New York, NY, USA.
Dudas
Maria E
ME
Department of PathologyGenitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer CenterWeill Cornell Medical College of Cornell UniversityDepartment of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer, Center, New York, NY, USA.
Gallagher
David J
DJ
Department of PathologyGenitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer CenterWeill Cornell Medical College of Cornell UniversityDepartment of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer, Center, New York, NY, USA.
Al-Ahmadie
Hikmat
H
Department of PathologyGenitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer CenterWeill Cornell Medical College of Cornell UniversityDepartment of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer, Center, New York, NY, USA.
Gopalan
Anuradha
A
Department of PathologyGenitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer CenterWeill Cornell Medical College of Cornell UniversityDepartment of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer, Center, New York, NY, USA.
Fine
Samson W
SW
Department of PathologyGenitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer CenterWeill Cornell Medical College of Cornell UniversityDepartment of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer, Center, New York, NY, USA.
Ishill
Nicole
N
Department of PathologyGenitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer CenterWeill Cornell Medical College of Cornell UniversityDepartment of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer, Center, New York, NY, USA.
Bajorin
Dean F
DF
Department of PathologyGenitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer CenterWeill Cornell Medical College of Cornell UniversityDepartment of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer, Center, New York, NY, USA.
Reuter
Victor E
VE
Department of PathologyGenitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer CenterWeill Cornell Medical College of Cornell UniversityDepartment of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer, Center, New York, NY, USA.
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D015398:Signal Transduction; D020123:Sirolimus / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology
D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus