Prognostic significance of endothelial Per-Arnt-sim domain protein 1/hypoxia-inducible factor-2alpha expression in a subset of tumor associated macrophages in invasive bladder cancer.
OBJECTIVE
Endothelial Per-Arnt-Sim domain protein 1 (EPAS1) is induced under hypoxia and it transactivates a series of genes involved in angiogenesis and energy metabolism. Recent studies showed that EPAS1 is expressed in tumor associated macrophages (TAMs), which have multifaceted roles in tumor progression. We hypothesized that EPAS1 expressed in TAMs may contribute to bladder cancer progression.


METHODS
Clinicopathological and followup data on 69 patients undergoing radical cystectomy for T1-4N0-2M0 high grade bladder urothelial carcinoma were reviewed. Quantitative immunohistochemical analysis of TAMs and EPAS1 was performed separately in invasive front and in other superficial parts of carcinoma tissues. TAM counts and EPAS1 positive cell counts were compared with pathological variables and cancer specific survival (CSS).


RESULTS
The 5-year CSS rate in the 69 patients was 69% at a median followup of 58 months (range 2 to 196). EPAS1 expression was restricted to a small subset of TAMs. Although TAM counts were not associated with T stage or lymph node metastasis, EPAS1 expressing TAM counts were significantly associated with higher T stage. On univariate and multivariate analyses higher EPAS1 expressing TAM counts in invasive front along with higher T stage and positive lymph node metastasis were significantly associated with shorter CSS, while total TAM counts or EPAS1 expressing TAM counts in other superficial parts did not.


CONCLUSIONS
Despite limited prognostic effects of total TAMs EPAS1 expressing TAMs were associated with a poor prognosis of invasive bladder cancer, suggesting that EPAS1 expressed in a subset of TAMs mediates bladder cancer progression.
Koga
Fumitaka
F
Department of Urology and Reproductive Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Kageyama
Yukio
Y
Kawakami
Satoru
S
Fujii
Yasuhisa
Y
Hyochi
Nobuhiko
N
Ando
Noboru
N
Takizawa
Touichiro
T
Saito
Kazutaka
K
Iwai
Aki
A
Masuda
Hitoshi
H
Kihara
Kazunori
K
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051792:Basic Helix-Loop-Helix Proteins; D002295:Carcinoma, Transitional Cell / Q000473:pathology*; D005260:Female; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D015534:Trans-Activators / Q000096:biosynthesis*; D001749:Urinary Bladder Neoplasms / Q000473:pathology*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D015534:Trans-Activators; D000099162:Endothelial PAS Domain-Containing Protein 1