Macrophages from irradiated tumors express higher levels of iNOS, arginase-I and COX-2, and promote tumor growth.
OBJECTIVE
To investigate the effects of single and fractionated doses of radiation on tumors and tumor-associated macrophages (TAMs), and to elucidate the potential of TAMs to influence tumor growth.


METHODS
A murine prostate cell line, TRAMP-C1, was grown in C57Bl/6J mice to 4-mm tumor diameter and irradiated with either 25 Gy in a single dose, or 60 Gy in 15 fractions. The tumors were removed at the indicated times and assessed for a variety of markers related to TAM content, activation status, and function.


RESULTS
In tumors receiving a single radiation dose, arginase (Arg-I), and cycloxygenase-2 (COX-2) mRNA expression increased as a small transient wave within 24 h and a larger persistent wave starting after 3 days. Inducible nitric oxide synthase (iNOS) mRNA was elevated only after 3 days and continued to increase up to 3 weeks. After fractionated irradiation, Arg-1 and COX-2 mRNA levels increased within 5 days, whereas iNOS was increased only after 10 fractions of irradiation had been given. Increased levels of Arg-I, COX-2, and, to a lesser extent, iNOS protein were found to associate with TAMs 1-2 weeks after tumor irradiation. Function of TAMs were compared by mixing them with TRAMP-C1 cells and injecting them into mice; TRAMP-C1 cells mixed with TAMs from irradiated tumors appeared earlier and grew significantly faster than those mixed with TAMs from unirradiated tumors or TRAMP-C1 alone.


CONCLUSIONS
Tumor-associated macrophages in the postirradiated tumor microenvironment express higher levels of Arg-1, COX-2, and iNOS, and promote early tumor growth in vivo.
Tsai
Chien-Sheng
CS
Department of Radiation Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taiwan.
Chen
Fang-Hsin
FH
Wang
Chun-Chieh
CC
Huang
Hsiang-Ling
HL
Jung
Shih-Ming
SM
Wu
Chi-Jung
CJ
Lee
Chung-Chi
CC
McBride
William H
WH
Chiang
Chi-Shiun
CS
Hong
Ji-Hong
JH
D000818:Animals; D001119:Arginase / Q000378:metabolism*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000528:radiation effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D012333:RNA, Messenger / Q000378:metabolism; D011879:Radiotherapy Dosage; D013997:Time Factors
D009363:Neoplasm Proteins; D012333:RNA, Messenger; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D001119:Arginase