Macrophages from irradiated tumors express higher levels of iNOS, arginase-I and COX-2, and promote tumor growth

Int J Radiat Oncol Biol Phys. 2007 Jun 1;68(2):499-507. doi: 10.1016/j.ijrobp.2007.01.041. Epub 2007 Mar 29.


Purpose: 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 and materials: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Arginase / metabolism*
  • Cell Line, Tumor
  • Cyclooxygenase 2 / metabolism*
  • Macrophages / metabolism
  • Macrophages / radiation effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Proteins / metabolism*
  • Nitric Oxide Synthase Type II / metabolism*
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / radiotherapy*
  • RNA, Messenger / metabolism
  • Radiotherapy Dosage
  • Time Factors


  • Neoplasm Proteins
  • RNA, Messenger
  • Nitric Oxide Synthase Type II
  • Cyclooxygenase 2
  • Arginase