Radiation-induced thymidine phosphorylase upregulation in rectal cancer is mediated by tumor-associated macrophages by monocyte chemoattractant protein-1 from cancer cells.
OBJECTIVE
The mechanisms of thymidine phosphorylase (TP) regulation induced by radiation therapy (XRT) in various tumors are poorly understood. We investigated the effect and mechanisms of preoperative XRT on TP expression in rectal cancer tissues.


METHODS
TP expression and CD68 and monocyte chemoattractant protein-1 (MCP-1) levels in rectal cancer tissues and cancer cell lines were evaluated before and after XRT in Western blotting, immunohistochemistry, enzyme-linked immunoassay, and reverse transcription-polymerase chain reaction studies. Isolated peripheral blood monocytes were used in the study of chemotaxis under the influence of MCP-1 released by irradiated colon cancer cells.


RESULTS
Expression of TP was significantly elevated by 9 Gy of XRT in most rectal cancer tissues but not by higher doses of XRT. In keeping with the close correlation of the increase in both TP expression and the number of tumor-associated macrophages (TAMs), anti-TP immunoreactivity was found in the CD68-positive TAMs and not the neoplastic cells. Expression of MCP-1 was increased in most cases after XRT, and this increase was strongly correlated with TP expression. However, this increase in MCP-1 expression occurred in tumor cells and not stromal cells. The XRT upregulated MCP-1 mRNA and also triggered the release of MCP-1 protein from cultured colon cancer cells. The supernatant of irradiated colon cancer cells showed strong chemotactic activity for monocyte migration, but this activity was completely abolished by neutralizing antibody.


CONCLUSIONS
Use of XRT induces MCP-1 expression in cancer cells, which causes circulating monocytes to be recruited into TAMs, which then upregulate TP expression in rectal cancer tissues.
Kim
Tae-Dong
TD
Department of Biochemistry, Chungnam National University College of Medicine, Daejon, Korea.
Li
Ge
G
Song
Kyoung-Sub
KS
Kim
Jin-Man
JM
Kim
Jun-Sang
JS
Kim
Jong-Seok
JS
Yun
Eun-Jin
EJ
Park
Jong-Il
JI
Park
Hae-Duck
HD
Hwang
Byung-Doo
BD
Lim
Kyu
K
Yoon
Wan-Hee
WH
D015703:Antigens, CD / Q000378:metabolism*; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000201:enzymology / Q000528:radiation effects; D054441:Cell Migration Assays, Leukocyte / Q000379:methods; D054442:Cell Migration Assays, Macrophage; D018932:Chemokine CCL2 / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D019073:HT29 Cells / Q000201:enzymology / Q000528:radiation effects; D006801:Humans; D008264:Macrophages / Q000502:physiology; D009000:Monocytes / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D011879:Radiotherapy Dosage; D012004:Rectal Neoplasms / Q000378:metabolism* / Q000532:radiotherapy; D013939:Thymidine Phosphorylase / Q000378:metabolism*; D020298:U937 Cells / Q000201:enzymology / Q000528:radiation effects; D015854:Up-Regulation / Q000502:physiology / Q000528:radiation effects*; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018932:Chemokine CCL2; D012333:RNA, Messenger; D013939:Thymidine Phosphorylase; C067980:CD68 antigen, human; D000097382:CD68 Molecule