CD4+ lymphocytes modulate prostate cancer progression in mice.
Chronic inflammation contributes to the development of prostate cancer in humans. Here, we show that male Apc(Min/+) mice also develop prostate carcinoma with increasing age, mimicking that seen in humans in their 5th or 6th decade of life. Proinflammatory cytokines were significantly linked with cancer and increasing age in our mouse model; however, prostate and bowel tissues lacked evidence of inflammatory cell infiltrates other than mast cells. Lymphocytes protected against cancer, and protection from prostate cancer resided in antiinflammatory CD4(+)CD25(+) regulatory (T(REG)) cells that downregulated inflammatory cytokines. Supplementation with syngeneic T(REG) cells collected from wild-type mice reduced the levels of interleukin (IL)-6 (p < 0.05) and IL-9 (p < 0.001) and lowered prostate cancer risk (p < 0.05). Depletion of CD25(+) cells in 2-month-old animals increased the expression of IL-6 (p < 0.005) within prostate and increased the frequency of high-grade prostatic intraepithelial neoplasia (p < 0.05) and microinvasive prostatic carcinoma (p < 0.05) in dorsolateral prostate. Depletion of CD25(+) cells in young animals also increased the frequency of intestinal cancer in Min mice. Taken together, chronically elevated proinflammatory cytokines promoted carcinoma in Apc(Min/+) mice. T(REG) lymphocytes downregulated inflammation-associated carcinogenic processes and contributed to immune and epithelial homeostasis.
Poutahidis
Theofilos
T
Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA.
Rao
Varada P
VP
Olipitz
Werner
W
Taylor
Christie L
CL
Jackson
Erin A
EA
Levkovich
Tatiana
T
Lee
Chung Wei
CW
Fox
James G
JG
Ge
Zhongming
Z
Erdman
Susan E
SE
D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D004379:Duodenal Neoplasms / Q000209:etiology / Q000473:pathology; D017491:Genes, APC / Q000502:physiology; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000276:immunology; D015850:Interleukin-6 / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000209:etiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D016207:Cytokines; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D012333:RNA, Messenger; C499308:Rag2 protein, mouse