IL-17 enhances the net angiogenic activity and in vivo growth of human non-small cell lung cancer in SCID mice through promoting CXCR-2-dependent angiogenesis.
In this study, we examined the biological action of IL-17 on human non-small cell lung cancer (NSCLC). Although IL-17 had no direct effect on the in vitro growth rate of NSCLC, IL-17 selectively augmented the secretion of an array of angiogenic CXC chemokines, including CXCL1, CXCL5, CXCL6, and CXCL8 but not angiostatic chemokines, by three different NSCLC lines. Endothelial cell chemotactic activity (as a measure of net angiogenic potential) was increased in response to conditioned medium from NSCLC stimulated with IL-17 compared with those from unstimulated NSCLC. Enhanced chemotactic activity was suppressed by neutralizing mAb(s) to CXCL1, CXCL5, and CXCL8 or to CXCR-2 but not to vascular endothelial growth factor-A. Transfection with IL-17 into NSCLC had no effect on the in vitro growth, whereas IL-17 transfectants grew more rapidly compared with controls when transplanted in SCID mice. This IL-17-elicited enhancement of NSCLC growth was associated with increased tumor vascularity. Moreover, treatment with anti-mouse CXCR-2-neutralizing Ab significantly attenuated the growth of both neomycin phosphotransferase gene-transfected and IL-17-transfected NSCLC tumors in SCID mice. A potential role for IL-17 in modulation of the human NSCLC phenotype was supported by the findings that, in primary NSCLC tissues, IL-17 expression was frequently detected in accumulating and infiltrating inflammatory cells and that high levels of IL-17 expression were associated with increased tumor vascularity. These results demonstrate that IL-17 increases the net angiogenic activity and in vivo growth of NSCLC via promoting CXCR-2-dependent angiogenesis and suggest that targeting CXCR-2 signaling may be a novel promising strategy to treat patients with NSCLC.
Numasaki
Muneo
M
Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine, Sendai, Japan.
Watanabe
Mika
M
Suzuki
Takashi
T
Takahashi
Hidenori
H
Nakamura
Akira
A
McAllister
Florencia
F
Hishinuma
Takanori
T
Goto
Junichi
J
Lotze
Michael T
MT
Kolls
Jay K
JK
Sasaki
Hidetada
H
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054360:Chemokine CXCL1; D054365:Chemokine CXCL5; D019743:Chemokines, CXC / Q000502:physiology; D002633:Chemotaxis / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000098:blood supply* / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000209:etiology*; D018123:Receptors, Interleukin / Q000032:analysis; D053722:Receptors, Interleukin-17; D023063:Receptors, Interleukin-8B / Q000502:physiology*; D014183:Transplantation, Heterologous
C475829:CXCL1 protein, human; C486263:CXCL5 protein, human; D054360:Chemokine CXCL1; D054365:Chemokine CXCL5; D019743:Chemokines, CXC; C109985:IL17RA protein, human; D036341:Intercellular Signaling Peptides and Proteins; D020381:Interleukin-17; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D023063:Receptors, Interleukin-8B