Sensitization of cerebral tissue in nude mice with photodynamic therapy induces ADAM17/TACE and promotes glioma cell invasion.
In the present study, we tested the hypothesis that a mild cerebral tissue injury promotes subsequent glioma invasion via activation of the ADAM17-EGFR-PI3K-Akt pathway. Mild injury was induced by photodynamic therapy (PDT), which employs tissue-penetrating laser light exposure following systemic administration of a tumor-localizing photosensitizer. Athymic nude mice were treated with sublethal PDT (80 J/cm2 with 2 mg/kg Photofrin). Hypoxic stress and ADAM17-EGFR-PI3K-Akt were measured using Western blot and immunostaining. Additional groups with/without pro-sublethal PDT were subsequently implanted with U87 glioma tumor cell. Tumor invasion and ADAM17-EGFR-PI3K-Akt pathway in tumor area were measured. After a sublethal dose of PDT, HIF-1alpha expression was increased by a factor of three in PDT-treated normal brain tissue compared to contralateral control brain tissue. PDT-treated brain tissue exhibited a significant increase in ADAM17, p-EGFR, p-Akt expression compared to non-treated tissue. ADAM17 positive area significantly increased from 1.78% to 10.89%. The percentage of p-EGFR and p-Akt positive cells significantly increased from 9.50% and 14.50% to 21.31% and 32.29%, respectively, PDT treatment significantly increased subsequent implanted U87 glioma cell invasion by 3.68-fold and increased ADAM17, EGFR, p-EGFR, Akt, p-Akt expression by 178%, 43.9%, 152.7%, 89.6%,and 164.2%, respectively, compared to control group. Our data showed that a sublethal sensitization of cerebral tissue with PDT significantly increased U87 cell invasion in nude mice, and that glioma cell invasion is highly correlated with activation of the ADAM17-EGFR-PI3K-Akt pathway (r=0.928, 0.775, 0.870, 0.872, and 0.883, respectively), most likely via HIF-1alpha.
Zheng
Xuguang
X
Department of Neurology, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, USA.
Jiang
Feng
F
Katakowski
Mark
M
Zhang
Xuepeng
X
Jiang
Hao
H
Zhang
Zheng Gang
ZG
Chopp
Michael
M
D051722:ADAM Proteins / Q000096:biosynthesis*; D000072198:ADAM17 Protein; D000818:Animals; D001921:Brain / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D045744:Cell Line, Tumor; D004790:Enzyme Induction; D005910:Glioma / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010778:Photochemotherapy / Q000009:adverse effects*
D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse