Activation of complement C3, C5, and C9 genes in tumors treated by photodynamic therapy.
Cancer therapies, which deliver a rapidly induced massive tumor tissue injury, such as photodynamic therapy (PDT), provoke a strong host response raised for dealing with the inflicted local trauma. Activated complement system was identified as an important element of host response elicited by tumor PDT. The expression of genes encoding complement proteins C3, C5, and C9 was studied following tumor PDT mediated by photosensitizer Photofrin using mouse Lewis lung carcinoma (LLC) model. Treated tumors and the livers of host mice were collected at different times after PDT and the expression of the investigated genes was analyzed by RT-PCR. The results show a significant up-regulation of C3, C5, and C9 genes in PDT-treated tumors at 24 h after therapy, while no significant increase in the expression of these genes was found in the liver tissues. The expression of C3, C5, and C9 genes also became up-regulated in untreated tumor-associated macrophages (TAMs) co-incubated in vitro with PDT-treated LLC cells. This effect was abolished or drastically reduced in the presence of antibodies blocking heat shock protein 70 (HSP70), Toll-like receptor (TLR) 2 and TLR4, and specific peptide inhibitors of TIRAP adapter protein and transcription factor NF-kappaB. The presented study reveals that complement genes C3, C5, and C9 become up-regulated in tumors treated by PDT, but not in the host's liver. Tumor-localized up-regulation of these genes can be largely attributed to monocytes/macrophages invading the treated lesion after PDT. This effect appears to be induced by the recognition of danger signals from PDT-treated tumor cells such as HSP70 by TAMs that involve the TLR2- and TLR4-triggered signal transduction pathways leading to the activation of NF-kappaB.
Stott
Brandon
B
British Columbia Cancer Agency, Vancouver, BC, Canada.
Korbelik
Mladen
M
D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000235:genetics*; D003176:Complement C3 / Q000235:genetics* / Q000378:metabolism; D003182:Complement C5 / Q000235:genetics* / Q000378:metabolism; D003186:Complement C9 / Q000235:genetics* / Q000378:metabolism; D017323:Dihematoporphyrin Ether / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D003176:Complement C3; D003182:Complement C5; D003186:Complement C9; D018840:HSP70 Heat-Shock Proteins; D017319:Photosensitizing Agents; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D017323:Dihematoporphyrin Ether