In vivo and in situ modulation of the expression of genes involved in metastasis and angiogenesis in a patient treated with topical imiquimod for melanoma skin metastases.
There is a growing body of evidence to support the efficacy of topical imiquimod in the treatment of primary skin carcinomas. Conflicting data exist concerning the use of imiquimod for the treatment of skin melanoma metastases. To date, only the impact of imiquimod on cytokines involved in immunological processes has been studied extensively. We report a woman successfully treated with imiquimod (once daily for 8 weeks) for skin melanoma metastases in whom we investigated the expression of molecules involved in metastasis and angiogenesis. Before and after treatment, a skin lesion was biopsied and the expression of the following molecules was investigated using real-time reverse transcription-polymerase chain reaction: matrix metalloproteinase (MMP)-1, 2 and 9 and their inhibitors KiSS-1 and tissue inhibitor of metalloproteinase (TIMP)-1, vascular endothelial growth factor (VEGF), fibroblast growth factor-2, and angiogenesis inhibitors (thrombospondin-1 and 2). Interferon (IFN)-alpha was also investigated as an in vivo marker of imiquimod activity. IFN-alpha was upregulated by the treatment. Under imiquimod, the following molecules were upregulated: TIMP-1, KiSS-1 and MMP-1. MMP-2 expression was not modified. MMP-9 expression was dramatically decreased. The expression of angiogenesis inhibitors was slightly increased but VEGF expression remained at a basal level. These results suggest that imiquimod could downregulate metastasis invasion and angiogenesis. However, these data were obtained at a transcriptional level and from a single case, and further investigations should include migration assays and additional cases in order to confirm that imiquimod may be safely used for treatment of melanoma metastases.
Hesling
C
C
Laboratory of Molecular Oncology/UMR 484, Centre Jean Perrin, Clermont-Ferrand, France.
D'Incan
M
M
Mansard
S
S
Franck
F
F
Corbin-Duval
A
A
Chèvenet
C
C
Déchelotte
P
P
Madelmont
J-C
JC
Veyre
A
A
Souteyrand
P
P
Bignon
Y-J
YJ
D000287:Administration, Topical; D000368:Aged; D000634:Aminoquinolines / Q000008:administration & dosage*; D020533:Angiogenesis Inhibitors / Q000032:analysis; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D000077271:Imiquimod; D016898:Interferon-alpha / Q000032:analysis; D059648:Kisspeptins; D020782:Matrix Metalloproteinases / Q000032:analysis; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000556:secondary*; D009389:Neovascularization, Pathologic / Q000235:genetics; D011506:Proteins / Q000032:analysis; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis; D025521:Tumor Suppressor Proteins; D042442:Vascular Endothelial Growth Factors / Q000032:analysis
D000634:Aminoquinolines; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D016898:Interferon-alpha; C106628:KISS1 protein, human; D059648:Kisspeptins; D011506:Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D025521:Tumor Suppressor Proteins; D042442:Vascular Endothelial Growth Factors; D020782:Matrix Metalloproteinases; D000077271:Imiquimod