IL-6 promotes malignant growth of skin SCCs by regulating a network of autocrine and paracrine cytokines.
Cytokines play a crucial role in tumor initiation and progression. Here, we demonstrate that interleukin (IL)-6 is a key factor by driving tumor progression from benign to malignant, invasive tumors in the HaCaT-model of human skin carcinoma. IL-6 activates STAT3 and directly stimulates proliferation and migration of the benign noninvasive HaCaT-ras A-5 cells in vitro. Furthermore, IL-6 induces a complex, reciprocally regulated cytokine network in the tumor cells that includes inflammatory and angiogenic factors such as IL-8, GM-CSF, VEGF and MCP-1. These IL-6 effects lead to tumor cell invasion in organotypic cultures in vitro and to the formation of malignant and invasive s.c. tumors in vivo. Tumor invasion is supported by the IL-6 induced overexpression of MMP-1 in vitro and in vivo. These data demonstrate a key function of IL-6 in the progression of skin SCCs by regulating a complex cytokine and protease network and suggest new therapeutic approaches to target this central player in skin carcinogenesis.
Lederle
Wiltrud
W
DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.
Depner
Sofia
S
Schnur
Sabine
S
Obermueller
Eva
E
Catone
Nicola
N
Just
Alexandra
A
Fusenig
Norbert E
NE
Mueller
Margareta M
MM
D001483:Base Sequence; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D049109:Cell Proliferation; D016207:Cytokines / Q000502:physiology*; D017931:DNA Primers; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D017403:In Situ Hybridization; D015850:Interleukin-6 / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D012878:Skin Neoplasms / Q000473:pathology*
D016207:Cytokines; D017931:DNA Primers; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human