title: Molecular pathobiology of human cervical high-grade lesions: paracrine STAT3 activation in tumor-instructed myeloid cells drives local MMP-9 expression.
abstract: In many tumors, the switch from precancerous lesions to malignancy critically relies on expression of the matrix-metalloprotease MMP-9, which is predominantly provided by infiltrating inflammatory cells. Our study defines a novel molecular cascade, how human neoplastic cells instruct tumor-associated myeloid cells to produce MMP-9. In biopsies of human papillomavirus-associated precancerous cervical intraepithelial neoplasia (CIN III lesions), we show broad activation of the transcription factor STAT3 and coexpression of MMP-9 in perivascular inflammatory cells. For the first time, we establish a causative link between tumor-mediated paracrine STAT3 activation and MMP-9 production by human tumor-instructed monocytes, whereas NF-κB activation is dispensable for this response. Our data provide evidence that STAT3 does not directly induce MMP-9 but first leads to a strong production of the monocyte chemoattractant protein-1 (CCL2) in the nanogram range. In a second phase, autocrine stimulation of the CCR2 receptor in the tumor-instructed monocytes amplifies MMP-9 expression via intracellular Ca(2+) signaling. These findings elucidate a critical mechanism in the molecular pathobiology of cervical carcinogenesis at the switch to malignancy. Particularly in tumors, which are associated with infectious agents, STAT3-driven inflammation may be pivotal to promote carcinogenesis, while at the same time limit NF-κB-dependent immune responses and thus rejection of the infected preneoplastic cells. The molecular cascade defined in this study provides the basis for a rational design of future adjuvant therapies of cervical precancerous lesions.
authors.affiliation: Center for Molecular Medicine Cologne and Institute of Virology, University of Cologne, Cologne, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Schröer
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pahne
authors.forename: Barbara
authors.initials: B
authors.lastname: Walch
authors.forename: Claudia
authors.initials: C
authors.lastname: Wickenhauser
authors.forename: Sigrun
authors.initials: S
authors.lastname: Smola
mesh_terms: D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000201:enzymology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D004790:Enzyme Induction; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000378:metabolism*; D009000:Monocytes / Q000201:enzymology; D016328:NF-kappa B / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology*
chemical_list: D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D020780:Matrix Metalloproteinase 9; D002118:Calcium