Molecular pathobiology of human cervical high-grade lesions: paracrine STAT3 activation in tumor-instructed myeloid cells drives local MMP-9 expression

• Published in: Cancer research (Chicago, Ill.) Ill.), 2011-01, Vol.71 (1), p.87-97
• Main Authors: Schröer, Nadine, Pahne, Jennifer, Walch, Barbara, Wickenhauser, Claudia, Smola, Sigrun
• Format: Article
• Language: English
• Subjects: Blotting, Western; Bone Marrow Cells - enzymology; Bone Marrow Cells - metabolism; Calcium - metabolism; Enzyme Induction; Female; Flow Cytometry; Fluorescent Antibody Technique; HeLa Cells; Humans; Matrix Metalloproteinase 9 - biosynthesis; Matrix Metalloproteinase 9 - metabolism; Monocytes - enzymology; NF-kappa B - metabolism; Signal Transduction; STAT3 Transcription Factor - metabolism; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - pathology
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-10-2193

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.