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.
Highlights
There is increasing evidence that neoplastic cells actively shape their microenvironment, which is critical for tumor progression [1]
Our study defines a novel STAT3-dependent molecular cascade of signals in human tumor-associated myeloid cells leading to MMP-9 induction, a matrix-metalloprotease critically contributing to epithelial tumorigenesis
High levels of MMP-9 expression are correlated with poor clinical prognosis [18]
Summary
There is increasing evidence that neoplastic cells actively shape their microenvironment, which is critical for tumor progression [1]. Infiltrating cells create a local milieu characterized by chronic inflammation sustaining proliferation and survival of the neoplastic cells [2,3,4]. The exact molecular mechanisms how human (pre)neoplastic cells instruct the infiltrating immune cells to acquire a protumorigenic inflammatory phenotype are still poorly understood. The different, well-defined stages of human cervical cancer development are an excellent model to study the interactions. Authors' Affiliations: 1Center for Molecular Medicine Cologne and Institute of Virology and 2Institute of Pathology, University of Cologne, Cologne, Germany and 3Institute of Virology, Saarland University, Homburg/Saar, Germany. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Wickenhauser: Institute of Pathology, University of Leipzig, Leipzig, Germany
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