Lipopolysaccharide-squamous cell carcinoma-monocyte interactions induce cancer-supporting factors leading to rapid STAT3 activation.
Oral and oro-pharyngeal squamous cell carcinomas (OSCC) exhibit surface breach, and recent studies have demonstrated bacterial contamination of primary and metastatic OSCC. Increasing concentrations of inflammatory products, such as interleukin (IL)-6 and vascular endothelial growth factor (VEGF), correlate with, and contribute to, cancer progression, but their regulation in OSCC is poorly understood. We hypothesized that monocyte-lineage cells and bacterial contamination may contribute important inflammatory products that can support OSCC progression. We found that relative to non-specific chronic mucositis, oral carcinoma-in-situ/superficially-invasive OSCC contained more monocyte-lineage cells. In vitro, we used lipopolysaccharide (LPS) to model bacterial contamination, and evaluated the effects of oral and oropharyngeal (O)SCC-monocyte interactions and of LPS on OSCC cells and on the production of IL-6 and VEGF. OSCC cell lines varied in constitutive cytokine and chemokine production, and OSCC-monocyte interactions in the absence of LPS stimulated IL-6 and VEGF occasionally, while LPS-OSCC-monocyte interactions were always strongly stimulatory. Importantly, LPS independently stimulated some OSCC lines to secrete monocyte-dendritic cell chemoattractants CCL2 and/or CCL20, as well as IL-6 and/or VEGF. While very little constitutive Y705-STAT3 phosphorylation (pY705-STAT3) was detectable in HNSCC lines, IL-6 rapidly induced pY705-STAT3 in OSCC lines that produced little IL-6 constitutively. Supernatants from LPS-OSCC-monocyte co-cultures always rapidly and strongly activated STAT3, which was partly due to IL-6. We conclude that monocytes and microbial contamination have the potential to contribute to OSCC progression, as STAT3 activation in OSCC cells depends on soluble factors, which are consistently available through LPS-OSCC-monocyte interactions.
Kurago
Zoya B
ZB
Department of Oral and Maxillofacial Pathology, Radiology and Medicine, College of Dentistry, New York University, New York, NY 10010, USA. zk8@nyu.edu
Lam-ubol
Aroonwan
A
Stetsenko
Anton
A
De La Mater
Chris
C
Chen
Yiyi
Y
Dawson
Deborah V
DV
D002278:Carcinoma in Situ / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009959:Oropharyngeal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000096:biosynthesis*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C508600:IL6 protein, human; D015850:Interleukin-6; D008070:Lipopolysaccharides; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A