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Normal Oral Keratinocytes and Head and Neck Squamous Carcinoma Cells Induce an Innate Response of Fibroblasts

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Normal Oral Keratinocytes and Head and Neck Squamous Carcinoma Cells Induce an Innate Response of Fibroblasts ANTICANCER RESEARCH 36: 2131-2138 (2016) Normal Oral Keratinocytes and Head and Neck Squamous Carcinoma Cells Induce an Innate Response of Fibroblasts MALIN HAKELIUS1, VAHID REYHANI2, KRISTOFER RUBIN2, BENGT GERDIN1 and DANIEL NOWINSKI1 Department of 1Surgical Sciences, Plastic Surgery, and 2Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden Abstract. Background: Tumor stroma is similar to the like milieu. There are ample examples of carcinomas arising connective tissue of chronic inflammation. The extracellular in tissues marked by a chronic inflammatory state that results matrix of tumors is formed by cancer-associated fibroblasts in tissue fibrosis. that also modulate the inflammatory response. Materials and Cancer-associated fibroblasts (CAFs) are major cellular Methods: We studied the ability of oral keratinocytes (NOK) constituents of the tumor stroma. CAFs share many and oral squamous cell carcinoma cells (SCC) to induce an similarities with the myofibroblasts of healing wounds and innate immune response in fibroblasts. Co-cultures with their metabolic activity is, to a large extent, geared towards fibroblasts in collagen gels and keratinocytes in inserts were the production of ECM, often resulting in desmoplasia (8, used. Pentraxin 3 (PTX3) was used as an indicator of an innate 9). These cells interact with malignant cells and infiltrating immune response. Results: SCC and NOK up-regulated leukocytes through paracrine factors, and through direct fibroblast mRNA expression and protein release of PTX3. cell–cell contacts, to promote stromal modification, as well mRNA levels were more pronounced in cultures with malignant as tumor-cell migration and invasion. The mechanisms of cells. The induction of PTX3 was abrogated by an interleukin- this interplay are only partially known. 1 receptor antagonist Conclusion: Keratinocytes have the We previously described several paracrine effects of capacity to induce an interleukin-1-dependent innate immune keratinocytes on fibroblasts and identified interleukin-1-alpha response by fibroblasts in vitro. This could be important for (IL1α) as a major soluble factor in this interplay (10-13). We subsequent fibroblast modulation of the inflammatory reaction have used an in vitro co-culture model system to elucidate in non-malignant and malignant disease processes. differential effects between malignant keratinocytes and normal keratinocytes on fibroblast gene expression. Genes The stromal compartment of tumors plays a vital role in tumor important for the turnover of ECM are differentially progression. The notion of an aberrant microenvironment with regulated in this system so that malignant keratinocytes are activated connective tissue cells and a modified extracellular lacking, or possess weaker anti-fibrotic mechanisms than matrix (ECM) that sets the stage for malignant cells to normal keratinocytes. Using a gene-expression microarray proliferate, migrate and invade is now widely accepted (1-3). approach, we identified activation of a group of genes This aberrant, activated connective tissue microenvironment involved in the innate immune system, mainly represented may form in areas of chronic inflammation, elicited by various by differential activation of the gene for pentraxin 3 (PTX3), tissue-damaging stimuli, and is further modified by but also of other genes related to an inflammatory response, interactions between malignant and stromal cells. e.g. chemokine (C-X-C motif) ligand 12 and tumor necrosis Ever since the time of Virchow, inflammation has been factor alpha-induced protein 6 (14). recognized as a risk factor for the establishment of PTX3 is a member of the pentraxin superfamily which also uncontrolled malignant growth (4-7). Chronic inflammation includes C-reactive protein and serum amyloid P. Those are drives transformation of the ECM towards a fibrotic, scar- well known acute-phase proteins and belong to the short pentraxins (15), while PTX3, a 45-kDa glycoprotein, belongs to the long pentraxins (16). PTX3 is highly conserved in evolution among many species (17) and is produced by a Correspondence to: Daniel Nowinski, MD, Ph.D., Department of large number of cell types and tissues, in particular by innate Surgical Sciences, Plastic Surgery, Uppsala University, 751 85 immunity cells, e.g. mononuclear phagocytes, dendritic cells, Uppsala, Sweden. E-mail: [email protected] fibroblasts, and endothelial cells (15) in response to primary Key Words: Co-culture, innate response, pentraxin 3, interleukin-1 inflammatory signals (e.g. tumor necrosis factor-alpha alpha, tumor stroma. (TNFα), IL1β) and Toll-like receptor (TLR) engagement (18). 0250-7005/2016 $2.00+.40 2131 ANTICANCER RESEARCH 36: 2131-2138 (2016) It plays a protective role by interacting with the complement collagenase and subcultured in DMEM with 10% bovine calf serum system and facilitating the clearance of foreign material from (HyClone) and 50 μg/ml gentamicin. Subconfluent cells were the circulation. IL1α is a well-known and strong inducer of washed with phosphate-buffered saline (PBS) and detached with trypsin. Cells in passage 1-5 were used for the experiments. pentraxin. However, the role of pentraxin in the dynamic, multifactorial paracrine interplay between keratinocytes and Co-culture. Fibroblasts were cultured in collagen gels. Briefly, a cold fibroblasts has not been previously reported. solution of 1.6 ml collagen type I (Vitrogen, Cohesion, Palo Alto, CA, In the present study, we wanted to further investigate the USA), 0.15 ml (10×) Hank’s balanced salt solution and 0.15 ml fetal hypothesis that the effect of both malignant and normal bovine serum with or without fibroblasts (2×105/well) was adjusted to keratinocytes on fibroblasts has several characteristics of an pH 7.4 with 5 M NaOH and added to 6-well plates. After innate response. To this end, we measured the effects of polymerization at 37˚C, 2 ml DMEM with 10% bovine calf serum keratinocytes on the expression and release of PTX3 by (HyClone) was added to each well. NOKs, or malignant keratinocytes at passage 16 or 17, were seeded in Falcon polyurethane cell culture fibroblasts in three-dimensional keratinocyte-fibroblast co- inserts (4.0 μm pore diameter) pre-incubated with a mixture of 10 cultures. As IL1 is one of the primary inflammatory signals, μg/ml bovine plasma fibronectin (Gibco BRL/Life Technology, and together with IL6 it is the main regulator of the Paisley, UK), 30 μg/ml bovine collagen (Vitrogen) and 10 μg/ml production of acute-phase proteins (19), its role in the bovine serum albumin (Sigma) for 2 h at 37˚C. NOK and malignant present observation was also assessed. oral keratinocytes were seeded in inserts, both in DMEM: HAM’s F12 (4:1) supplemented with 5 μg/ml Zn-free insulin (Sigma Materials and Methods Chemical Co.), 2 nM 3,3’,5-triido-D-thyronine (Sigma), 0.4 μg/ml hydrocortisone (Sigma), 0.1 nM cholera toxin (Sigma), 10 ng/ml EGF Cells and reagents. Approval from the local Ethics Committee (Austral Biologicals), 24 μg/ml adenine, 10% fetal bovine serum (Uppsala University) was obtained (Dnr 2005:332). This approval (HyClone), and 50 μg/ml gentamicin. After 24 h, the medium was entailed written informed consent and written patient information. changed in wells and in inserts to 2 ml DMEM/Ham’s F12 (4:1) Three different head and neck squamous cell carcinoma (SCC) (UT- supplemented with 0.5% fetal calf serum in each. Inserts and wells SCC-30, UT-SCC-81, UT-SCC-87) cell lines established at the with collagen gels were combined and propagated as co-cultures for 5 University of Turku were used in this study. The cell lines were an additional 48 h. As control, 1.5×10 fibroblasts were seeded in established from previously untreated primary tumor of the mobile inserts instead of keratinocytes. Experiments were performed with tongue. The donor of UT-SCC-30 was a 77-year-old female with different seeding densities of NOK and malignant keratinocytes, and T3N1M0 grade 1 SCC; UT-SCC-81 was established from a 48-year- the number of cells after 48 h was assessed with a cell-counter (Z2 old male patient presenting with a T2N0M0 grade 1 SCC; and the Cell and Particle Counter; Beckman Coulter AB, Pasadena, CA, donor of UT-SCC-87 was a 29-year-old female with T3N1M0 grade 1 USA). The reason for the different seeding numbers for normal and SCC. None of the donors were smokers. The methods used to establish malignant cells was to compensate for observed higher proliferation and characterize the cell lines have been described previously (20, 21) of malignant cells. After titration with different seeding densities, 5 5 Normal oral keratinocytes (NOK) were obtained from three patients 3.0×10 for NOK and 1.6×10 for malignant cells were chosen for undergoing minor surgery at the Department of Oral and Maxillofacial the experiments. In this way, the average cell number at the 6 6 Surgery: from the gingiva of a 28-year-old male; from the oral mucosa termination of co-cultures was 0.45×10 for NOK and 0.43×10 for of a 31-year-old male; and from the same location from a 51-year-old malignant cells, and a cell-density of about 80% was reached in all male (NOK1, NOK2, NOK3). All three patients were previously samples at the end of the co-culture experiments. healthy without ongoing infections and were non-smokers. Human primary dermal fibroblasts were obtained from patients undergoing RNA extraction. Collagen gels with cells were dissolved and RNA reconstructive breast surgery at the Department of Plastic Surgery. was extracted using a modified version of the one-step Fibroblasts from one healthy female were used for the experiments. phenol–chloroform method (23). Shortly thereafter, gels were The recombinant IL-receptor antagonist (rIL1Ra) anakinra dissolved in TRIzol (Thermo Fisher, Waltham, MA, USA) under (Kineret®) came from Amgen (Breda, Holland). extensive vortexing for 60 s, and then mixed with chloroform (1:1 v/v, TRIzol:chloroform).
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