Clinicum

Oral tongue squamous cell carcinoma (OTSCC) has a high mortality rate and the incidence is rising worldwide. Despite advances in treatment, the disease lacks specific prognostic markers and treatment modality. The spreading of OTSCC is dependent on the tumor microenvironment and involves tumor-associated macrophages (TAMs). Although the presence of TAMs is associated with poor prognosis in OTSCC, the specific mechanisms underlying this are still unknown. The aim here was to investigate the effect of macrophages (Mfs) on HSC-3 tongue carcinoma cells and NF-kappaB activity. We polarized THP-1 cells to M1 (inflammatory), M2 (TAM-like) and R848 (imidazoquinoline-treated) type Mfs. We then investigated the effect of Mfs on HSC-3 cell migration and NF-kappaB activity, cytokine production and invasion using several different in vitro migration models, a human 3D tissue invasion model, antibody arrays, confocal microscopy, immunohistochemistry and a mouse invasion model. We found that in co-culture studies all types of Mfs fused with HSC-3 cells, a process which was partially due to efferocytosis. HSC-3 cells induced expression of epidermal growth factor and transforming growth factor-beta in co-cultures with M2 Mfs. Direct cell-cell contact between M2 Mfs and HSC-3 cells induced migration and invasion of HSC-3 cells while M1 Mfs reduced HSC-3 cell invasion. M2 Mfs had an excess of NF-kappaB p50 subunit and a lack of p65 subunits both in the presence and absence of HSC-3 cells, indicating dysregulation and pro-tumorigenic NF-kappaB activation. TAM-like cells were abundantly present in close vicinity to carcinoma cells in OTSCC patient samples. We conclude that M2 Mfs/TAMs have an important role in OTSCC regulating adhesion, migration, invasion and cytokine production of carcinoma cells favouring tumor growth. These results PLOS ONE |

Maisi P, Prikk K, Sepper R, Pirilä E, Salo T, Hietanen J, Sorsa T. Soluble membrane-type 1 matrix metalloproteinase (MT1-MMP) and gelatinase A (MMP-2) in induced sputum and bronchoalveolar lavage fluid of human bronchial asthma and bronchiectasis. APMIS 2002;110:771-82.

Matrix metalloproteinases (MMPs), especially collagenase-2 (MMP-8), are key mediators of irreversible tissue destruction associated with periodontitis and peri-implantitis. MMP-8 is known to exist in elevated amounts and in active form in the gingival crevicular fluid (GCF) and peri-implant sulcular fluid (PISF) from progressing periodontitis and peri-implantitis lesions and sites, respectively. (Sorsa et al. Ann. N.Y. Acad. Sci. 737: 112-131 [1994]; Teronen et al. J. Dent. Res. 76: 1529-1537 [1997]). We have developed monoclonal antibodies to MMP-8 (Hanemaaijer et al. J. Biol. Chem. 272: 31504-31509 [1997]) that can be used in a chair-side dipstick test to monitor the course and treatment of periodontitis and peri-implantitis. Monoclonal and polyclonal antibody tests for MMP-8 coincided with the classical functional collagenase activity test from GCF and PISF (Sorsa et al. J. Periodont. Res. 22: 386-393 [1988]) in periodontal and peri-implant health and disease. In future a chair-side functional and/or immunological MMP-test can be useful to diagnose and monitor periodontal and peri-implant disease and health.

Regional lymph node (LN) metastasis in oral cancer patients is the most significant grave prognostic factor. We evaluated the relationship between clinical outcomes and different histopathological changes in tumornegative LNs (LN0) selected from neck dissections without metastatic disease (pN0). A total of 435 LN0 selected from pN0 neck dissections (up to three nodes in each level) were scored for histopathological parameters of LN areas, capsule thickness, subcapsular and medullary sinus ectasia, lobular architecture and percent of cortical reactive follicles. These were compared to 328 LN0 selected from neck dissections with metastases (pN?) after exclusion of metastatic LNs. Data were presented by maximum scores of each parameter in I-III (close) and in IV-V (distant) levels. Limited data from level V and regression analyses inferred that the values in level IV represented the worst changes for most patients. Cox proportional hazard regression on each parameter in close and distant levels demonstrated that capsule thickness, number of lobules and percent of reactive follicles were significantly associated with time to death from disease. The higher the change in distant levels, the shorter the time to death, while the higher the change in close levels (given a stable change in distant levels), the longer the time to death. After adjustment for gender, age and location, only the effect of the percent of reactive follicles retained their significant effect. Logistic regression of metastases demonstrated that all parameters except for percent of reactive follicles were significantly associated with risk of metastases, with differences between close and distant levels similar to those found for time to death. After adjustment for gender, age and location, only the area and number of lobes retained their significance. The findings of this study suggested that selective histopathological changes in tumor-negative LNs in metastatic-free patients provide new valuable prognostic parameters.

Salivary gland tumors (SGTs) of epithelial origin are relatively rare, and worldwide reports show considerable variations in their epidemiology. The aim of this study was to examine, for the first time, the records of SGTs from two very distant geographical locations, Finland (two medical centers) and Israel (one medical center) between 1999 and 2008, based exclusively on the 2005 WHO classification of head and neck tumors, and to compare those data to the other available (single-center) studies that used the same classification. A total of 2,218 benign and malignant tumors diagnosed in the three centers were analyzed. Differences in classification of the tumors were found between the two geographical locations as well as between the two centers from Finland. There was a higher ratio of benign-to-malignant SGTs in the Finnish centers (5.4:1 and 7:1) compared to the Israeli center (2:1), a higher frequency of tumors of minor salivary glands in the Israeli center (34%) than in the Finnish centers (4 and 11%), and a higher frequency of malignant SGTs in the minor salivary glands in Israel (64.5%) than in Finland (10.9 and 27%). The diversity of these multicenter data are compatible with reports from different parts of the world. We conclude that conducting epidemiologic surveys based on the latest WHO classification provides clinicopathologic correlations on SGTs that seem to be characteristic even in small geographical regions.

Tissue destruction during periodontitis is believed to be primarily brought about by leukocyte proteinases. We postulate that oral spirochetes cause discharge of polymorphonuclear leukocyte (PMN) lysosomal enzymes. Effects of Treponema denticola 53-kDa outer membrane protein, lipopolysaccharide (LPS), and peptidoglycan on degranulation of matrix metalloproteinases (MMP)-8 (collagenase) and -9 (gelatinase), cathepsin G, and elastase by human peripheral blood PMNs were studied by specific enzyme assays and Western blot analysis. T. denticola 53-kDa outer membrane protein was found to be a particularly efficient inducer of MMP-8 release. The induction was comparable with that of phorbol myristate acetate, a known inducer of PMN specific granule discharge. All of the treponemal substances, most notably the 53-kDa protein and LPS, induced release of MMP-9, a component of C-type granules. Both collagenase and gelatinase released from PMNs were mostly in active forms. Release of cathepsin G and elastase was also observed with the 53-kDa protein treatment. The other T. denticola substances did not induce release of these serine proteinases. Lactate dehydrogenase was not released from PMNs by the treatments, indicating that the degranulation was specific and not caused by toxic effects of the substances. This was confirmed by transmission electron microscopy of PMNs treated with the 53-kDa protein that showed rapid vacuole formation and cell shape changes but no disintegration of the cells. Thus, T. denticola may participate in the PMN-dependent extracellular matrix degradation during the course of periodontal inflammation by triggering the secretion and activation of matrix metalloproteinases.