Imbalance between Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases Promotes Invasion and Metastasis of Head and Neck Squamous Cell Carcinoma.

BACKGROUND: The balance between collagenolysis and its inhibition is critical during extracellular matrix remodeling in head and neck squamous cell carcinoma (HNSCC). An imbalance between matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) plays a critical role in the development of tumor cell invasion and metastasis. The purpose of the study was to determine MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios in the sera of patients with HNSCC in relation to clinicopathological parameters. METHODS: Serum samples from seventy patients with HNSCC were measured by ELISA, before and 2 days after surgery. Forty healthy volunteers were selected as controls. RESULTS: Preoperative MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios were significantly higher in HNSCC patients than in the control group (p < 0.001 and p = 0.002, respectively). Changes in MMP-9 concentration and MMP9/TIMP-1 ratio after surgery had a negative correlation with lymph node involvement (r = - 0.35, p = 0.021 and r = - 0.37, p = 0.013), while changes in TIMP-1 had a positive one (r = 0.45, p = 0.006). Histological grade was positively correlated with the changes in circulating TIMP-2 level (r = 0.39, p = 0.021). No significant correlation was discovered between MMP-2/TIMP-2 ratio and tumor grade or any clinicopathological variables. CONCLUSIONS: Our results suggest that an imbalance between MMP-9 and TIMP-1 could play an important role in metastatic spread via lymphatic pathways of HNSCC cells. MMP-9/TIMP-1 ratio and, in particular, MMP-9, TIMP-1, TIMP-2, may represent suitable biomarkers for early diagnosis and detection of disease progression and dissemination in HNSCC patients.

Serum Level of Matrix Metalloproteinase-9 in Patients with Head and Neck Squamous Cell Carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is characterized by the upregulation of a large number of matrix metalloproteinases (MMPs). The aim of the study was to investigate the level of MMP-9 in the sera of HNSCC patients and its relationship to clinicopathological features. METHODS: Serum samples from sixty-five patients (56M/9F, 59.11 ± 9.02 years) with HNSCC were quantitatively measured by ELISA assay, before and two days after surgery. Forty healthy volunteers served as controls (29M/ 11F, 56.21 ± 12.13 years). RESULTS: Median serum concentrations of MMP-9 were consistently upregulated in HNSCC patients both preoperatively (1593.0 ng/mL, IQR: 833.0 - 1942.0 ng/mL) and postoperatively (1382.0 ng/mL, IQR: 778.6 - 2062.0 ng/mL) in comparison to healthy controls (291.3 ng/mL, IQR: 223.8 - 330.5 ng/mL) (p < 0.001). Pretreatment levels of MMP-9 were related to the size of primary tumor (p = 0.018) and lymph node involvement (p = 0.045). No statistically significant association was found between serum MMP-9 concentrations and clinical stage or degree of differentiation of the tumor cells. CONCLUSIONS: Serum MMP-9 level could be used as a diagnostic tool for early detection of HNSCC and for determining prognosis. Moreover, our results suggest that MMP-9 might be a good marker in evaluating the size of the primary tumor and lymph node involvement. Further studies are needed to show whether MMP-9 could serve as a marker for recurrence.

Investigation of Th1/Th2 cytokine profiles in patients with laryngo-pharyngeal, HPV-positive cancers.

The aim of this study was to reveal the relationships between the features of the primary tumour, the degree of tumour stage, the presence of human papillomaviruses (HPV) in blood and the severity of Th1/Th2 serum cytokine imbalance in patients with laryngo-pharyngeal cancer. The study was performed on 50 patients (47 men and 3 women), with age ranging from 40 to 83 years (the mean of the patients' ages was 58.4 ± 9.43 years, with a median of 60 years). A control group was represented by age-matched healthy patients (with no clinical diseases). The viral DNA was detected by PCR; the cytokine levels were determined by ELISA. A clear switch from cytokine Th1 to cytokine Th2 in cancer patients, low levels of IL-2 and IFNγ in advanced stages, as well as a positive correlation of increased levels of both IL-2 and IL-12 with the early stages of laryngo-pharyngeal cancer was observed. Loco-regional metastases were correlated with increased levels of IL-8 and IL-10 and drastic decrease of IFNγ. In advanced cancer stages, we found that the most affected were IL-2 and IFNγ correlated with increased levels of Th2 cytokines. Patients with HPV present in both primary tumours and blood showed increased values of IL-4:IL-2 ratio as compared with patients with HPV-positive primary tumours only, demonstrating the aggravation of the immunosuppressive state. The most important finding of our study is that for a correct evaluation of the Th1 to Th2 switch in cancer patients, it is necessary to establish not only the negative/positive correlations between different Th1 and Th2 type cytokines, but also the ratio between them. These parameters allowed us to state that the presence of HPV DNA in blood was associated with the most severe immunological imbalance that could potentially lead to a poor prognosis of these patients. Our findings encourage us to consider that the ratio between different Th1 and Th2 cytokines could represent a useful marker for clinical and pathological evaluation of cancer patients.