Matrix metalloproteinases 2 and 9 activity and tumor-associated macrophages in human gastric cancer: correlation with metastasis

Mamontova L.A.1, Gumenyuk L.D.1, Merentsev S.P.2, Ganusevich I.I.3

L.A. Mamontova1, L.D. Gumenyuk1, S.P. Merentsev2, I.I. Ganusevich1

1R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv, Ukraine 

2City Clinical Oncological Center, Kyiv, Ukraine

mamontova.lesya@bk.ru, osion@onconet.kiev.ua

Introduction: Matrix metalloproteinases-2 and 9 (MMP-2 and -9) participate in the degradation of extracellular matrix (ECM) in tumor that results in the invasion, neoangiogenesis and metastasis. It is also known that tumor-associated macrophages (TAM) are important source of MMPs. Aim: To study the interrelationship between TAM number (CD68-positive cells) and concentration of MMP-2 and -9 active forms in tumor tissue as well as their link with clinicopathologic characteristics, metastasis into lymph node (LN) and survival of patients with gastric cancer (GC). Material and Methods: 112 resected specimens of primary gastric cancer were used. CD68 (tumor-associated macrophages) expression was evaluated using immunohistochemistry, and MMP-2 and MMP-9 activity, zymography. Statistical analysis was conducted using Spearmans’s test, Kaplan — Meier survival analysis, log-rank test and Cox proportional hazards model. All patients were thoroughly informed about the study, which was approved by the local Ethics Committee. Results: It was shown that TAM number in GC categorized as N1–2 and Mwas significantly higher than that in GC categorized as Nand M0 (< 0.05). Correlation of concentration of MMPs active forms in GC categorized as N0 and N1–2 was not statistically significant. At the same time MMP-2 activity was higher by 1.5-fold in tumors categorized as N1 in comparison with those in tumors categorized as N0 (< 0.05). Moreover, the inverse correlation between tumor concentration of MMP-2 active form and M category was shown: concentration of MMP-2 active form in tumor was higher by 2-fold in patients without distant metastasis (< 0.05). The positive correlation between TAM number and tumor concentration of active form of both MMP-2 and MMP-9 was observed (rho = 0.4 and rho = 0.51, respectively; < 0.05). Overall survival (OS) of patients with concentration of active form of MMP-2 (< 2 μg/g) was significantly better than that in patients with higher activity of MMP-2 in tumor (p=0.004). It was also shown that risk of unfavorable outcome increased by more than a factor of 3.5 (hazard ratio 3.8, (95% CI 0.78–8.2; < 0.05) in patients with high concentration of active MMP-2 in tumor. OS of patients with concentration of active form of MMP-9 (< 4.5 μg/g) was also significantly better than that in patients with higher activity of MMP-9 in tumor (p=0.015). Hazard ratio for patients with MMP-9 activity of tumor > 4.5 μg/g (HR 4.7, 95% CI 0.83–7.7; p<0.05) was significantly higher than that for patients with MMP-9 activity < 4.5 μg/g. The survival rate of patients with high number of TAM in tumor tissue (number of CD68-positive cells > 23%) was significantly lower than that of those with a low TAM number (= 0.003). Risk of unfavorable outcome in patients with TAM number higher than the median value (> 23%) increased by more than a factor of 2 (HR=2.4; 95% CI 0.86–7.25; < 0.05). Conclusion: It was suggested that TAM number and concentration of active form of MMP-2 and MMP-9 in gastric cancer may be used to the disease prognosis.

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