Shtabinskaya T.T., Bodnar M.

Grodno State Medical University, Belarus

PROGNOSTIC SIGNIFICANCE OF MATRIX METALLOPROTEINASEs EXPRESSION
IN COLON ADENOCARCINOMA
WITH SYNCHRONOUS HEMATOGENIC METASTASES

The family of matrix metalloproteinases (MMP) includes about 28 representatives of several classes (collagenase, gelatinase and stromelysins), but only gelatinases (MMP-2 and MMP-9) are capable of hydrolyzing the basic structural protein of the basal membrane - type IV collagen - and participate in the invasive and metastatic potential of tumors [1-3]. MMPs are involved in another mechanism of neoangiogenesis, vascular mimicry, during which tumor cells are able to form communicating channels between the islands of neoplastic cells [4]. These processes do not exclude each other, moreover, in many cases are related to each other, coexisting in both physiological and pathological neovascularization.

Purpose: to assess the expression of matrix metalloproteinases in colon adenocarcinoma, depending on the presence of synchronous hematogenous metastases and its significance for predicting the course of the disease.

Materials and methods. Criteria for inclusion in the study: adenocarcinomas of different degrees of differentiation. Exclusion criteria from the study: primary-multiple cancers and neoplasms that have the histological structure of the mucosa, micropapillary adenocarcinoma, kribroformnoy comedom carcinoma, ring-cell, squamous and undifferentiated cancer.

The significance of MMP expression in colon adenocarcinoma for the prognosis of the adjusted disease-free survival was established by a prospective longitudinal study of 72 tumors verified and removed in 29 men (40.3%) and 43 (59.7%) women. The age of patients ranged from 37.3 to 82.8 years. The median age at the time of surgery was 65.06 (60.42-72.86) years. The duration of follow-up was from 1 to 180 months.

The immunohistochemical study was performed using mouse monoclonal antibodies to MMP-2 (NCL-MMP2-507, clone 17B11) and rabbit polyclonal antibodies to MMP-9 (Dako A0150) by a standard procedure.

A quantitative evaluation of the expression level was performed using the Aperio Image Scope program [5]. The total, parenchymal and stromal positivity of MMP in the tumor was calculated.

Statistical analysis was performed using STATISTICA 10.0 (SNAXAR207F394425FA-Q). Due to the fact that the distribution of quantitative parameters differed from normal (p <0.05), a comparative analysis was conducted using nonparametric statistics methods.

Results. In 12 (16.7%) patients from the study group, hematogenous metastases were found at the time of diagnosis. In 8 patients (11.1%) at the time of detection of the disease, both lymphogenous and hematogenous were determined (in the liver and lungs - 75% and 25%, respectively). Positivity levels of MMP-2, MMP-9 were determined in the parenchymal and stromal components of the tumor, as well as the overall level of positivity (Table 1).

Table 1. – MMPs expression depending on the hematogenous spread

Positivity of expression		Hematogenous spread		р
		рМ0	рМ1
MMP-2	Total	0,042 (0,024-0,080)	0,025 (0,018-0,059)	0,184
	Parenchymatous	0,027 (0,006-0,052)	0,012 (0,007-0,023)	0,216
	Stromal	0,046 (0,019-0,087	0,031 (0,017-0,093)	0,505
MMP-9	Total	0,573 (0,373-0,651)	0,517 (0,414-0,679)	0,948
	Parenchymatous	0,679 (0,462-0,803)	0,591 (0,520-0,836)	0,896
	Stromal	0,381 (0,258-0,483)	0,422 (0,182-0,542)	0,986

As can be seen from Table 1, the expression area of matrix metalloproteinases was higher in adenocarcinoma without synchronous metastases, but these differences were insignificant (p> 0.05). Also, there were no significant differences in the expression of the studied marker of angiogenesis, depending on the appearance of new metastases (p> 0.05).

The construction of a multifactor model for predicting the 5-year outcome depending on hematogenous distribution and the expression of MMPs was carried out using Cox regression by a direct step-by-step method. The grouping sign was the outcome of cancer at 5 years from the moment of surgery, as assessed by the adjusted disease-free survival. It has been established that only lymphogenous and hematogenous metastasis significantly affects the five-year survival rate.

 The values of the likelihood function, the statistical criteria of the model for each of the regression steps, the numerical values of the coefficients of independent variables and their characteristics are described in the previous article [6].

Conclusion. The levels of MMPs expression can not be used as an independent prognostic factor.

Literature:

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5. Штабинская, Т.Т. Прогностическое значение уровня экспрессии фактора роста эндотелия сосудов в колоректальном раке / Т.Т. Штабинская [и др.] // Научно-практический журнал УО «Гродненский государственный медицинский университет». – 2015. - № 3(51). – С. 64-69.

6. Shtabinskaya, T. T. Prognostic significance of endoglin expression in colon adenocarcinoma with synchronous metastases / T. T. Shtabinskaya, M. Bodnar // Научният потенциал на света – 2017: материали XIII Междунар. науч.-практ. конф., София, 15-22 Септември, 2017. – София, 2017. – P. 14-16.