Key VEGF signaling system components and matrix metalloproteinases in the diagnosis and prognosis of overall survival of patients with renal cell cancer

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Abstract

Background: Evaluation and search for new molecular markers of renal cell cancer, first of all, associated with angiogenic and invasive activity, continue to be highly relevant. In our previous publications, we have assessed the potential diagnostic value of matrix metalloproteinases (MMP) 2, 7, 8, and 9, their tissue inhibitor type 1 (TIMP1) and components of the VEGF signaling system in renal cell cancer. Aim: To assess the role of serum VEGF, VEGFR1, VEGFR2, MMP2, 7, 8, 9, and TIMP1 levels in renal cell patients as diagnostic and prognostic markers of overall survival. Materials and methods: 99 renal cell cancer patients (94 primary and 5 at progression) were recruited into the study. The control group included 97 healthy control blood donors. Ninety three (93) primary patients with renal cell cancer were followed for 1 to 45 (median, 26) months for assessment of their overall survival. Serum concentrations of the study proteins were measured by direct immunoenzyme analysis (Quantikine® ELISA kits, R&D Systems, США). Results: Serum VEGF, VEGFR1, VEGFR2, MMP7, MMP8, and TIMP1 levels in renal cell cancer patients are significantly higher than those in the control group. The diagnostic characteristics of the markers are considerably different, the most reliable marker with 84% sensitivity at 87.5% specificity being MMP7. VEGFR1, MMP7, MMP8, and TIMP1 were positively associated with disease stage and TNM indices. MMP7 and TIMP1 levels also increased with a higher tumor grade. MMP7 was found to be a significant unfavorable prognostic factor for overall survival: the 3-years survival in those with low (< 6.3 ng/ml) marker level amounted to 93%, whereas with high, 51% (p < 0.001). MMP7 prognostic value remained significant also in stage I renal cancer: after 3-years' follow-up, all patients with low MMP7 were alive, while survival of those with high marker levels was 72% (p=0.02). Increased serum MMP8 level (> 51 ng/ml) also had an unfavorable prognostic value in the whole renal cell cancer patient group, with 3-years' survival being 78 and 58% for low and high levels, respectively (p < 0.01). The components of VEGF signaling system, MMP2, MMP9, and TIMP1 had no significant prognostic values. Conclusion: MMP7 should be viewed as the most promising diagnostic and prognostic renal cell cancer marker. VEGF and its soluble receptors could be useful for monitoring of patients receiving anti-angiogenic treatments and prediction of their sensitivity to these agents.

About the authors

N. E. Kushlinskii

N.N. Blokhin National Medical Research Centre of Oncology

Author for correspondence.
Email: biochimia@yandex.ru
ORCID iD: 0000-0002-3898-4127

Nikolay E. Kushlinskii - MD, PhD, Professor, Member of Russian Academy of Sciences, Head of the Laboratory of Clinical Biochemistry.

24 Kashirskoe shosse, Moscow, 115478.

Tel.: +7 (499) 324 11 79.

Russian Federation

E. S. Gershtein

N.N. Blokhin National Medical Research Centre of Oncology

Email: esgershtein@gmail.com
ORCID iD: 0000-0002-3321-801X

Elena S. Gershtein - PhD, Doctor of Biol. Sci., Professor, Leading Research Fellow, Laboratory of Clinical Biochemistry.

24 Kashirskoe shosse, Moscow, 115478.

Russian Federation

A. V. Kolpakov

A.I. Yevdokimov Moscow State University of Medicine and Dentistry

Email: fake@neicon.ru

Andrey V. Kolpakov - MD, Urologist, Chair-Applicant of the Department of Urology.

20 Delegatskaya ul., Moscow, 127473.

Russian Federation

S. D. Bezhanova

N.N. Blokhin National Medical Research Centre of Oncology

Email: fake@neicon.ru
ORCID iD: 0000-0001-7336-9210

Svetlana D. Bezhanova - Postgraduate Student, Department of the Pathologic Anatomy and Molecular Genetic Diagnostics of the Tumors.

24 Kashirskoe shosse, Moscow, 115478.

Russian Federation

V. V. Mushtenko

A.I. Yevdokimov Moscow State University of Medicine and Dentistry

Email: fake@neicon.ru

Vladimir V. Mushtenko - MD, Urologist, ChairApplicant of the Department of Urology.

20 Delegatskaya ul., Moscow, 127473.

Russian Federation

E. A. Korotkova

N.N. Blokhin National Medical Research Centre of Oncology

Email: katinka-kor@ya.ru
ORCID iD: 0000-0002-2509-5232

Ekaterina A. Korotkova - PhD (in Biology), Senior Research Fellow, Laboratory of Clinical Biochemistry.

24 Kashirskoe shosse, Moscow, 115478.

Russian Federation

D. Yu. Pushkar

A.I. Yevdokimov Moscow State University of Medicine and Dentistry

Email: fake@neicon.ru

Dmitry Yu. Pushkar - MD, PhD, Professor, Member of Russian Academy of Sciences, Head of the Department of Urology.

20 Delegatskaya ul., Moscow, 127473.

Russian Federation

V. V. Bazaev

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru

Vladimir V. Bazaev - MD, PhD, Professor, Leading Research Fellow, Department of Urology.

61/2 Shchepkina ul., Moscow, 129110.

Russian Federation

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Copyright (c) 2020 Kushlinskii N.E., Gershtein E.S., Kolpakov A.V., Bezhanova S.D., Mushtenko V.V., Korotkova E.A., Pushkar D.Y., Bazaev V.V.

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