O.N. Merkuryeva1, I.V. Babkina2, I.V. Bulycheva3, P.L. Prishchep4, O.M. Romantsova5, S.R. Varfolomeeva6, N.E. Kushlinskii7

1,2 A.I. Evdokimov Moscow State University of Medicine and Dentistry
of the Ministry of Health of Russia (Moscow, Russia)

3,7 N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia (Moscow, Russia)

4–6 Research Institute of Pediatric Oncology and Hematology
N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia (Moscow, Russia)

Formulation of the problem. Primary malignant tumors (sarcomas) of bones are characterized by a peak incidence in the pubertal period, high metastatic activity, low sensitivity to chemotherapy, and poor survival prognosis, which makes the search for promising diagnostic and prognostic markers, as well as predictors of metastasis, relevant. One of them is endostatin, a C-terminal fragment of type XVIII collagen capable of inhibiting angiogenesis.

Aim of the work – to analyze the diagnostic and prognostic significance of the serum level of endostatin in adolescents with bone sarcomas.

The study included 29 adolescents aged 15 to 18 years with a histologically confirmed diagnosis of a malignant bone neoplasm (osteosarcoma - 19, Ewing's sarcoma - 5, chondrosarcoma - 4, undifferentiated pleomorphic sarcoma - 1), who were examined and treated at the Research Institute of Oncology and Hematology of the Federal State Budgetary Institution N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia. The control group included 26 healthy donors of the appropriate age and sex. A statistically significant increase in the serum level of endostatin was found in children with bone sarcomas compared with the control group: median marker concentrations were 148.0 and 110.4 ng/ml, respectively (p<0.01). According to the results of the ROC analysis, the threshold value of endostatin was 120.1 ng/ml (the sensitivity and specificity of the method were 89.7% and 84.6%, respectively).

Evaluation of the complex influence of factors revealed a statistically significant decrease in overall survival in patients with bone sarcomas with an increase in the serum level of endostatin by 1 ng/ml by 1.02 times (p=0.03). Using the Cox proportional hazards model, it was shown that with a serum endostatin level above 135.8 ng / ml, after 5 years, the risk of death reaches 50%. There was no significant effect of the marker on metastatic-free survival.

Merkuryeva O.N., Babkina I.V., Bulycheva I.V., Prishchep P.L., Romantsova O.M., Varfolomeeva S.R., Kushlinskii N.E. Clinical and laboratory significance of endostatin in the blood serum of adolescents with bone sarcomas. Technologies of Living Systems. 2022. V. 19. № 4. Р. 24-32. DOI: https://doi.org/10.18127/j20700997-202204-02 (In Russian)

1. Choi J.H., Ro J.Y. The 2020 WHO Classification of Tumors of Bone: An Updated Review. Adv. Anat. Pathol. 2021. V. 28. № 3. P. 119–138.
2. Chernomaz I.S., Babkina I.V., Kuznetsov I.N., Bulycheva I.V., Aliyev M.D. Sravnitelnyy analiz tkanevykh ingibitorov matriksnykh metalloproteinaz pri zlokachestvennykh i pogranichnykh opukholyakh kostey. Tekhnologii zhivykh sistem. 2019. T. 16. № 4. S. 16–21.
   (in Russian).
3. Eyre R., Feltbower R.G, Mubwandarikwa E., Eden T.O.B., McNally R.J.Q. Epidemiology of bone tumors in children and young adults. Pediatr. Blood Cancer. 2009. V. 53. № 6. P. 941–952.
4. Rykov M.Yu., Polyakov V.G. (red.). Epidemiologiya zlokachestvennykh novoobrazovaniy u detey: osnovnyye pokazateli v 2011–2016 gg. M.: Pervyy MGMU im. I.M. Sechenova. 2017. (in Russian).
5. Liu Y., Huang N., Liao S., Rothzerg E., Yao F., Li Y. et al. Current research progress in targeted anti-angiogenesis therapy for osteosarcoma. Cell Prolif. 2021. V. 54. № 9. P. e13102.
6. Kempf-Bielack B., Bielack S.S., Jürgens H., Branscheid D., Berdel W.E., Exner G.E. et al. Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J. Clin. Oncol. 2005. V. 23. № 3. P. 559–568.
7. Goel S., Duda D. G., Xu L. Munn L.L., Boucher Y., Fukumura D. et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol. Rev. 2011. V. 91. № 3. P. 1071–1121.
8. O’Reilly M.S., Boehm T., Shing Y., Fukai N., Vasios G., Laneet W.S. et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997. V. 18. № 2. P. 277–285.
9. Ackley B.D., Crew J.R., Elamaa H., Pihlajaniemi T., Kuo C.J., Kramer J.M. The NC1/endostatin domain of Caenorhabditis elegans type XVIII collagen affects cell migration and axon guidance. J. Cell Biol. 2001. V. 152. № 6. P. 1219–1232.
10. Jiang W.G., Lu X.A., Shang B.Y., Fu Y., Zhang S.H., Zhou D. et al. Genetically engineered endostatin-lidamycin fusion proteins effectively inhibit tumor growth and metastasis. BMC Cancer. 2013. V. 13. P. 479.
11. Dou B., Chen T., Chu Q., Zhang G., Meng Z. The roles of metastasis-related proteins in the development of giant cell tumor of bone, osteosarcoma and Ewing’s sarcoma. Technol. Health Care. 2021. V. 29. S1. P. 91–101.
12. Koç M., Göçmen E., Kiliç M., Ozbay M., Oktem M., Tez M. Serum endostatin levels in gastric cancer patients: correlation with clinicopathological parameters. Hepatogastroenterology. 2006. V. 53. № 70. P. 616–618.
13. Kantola T., Väyrynen J.P., Klintrup K., Mäkelä J., Karppinen S.M., Pihlajaniemi T. et al. Serum endostatin levels are elevated in colorectal cancer and correlate with invasion and systemic inflammatory markers. Br. J. Cancer. 2014. V. 111. № 8. P. 1605–1613.
14. Folkman J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 1971. V. 285. № 21. P. 1182–1186.
15. Urunbaev S., Abdikarimov K.G., Polatova D.S. Serum factors of angiogenesis and the growth of fibroblasts in osteogenic sarcoma. Ann. Oncol. 2014. V. 25. Suppl. 4. iv494-iv510.
16. Chen Z., Chen Q.X., Hou Z.Y., Hu J., Cao Y.G. Clinical predictive value of serum angiogenic factor in patients with osteosarcoma. Asian Pac. J. Cancer Prev. 2012. V. 13. № 9. P. 4823–4826.