RADIATION & RISK
Bulletin of the National Radiation and Epidemiological Registry
since 1992
About the Journal : 2017 : vol. 26, No. 3 : Radiosensitising effect of mesenchymal stem cells on sarcoma M-1 under local gamma-irradiation

Radiosensitising effect of mesenchymal stem cells on sarcoma M-1 under local gamma-irradiation

«Radiation and Risk», 2017, vol. 26, No. 3, pp.100-115

DOI: 10.21870/0131-3878-2017-26-3-100-115

Authors

Sevankaeva L.E. – Senior Researcher. A. Tsyb MRRC, Obninsk.
Yuzhakov V.V. – Head of Lab., C.Sc., Med. A. Tsyb MRRC, Obninsk. Contacts: 4 Korolev str., Obninsk, Kaluga region, Russia, 249036. Tel.: +7 (903) 635 79 71; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it. .
Konoplyannikov A.G. – Head of Dep., D.Sc., Biol., Prof. A. Tsyb MRRC, Obninsk.
Romanko Yu.S. – Head of Dep., MD, Prof. A. Tsyb MRRC, Obninsk.
Bandurko L.N. – Lead. Researcher, C.Sc., Med. A. Tsyb MRRC, Obninsk.
Fomina N.K. – Senior Researcher, C.Sc., Biol. A. Tsyb MRRC, Obninsk.
Ingel I.E. – Senior Researcher, C.Sc., Biol. A. Tsyb MRRC, Obninsk.
Yakovleva N.D. – Lead. Researcher, C.Sc., Biol. A. Tsyb MRRC, Obninsk.
Tsyganova M.G. – Researcher. A. Tsyb MRRC, Obninsk.
Konoplyannikov M.A. – Head of Lab., C.Sc., Biol. FSCC FMBA of Russia, Moscow.

Abstract

Very little information about effects of mesenchymal stem cells on malignant neoplasms radiosensitivity is available. The research aims to study impact of human mesenchymal stem cells (hMSC) on survival of tumor-bearing animals, tumor growth rate and morphology following single local irradiation of sarcoma M-1 by 60Co γ-rays with dose of 30 Gy. Immunostaining technique for PCNA, CD31, pimonidazole and computer-assisted analysis of microscopic images are used to detect the effects. The results demonstrate activation of angiogenesis in tumor growth zones, increase in concentration of proliferating tumor cells in the neoplasm parenchyma, twofold reduction of hypoxic cells fraction following hMSCs transplantation. Quantitative analysis of impact of transplanted mesenchymal stem cells and local irradiation of the tumor identifies more pronounced radiation inactivation of tumor cells. In post-radiation period the growth rate of irradiated tumor cells reduces by 1.8 times, and cumulative survival fraction of tumor-bearing rats increases by 31%, as compared with the gamma-irradiated stem cells free animals with M-1 sarcoma. The results of research provide opportunity to identify and document radiosensitizing effect of hMSC administered prior to local irradiation of transplantable connective tissue tumor for the first time. There are reasons to suppose that increased radiosensitivity of sarcoma M-1 is caused by reduction of the most radioresistant hypoxic cells fraction in the irradiated area.

Key words
Mesenchymal stem cells, γ-radiation, М-1 sarcoma, hypoxia, radiosensitization, angiogenesis, immunohistochemistry, PCNA, CD31, pimonidazole.

References

1. Baskar R., Lee K.A., Yeo R., Yeoh K.W. Cancer and radiation therapy: current advances and future directions. Int. J. Med. Sci., 2012, vol. 9, no. 3, pp. 193-199.

2. Maier P., Hartmann L., Wenz F., Herskind C. Cellular pathways in response to ionizing radiation and their targetability for tumor radiosensitization. Int. J. Mol. Sci., 2016, vol. 17, no. 1, pii: E102. doi: 10.3390/ijms17010102.

3. Kim B.M., Hong Y., Lee S., Liu P., Lim J.H., Lee Y.H., Lee T.H., Chang K.T., Hong Y. Therapeutic implications for overcoming radiation resistance in cancer therapy. Int. J. Mol. Sci., 2015, vol. 16, no. 11, pp. 26880-26913.

4. Hong B.J., Kim J., Jeong H., Bok S., Kim Y.E., Ahn G.O. Tumor hypoxia and reoxygenation: the yin and yang for radiotherapy. Radiat. Oncol. J., 2016, vol. 34, no. 4, pp. 239-249.

5. Horsman M.R., Overgaard J. The impact of hypoxia and its modification of the outcome of radiotherapy. J. Radiat. Res., 2016, vol. 57, Suppl. 1, pp. i90-i98.

6. Horsman M.R., Vaupel P. Pathophysiological basis for the formation of the tumor microenvironment. Front. Oncol., 2016, vol. 6, pp. 1-11.

7. Wigerup C., Påhlman S., Bexell D. Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmac. Ther., 2016, vol. 164, pp. 152-169.

8. Son B., Lee S., Youn H., Kim E., Kim W., Youn B. The role of tumor microenvironment in therapeutic resistance. Oncotarget, 2017, vol. 8, no. 3, pp. 3933-3945.

9. Harada H. How can we overcome tumor hypoxia in radiation therapy? J. Radiat. Res., 2011, vol. 52, no. 5, pp. 545-556.

10. Phillips R.M. Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs. Cancer Chemother. Pharmacol., 2016, vol. 77, no. 3, pp. 441-457.

11. Shinohara E.T., Maity A. Increasing sensitivity to radiotherapy and chemotherapy by using novel biological agents that alter the tumor microenvironment. Curr. Mol. Med., 2009, vol. 9, no. 9, pp. 1034-1045.

12. Suzuki K., Sun R., Origuchi M., Kanehira M., Takahata T., Itoh J., Umezawa A., Kijima H., Fukuda S., Saijo Y. Mesenchymal stromal cells promote tumor growth through the enhancement of neovascularization. Mol. Med., 2011, vol. 17, no. 7-8, pp. 579-587.

13. Yuzhakov V.V., Sevan'kaeva L.E., Konoplyannikov A.G., Bandurko L.N., Konoplyannikov M.A., Ingel I.E., Fomina N.K., Tsyganova M.G., Kal'sina S.Sh. A morphofunctional study of mesenchymal stem cells’ effects on sarcoma M-1. Molekulyarnaya meditsina – Molecular Medicine, 2015, no. 1, pp. 39-45. (In Russian).

14. Farias V. de A., O'Valle F., Lerma B.A., Ruiz de Almodóvar C., López-Peñalver J.J., Nieto A., Santos A., Fernández B.I., Guerra-Librero A., Ruiz-Ruiz M.C., Guirado D., Schmidt T., Oliver F.J., Ruiz de Almodóvar J.M. Human mesenchymal stem cells enhance the systemic effects of radiotherapy. Oncotarget, 2015, vol. 6, no. 31, pp. 31164-31180.

15. Iuzhakov V.V., Sevan'kaeva L.E., Ul'ianenko S.E., Iakovleva N.D., Kuznetsova M.N., Tsyganova M.G., Fomina N.K., Ingel' I.E., Lychagin A.A. The effectiveness of fractionated exposure of sarcoma M-1 to gamma-radiation and fast neutrons. Radiacionnaja biologija. Radiojekologija – Radiation Biology. Radioecology, 2013, vol. 53, no. 3, pp. 267-79. (In Russian).

16. Tsyb A.F., Konoplaynnikov A.G., Kolesnikova A.I., Pavlov V.V. Production of cell cultures from mesenchymal stem cells of the human bone marrow and their use in medicine. Vestnik RAMN – Bulletin of the Russian Academy of Medical Sciences, 2004, vol. 59, no. 9, pp. 71-76. (In Russian).

17. Yuzhakov V.V., Burmistrova N.V., Fomina N.K., Bandurko L.N., Sevankaeva L.E., Starovoytova A.V., Yakovleva N.D., Tsyganova M.G., Ingel I.E., Ostroverhov P.V., Kaplan M.A., Grin M.A., Majouga A.G., Mironov A.F., Galkin V.N., Romanko Yu.S. Morphofunctional characteristics of rat sarcoma M-1 after photodynamic therapy with the bacteriochlorophyll a derivative. Biomedical Photonics, 2016, vol. 5, no 4, pp. 4-14. (In Russian).

18. Harris A.L. Hypoxia – a key regulatory factor in tumour growth. Nat. Rev. Cancer, 2002, vol. 2, no. 1, pp. 38-47.

19. Ogawa K., Boucher Y., Kashiwagi S., Fukumura D., Chen D., Gerweck L.E. Influence of tumor cell and stroma sensitivity on tumor response to radiation. Cancer Res., 2007, vol. 67, pp. 4016-4021.

20. Ahn G., Brown J.M. Influence of bone marrow-derived hematopoietic cells on the tumor response to radio-therapy. Cell Cycle, 2009, vol. 8, no. 7, pp. 970-976.

21. Lazennec G., Jorgensen C. Concise review: adult multipotent stromal cells and cancer: risk or benefit? Stem Cells, 2008, vol. 26, no. 6, pp. 1387-1394.

22. Reagan M.R, Kaplan D.L. Concise review: mesenchymal stem cell tumor-homing: detection methods in disease model systems. Stem Cells, 2011, vol. 29, no. 6, pp. 920-927.

23. Spaeth E.L., Dembinski J.L., Sasser A.K., Watson K., Klopp A., Hall B., Andreeff M., Marini F. Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS ONE, 2009, vol. 4, no. 4, pp. e4992. doi: 10.1371/journal.pone.0004992.

24. Roorda B.D., ter Elst A., Kamps W.A., de Bont E.S. Bone marrow-derived cells and tumor growth: Contribution of bone marrow-derived cells to tumor micro-environments with special focus on mesenchymal stem cells. Crit. Rev. Oncol. Hematol., 2009, vol. 69, no. 3. pp. 187-198.

25. Khakoo A.Y., Pati S., Anderson S.A., Reid W., Elshal M.F., Rovira I.I., Nguyen A.T., Malide D., Combs C.A., Hall G., Zhang J., Raffeld M., Rogers T.B., Stetler-Stevenson W., Frank J.A., Reitz M., Finkel T. Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi’s sarcoma. J. Exp. Med., 2006, vol. 203, no. 5, pp. 1235-1247.

26. Lu Y.R., Yuan Y., Wang X.J., Wei L.L., Chen Y.N., Cong C., Li S.F., Long D., Tan W.D., Mao Y.Q., Zhang J., Li Y.P., Cheng J.Q. The growth inhibitory effect of mesenchymal stem cells on tumor cells in vitro and in vivo. Cancer Biol. Ther., 2008, vol. 7, no. 2, pp. 245-251.

27. Ganta C., Chiyo D., Ayuzawa R., Rachakatla R., Pyle M., Andrews G., Weiss M., Tamura M., Troyer D. Rat umbilical cord stem cells completely abolish rat mammary carcinomas with no evidence of metastasis or recurrence 100 days post-tumor cell inoculation. Cancer Res., 2009, vol. 69, no. 5, pp. 1815-1820.

28. Nicolay N.H., Lopez-Perez R., Saffrich R., Huber P.E. Radio-resistant mesenchymal stem cells: mechanisms of resistance and potential implications for the clinic. Oncotarget, 2015, vol. 6, no. 23, pp. 19366-19380.

Full-text article (in Russian)