Ultrastructural aspects of mitochondrial translocation in colorectal cancer as a possible pathway of tumorigenesis

Aim. To study the ultrastructural features of rectal cancer cells and to detect signs of mitochondrial translocation from the tumor to the resection line area with an assessment of the possibility of the formation of new malignant cells. Materials and methods. The present study encompassed the data obtained from 44 patients with an average age of 66 (58–73) years, who underwent surgical intervention for rectal cancer T2–3N0M0 with differentiation grade G2. A portion of the tumor specimen and intestinal tissue along the resection line were preserved in a formaldehyde-glutaraldehyde fixative solution. Standard methods of section preparation were employed. Sections were subsequently examined using a Jeol JEM-1011 electron microscope (JEOL Inc., Japan).

Results. The ultrastructure of rectal adenocarcinoma was characterized by a high density of arrangement and varying sizes and shapes of tumor cells with a large nucleus and deep invaginations of the nuclear membrane, as well as an accumulation of multiple mitochondria at one of the cell poles. The process of pinching off a cytoplasmic fragment, which was found to be densely packed with mitochondria, was observed. This phenomenon was subsequently identified as a mitochondriome. Following this observation, the mitochondria were found to have translocated into healthy intestinal tissues along the resection line. Electron diffraction data revealed the active movement of mitochondria in the form of small spheroids and mitovesicles along the boundaries of the multilayer structure of the rectal submucosa, and subsequent fusion into large organelles capable of implementing nuclear synthesis from transported mitochondrial and nuclear DNA. We observed the presence of individual nuclear structures in conjunction with groups of mitochondria, followed by the self-assembly of abnormal cells.

Conclusion. The ultrastructural analysis of rectal adenocarcinoma indicates the need for mitochondrial translocation to free up intracellular space and prevent the metabolic threat of reactive oxygen species (ROS) accumulation in tumor cells. It also points to the key role of mitochondria in initiating tumor energy and information transfer as leaders of these processes. This observation suggests the possibility of early recurrence and metastasis in rectal cancer cases.

1. Кит О.И., Геворкян Ю.А., Солдаткина Н.В., Гусарева М.А., Харагезов Д.А., Милакин А.Г. и др. Полный клинический ответ рака прямой кишки на химиолучевое лечение: Тактика. Вопросы онкологии. 2017;63(6):838–842. DOI: 10.37469/0507-3758-2017-63-6-838-842.

2. Luo M., Yang X., Chen N.N., Nizza E.C., Huang K. Drug resistance in colorectal cancer: an epigenetic review. Biochim. et Biophys. Acta (BBA) – Cancer Reviews. 2021;1876(2). DOI: 10.1016/j.bbcan.2021.188623.

3. Hossain M.S., Karunyawati H., Jairoon A.A., Urbi Z., Ooi D.J., John A. et al. Colorectal cancer: a review of carcinogenesis, global epidemiology, current challenges, risk factors, prevention and treatment strategies. Cancer Diseases. 2022;14(7). DOI: 10.3390/cancers14071732.

4. Кит О.И., Геворкян Ю.А., Солдаткина Н.В., Колесников В.Е., Бондаренко О.К., Дашков А.В. Современные хирургические стратегии лечения метастатического колоректального рака (обзор литературы). Южно-Российский онкологический журнал. 2024;5(3):102–110. DOI: 10.37748/2686-9039-2024-5-3-9.

5. Biller L.H., Schrag D. Diagnosis and treatment of metastatic colorectal cancer: a review. JAMA. 2021;325(7):669–685. DOI: 10.1001/jama.2021.0106.

6. Bonnay F., Veloso A., Steinmann V., Köcher T., Abdusselamoglu M.D., Bajaj S. et al. Oxidative metabolism drives immortalization of neural stem cells during tumorigenesis. Cell. 2020;182(6):1490–1507.e19. DOI: 10.1016/j.cell.2020.07.039.

7. Sessions D.T., Kashatus D.F. Mitochondrial dynamics in cancer stem cells. Cell Life Science. 2021;78(8):3803–3816. DOI: 10.1007/s00018-021-03773-2.

8. Франциянц Е.М., Нескубина И.В., Шейко Е.А. Митохондрии трансформированной клетки как мишень противоопухолевого воздействия. Исследования и практика в медицине. 2020;7(2):92–108. DOI: 10.17709/2409-22312020-7-2-9.

9. Chen W., Zhao H., Li Y. Mitochondrial dynamics in health and disease: mechanisms and potential targets. Signal Transl. Purpose Tam. 2023;8(1):333. DOI: 10.1038/s41392-023-01547.

10. Chan D.K. Mitochondrial dynamics and its involvement in disease. Annu. Rev. Pathol. 2020;15:235–259. DOI: 10.1146/annurev-pathmechdis-012419-032711.

11. Zhou Z., Fan W., Zong R., Tang Q. Mitochondrial unfolded protein reaction: a multitasking giant in the fight against human diseases. Aging Editorial. 2022;81:101702. DOI: 10.1016/j.arr.2022.101702.

12. Singh B., Modica-Napolitano J.S., Singh K.K. Defining the momiome: Promiscuous information transfer by mobile mitochondria and the mitochondrial genome. Semin. Cancer Biol. 2017;47:1–17. DOI: 10.1016/j.semcancer.2017.05.004.

13. Davis C.H., Kim K.Y., Bushong E.A., Mills E.A., Boassa D., Shih T. et al. Transcellular degradation of axonal mitochondria. Proc. Natl. Acad. Sci. USA. 2014;111(26):9633–9638. DOI: 10.1073/pnas.1404651111.

14. Giacomello M., Pyakurel A., Glitsu S., Scorrano L. Cell biology of mitochondrial membrane dynamics. Nat. Rev. Mol. Cell Biol. 2020;21(4):204–224. DOI: 10.1038/s41580-020-0210-7.

15. Kłos P., Dabravolski S.A. The role of mitochondria dysfunction in inflammatory bowel diseases and colorectal cancer. Int. J. Mol. Sci. 2021;22(21):11673. DOI: 10.3390/ijms222111673.

16. Wang S., Xiao W., Shan S., Jiang S., Chen M., Zhang W. et al. Multistep dynamics of mitochondrial fission and fusion in living cells. PLoS One. 2012;7(5):e19879. DOI: 10.1371/journal.pone.0019879.

17. Cunniff B., McKenzie A.J., Heintz N.H., Howe A.K. AMPK activity regulates trafficking of mitochondria to the leading edge during cell migration and matrix invasion. Mol. Biol. Cell. 2016;27:2662–2674. DOI: 10.1091/mbc.e16-05-0286.

18. Schuler M.-H., Lewandowska A., Di Caprio G., Skillern W., Upadhyayula S., Kirchhausen T. et al. Miro1-mediated mitochondrial positioning shapes intracellular energy gradients required for cell migration. Mol. Biol. Cell. 2017;28:2159–2169. DOI: 10.1091/mbc.e16-10-0741.

19. Lyamzaev K.G., Nepryakhina O.K., Saprunova V.B., Bakeeva L.E., Pletjushkina O.Y., Chernyak B. et al. Novel mechanism of elimination of malfunctioning mitochondria (mitoptosis): Formation of mitoptotic bodies and extrusion of mitochondrial material from the cell. Biochim. Biophys. Acta (BBA) Bioenerg. 2008;1777:817–825. DOI: 10.1016/j.bbabio.2008.03.027.

20. Nakajima A., Kurihara H., Yagita H., Okumura K., Nakano H. mitochondrial extrusion through the cytoplasmic vacuoles during cell death. J. Biol. Chem. 2008;283:24128–24135. DOI: 10.1074/jbc.M802996200.

21. Parone P.A., Da Cruz S., Tondera D., Mattenberger Y., James D.I., Maechler P. et al. Preventing mitochondrial fission impairs mitochondrial function and leads to loss of mitochondrial DNA. PLoS One. 2008;3(9):e3257. DOI: 10.1371/journal.pone.0003257.

22. Wu Z., Xiao S., Long J., Huang W., Yu F., Li S. Mitochondrial dynamics and biology of colorectal cancer: mechanisms and potential targets. Cell Commun. Signal. 2024;22(1):91. DOI: 10.1186/s12964-024-01490-4.