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. 2024 Jun 6;10(12):e32626.
doi: 10.1016/j.heliyon.2024.e32626. eCollection 2024 Jun 30.

Mitochondrial dysfunction significantly contributes to the sensitivity of tumor cells to anoikis and their metastatic potential

G I Solyanik  1 , D L Kolesnik  1 , I V Prokhorova  1 , O V Yurchenko  1 , O N Pyaskovskaya  1
Affiliations

Mitochondrial dysfunction significantly contributes to the sensitivity of tumor cells to anoikis and their metastatic potential

G I Solyanik et al. Heliyon. .

Abstract

It is well-known that the survival of metastatic cells during their dissemination plays an important role in metastasis. However, does this mean that the final result of the metastatic cascade (the volume of metastatic damage to distant organs and tissues) depends on, or at least correlates with, the degree of resistance to anoikis (distinctive hallmarks of metastatic cells)? This question remains open.The aim of the work was to study in vitro the changes in the survival rates, proliferative activity, oxidative stress, and glycolysis intensity during three days of anchorage-dependent and anchorage-independent growth of two Lewis lung carcinoma cell lines (LLC and LLC/R9) and compare these changes with the status of mitochondria and metastatic potential of the cells in vivo.

Methods: The number and volume of lung metastases were estimated for each cell line after intramuscular inoculation of the cells in C57Bl/6 mice. For the in vitro study, the cells were seeded on Petri dishes pretreated with poly-HEMA or untreated dishes and then allowed to grow for 3 days. Cell viability, cell cycle progression, the level of reactive oxygen species (ROS), glucose consumption and lactate production rates were investigated daily in both growth conditions. An electron microscopy study of intracellular structures was carried out.

Results: The study showed (as far as we know for the first time) a correlation between the metastatic potential of cells (determined in vivo) and their sensitivity to anoikis (assessed in vitro). The transition of LLC/R9 cells with an inherently defective mitochondrial system to the conditions of anchorage-independent growth was characterized by a decrease in survival, a slowdown in growth rates, an increase in both glucose consumption rate and intracellular ROS levels and manyfold lower metastatic potential, compared to highly metastatic LLC cells with the normal mitochondrial system.

Keywords: Anchorage-independent growth; Metastatic potential; Mitochondrial dysfunction.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Growth kinetics of LLC and LLC/R9 cells.
Fig. 2
Fig. 2
Pronounced polymorphism of LLC/R9 cells (b; the amount of magnification is 400) compared to LLC cells (a, the amount of magnification is 200).
Fig. 3
Fig. 3
Blood vessel (a) and manifestations of phagocytic activity (b) in LLC/R9 tumor (the amount of magnification is 400).
Fig. 4
Fig. 4
Growth kinetics of LLC (a) and LLC/R9 (b) cells during adhesive (white columns) and deadhesive (gray columns) growth. Note: * – the significant difference compared to the corresponding indices for adhesive growth conditions (p˂0.05).
Fig. 5
Fig. 5
Glucose (a, b) and lactate (c, d) levels in incubation medium during adhesive (white columns) and deadhesive (gray columns) growth of LLC (a, c) and LLC/R9 (b, d) cells. Note: * − differences are statistically significant compared to the corresponding value for adhesive growth (p < 0.05).
Fig. 6
Fig. 6
Changes in cell cycle progression of LLC (a, b) and LLC/R9 (c, d) cells during adhesive (a, c) and deadhesive (b, d) growth. Number of cells (in %) in G2/M phase (gray), S phase (white) and G1/G10 phase (black).
Fig. 7
Fig. 7
Changes in the number of apoptotic LLC (a) and LLC/R9 (b) cells during adhesive (white columns) and deadhesive (gray columns) growth. Note: * – the significant difference (p˂0.05) compared to the corresponding indices for adhesive growth.
Fig. 8
Fig. 8
The intracellular ROS levels in LLC (a) and LLC/R9 (b) cells during adhesive (white column) and deadhesive (gray column) growth (as a percentage of the corresponding ROS levels on the 1st day of adhesive growth). Note: * − the significant difference (p < 0.01) compared to the corresponding indices for adhesive growth.
Fig. 9
Fig. 9
Electron microscopic study of LLC (а) and LLC/R9 (b) cells during adhesive growth (х10000). Normal mitochondria (green arrows) and optically dense (yellow arrows).
Fig. 10
Fig. 10
LLC/R9 (a, b, c) and LLC (d, e) cells after 3 days of adhesive (a – for LLC/R9; d – for LLC) and deadhesive (b, c − for LLC/R9; e − for LLC) growth.
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