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. 2019 Jun 26;9(1):9280.
doi: 10.1038/s41598-019-45643-9.

Melanin presence inhibits melanoma cell spread in mice in a unique mechanical fashion

Michal Sarna  1 , Martyna Krzykawska-Serda  2 , Monika Jakubowska  2 , Andrzej Zadlo  2 , Krystyna Urbanska  2
Affiliations

Melanin presence inhibits melanoma cell spread in mice in a unique mechanical fashion

Michal Sarna et al. Sci Rep. .

Abstract

Melanoma is a highly aggressive cancer that exhibits metastasis to various critical organs. Unlike any other cancer cells, melanoma cells can synthesize melanin in large amounts, becoming heavily pigmented. Until now the role of melanin in melanoma, particularly the effect of melanin presence on the abilities of melanoma cells to spread and metastasize remains unknown. Recently, we have shown that melanin dramatically modified elastic properties of melanoma cells and inhibited the cells invasive abilities in vitro. Here, we inoculated human melanoma cells with different melanin content into nude mice and tested the hypothesis that cell elasticity is an important property of cancer cells for their efficient spread in vivo. The obtained results clearly showed that cells containing melanin were less capable to spread in mice than cells without the pigment. Our findings indicate that the presence of melanin inhibits melanoma metastasis, emphasizing possible clinical implications of such an inhibitory effect.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Determination of melanin in cell samples used in the experiments. EPR spectra of non-pigmented melanoma cells (A) and of pigmented melanoma cells with different levels of melanin pigmentation: moderately-pigmented (B) and heavily-pigmented (C) cells. The melanin EPR signal of pigmented cells is a superposition of pheomelanin signal (low field component) and eumelanin signal (high field component). Insets show images of cell pallets taken before freezing for EPR analysis. Note that the pellet of non-pigmented cells is white i.e. the cells are amelanotic, whereas the pellets of pigmented cells have a yellow-reddish color, which is typical for samples containing a mixture of pheomelanin and eumelanin.
Figure 2
Figure 2
Nanomechanical properties of melanoma cells used in this study. Box plots of the Young’s modulus values (A) and of maximum elastic deformation (B) for melanoma cells with different levels of melanin pigmentation and for non-pigmented melanoma cells. Square dots in box plots indicate the median values, whereas horizontal lines represent means. *Statistically significant vs. non-pigmented cells; **statistically significant vs. moderately-pigmented cells. For all values P < 0.0001.
Figure 3
Figure 3
Results obtained from in vivo experiments. Box plots of liver masses (A) taken from mice, which had inoculated melanoma cells with different levels of melanin pigmentation followed by box plot of the number of metastatic tumors (B) that were visible on the livers during autopsy. Square dots in box plots indicate the median values. *Statistically significant vs. non-pigmented cells (P < 0.05); **statistically significant vs. non-pigmented cells (P < 0.01).
Figure 4
Figure 4
Tissue samples with metastatic tumors isolated from mice. Liver samples isolated from mice, which had inoculated melanoma cells with different levels of melanin pigmentation: non-pigmented (A,D), moderately-pigmented (B,E) and heavily-pigmented (C,F). Upper row images show entire livers, whereas lower row images show histological samples of the livers. Arrows in the upper row images indicate the locations of metastatic colonies, whereas arrow heads in the lower row images indicate individual tumors. Note the morphology of the lobules of livers in the case of mice inoculated with non-pigmented melanoma cells is much more compact than in the case of mice inoculated with pigmented cells, indicating higher tissue density. Higher tissue compaction is indicated by chevrons. Scale pitch on the rulers represents one millimeter, whereas scale bars represent 200 μm.
Figure 5
Figure 5
Loss of melanin in dividing melanoma cells. EPR spectra of 106 heavily-pigmented SKMEL-188 cells immediately after melanin synthesis (A), and after 14 days of culture (B) under such conditions the cells did not synthesize melanin. As evident, no detectable melanin signal was observed in the cells after two weeks of culture indicating the loss of pigment by the cells due to consecutive cell division.
Figure 6
Figure 6
Growth curves of tumor progression for pigmented and non-pigmented SKMEL-188 cells in nude mice. Tumor volume (y axis) is plotted in logarithmic scale. To determine the volume of the tumors, the oblate spheroid approximation was used. In calculation of the spheroids volume, the two horizontal axes were averaged giving the equatorial diameter of a spheroid, whereas tumor height indicated half of the spheroid’s polar diameter.
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