A Melanoma Transplanted in Nude Mice Has Both Host‐ and Tumor‐Derived Blood Vessel‐ and Nerve‐Like Structures

Nestin-expressing stem cells located in the bulge area of the hair follicle can give rise to multiple cell types. In the present study, we subcutaneously transplanted red fluorescent protein (RFP)-labeled SK-MEL-5 human melanoma cells into nestin-driven green fluorescent protein (ND-GFP)-nude mice. Nestin-GFP-positive cells differentiated into CD31-positive endothelial cells and αSMA-positive pericytes, and βIII-tubulin-positive neurons, forming blood vessel-like and nerve-like structures within the transplanted melanoma. Bevacizumab, a vascular endothelial growth factor (VEGF)-targeting monoclonal antibody, suppressed nestin-positive blood-vessel structures and nerve structures from forming within the tumor but did not significantly inhibit tumor growth. Due to bevacizumab treatment, blood-vessel-like and nerve-like structures expressing CD31, αSMA, and βIII tubulin formed without the expression of nestin in the transplanted melanoma but remained RFP-positive, suggesting that they trans-differentiated from melanoma cells. Relative mRNA expression of VEGFA also significantly decreased in the melanoma after bevacizumab treatment of the mice. In contrast, VEGFR2 and FGF6, markers that are related to blood vessels, significantly increased compared with the non-treated mice. In the bevacizumab-treated mice, mRNA expression of Tuj1, BDNF, and IGF1 markers related to nerves significantly increased within the melanoma. In the bevacizumab-treated mice, nestin expression was not detected, but RFP was maintained in the blood-vessel-like and nerve-like structures in the melanoma. Since nestin was not detected and RFP was maintained, it suggests these structures trans-differentiated from the melanoma cells. The present study suggests that both the host and cancer cells can differentiate into blood-vessel-like and nerve-like structures in the melanoma.