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Molecular Role(s) for Integrins in Human Melanoma Invasion

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Abstract

There are fundamental issues regarding the role of integrins in human disease which remain to be elucidated. Human cutaneous melanoma is an attractive model for studying integrin involvement in tumor progression because it generally follows a sequential series of definable stages. Furthermore, the most specific marker for the transition of cells from the more benign, non-metastatic radial growth phase stage to the more malignant, metastatically competent vertical growth phase stage is associated with the onset of αvβ3 integrin expression and function. This same pattern, however, does not hold true for human ocular/uveal melanomas which do not progress through these stages, but preferentially metastasize to the liver by dissemination of the cells via a direct hematogenous pathway. It is also unclear whether the αvβ3 integrin is functionally involved in uveal melanoma metastasis or not. Our results show that perturbation of the αvβ3 integrin on moderately invasive A375M human cutaneous melanoma cells with either specific antibodies or ligands results in an increase in the cells' ability to invade in vitro coincident with an increase in the cells' expression and extracellular levels of matrix metalloproteinase-2 (MMP-2, gelatinase A). The highly invasive C8161 human cutaneous melanoma cells express little-to-no αvβ3 integrin, but are more invasive and express higher levels of MMPs after perturbation of their α5β1 integrin. This augmented invasiveness could subsequently be abrogated with a function-blocking anti-MMP-2 antibody. Primary uveal melanoma cells and cells derived from uveal metastases appear to grow in either a spindle or epithelioid morphology. The less invasive uveal melanoma cells are spindle shaped and express higher levels of the αvβ3 integrin, while the more invasive cell lines are epithelioid shaped and express reduced levels of the αvβ3 integrin. The apparent conflict between these results and the current model for cutaneous melanoma progression may be addressed as follows: The expression and function of the αvβ3 integrin plays an important role(s) during the transition of cells from the radial growth phase stage to the vertical growth phase stage. However, further progression leading to metastases may require changes in the cells' integrins that would facilitate their ability to leave the primary tumor, and aid in their ability to invade and ultimately form metastases. It is also conceivable that the αvβ3 integrin is reexpressed during various stages of metastatic dissemination, and, in particular, during tumor reestablishment.

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  1. Department of Anatomy and Cell Biology, The University of Iowa Cancer Center, College of Medicine, The University of Iowa, Iowa City, Iowa, USA

    Richard E.B. Seftor, Elisabeth A. Seftor & Mary J.C. Hendrix

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Seftor, R.E., Seftor, E.A. & Hendrix, M.J. Molecular Role(s) for Integrins in Human Melanoma Invasion. Cancer Metastasis Rev 18, 359–375 (1999). https://doi.org/10.1023/A:1006317125454

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