Induction of secreted matrix metalloproteinase-9 activity in human melanoma cells by extracellular matrix proteins and cytokines

Degradation of matrix proteins that constitute the dermal-epidermal junction and dermis by proteolytic enzymes is an essential step of melanoma invasion and metastasis, and this is primarily achieved by the matrix metalloproteinases. In this report, using zymography, we compared the basal secretion levels of active matrix metalloproteinase-2 and matrix metalloproteinase-9 to levels in response to various extracellular matrix proteins, cytokines, and growth factors in normal human melanocyte cells and melanoma cell lines from different stages of neoplastic progression. Basal matrix metalloproteinase-9 activity was only detected in vertical growth phase and metastatic melanoma cell lines, suggesting that matrix metalloproteinase-9 is a candidate biomarker for identifying vertical growth phase and metastatic melanomas. Most melanoma cell lines and cultured normal melanocytes produced high levels of matrix metalloproteinase-2. In addition, both tumor necrosis factor-alpha and interleukin-1beta are strong inducers of active matrix metalloproteinase-9 in vertical growth phase melanoma cell lines, indicating a possible role of these cytokines in the switch from radial growth phase to vertical growth phase. We propose that these proinflammatory cytokines promote melanoma invasion in part through upregulating matrix metalloproteinase-9. Both these cytokines are released from keratinocytes in the epidermis by ultraviolet radiation. Thus, our study suggests that the microenvironment of melanoma cells is an important feature in melanoma progression, and ultraviolet-radiation-induced cytokines might promote the progression of melanoma through the release or activation of matrix metalloproteinases.