Loss of E-cadherin as Part of a Migratory Phenotype in Melanoma Is Associated With Ulceration

Abstract

It has been suggested that embryogenic properties of migratory cells are reactivated during wound healing and metastasis in adults. This might explain the association between wound-induced inflammation and poor survival in patients with ulcerated melanoma. Linking inflammation with a migratory phenotype, we characterize the infiltration of innate inflammatory cells, loss of cell-to-cell adhesion (E-cadherin), factors associated with extracellular matrix degradation [matrix metalloproteinase-9 (MMP-9), and neutrophil elastase (NE)], and spindle-shaped cell morphology, between ulcerated (n = 179) and nonulcerated (n = 206) melanoma. In addition, the presence of "extravascular migratory metastasis" (angiotropism) and tumor-vessel density were evaluated as important factors for tumor cell dispersal in ulcerated melanoma. We showed a correlation between expression of the granulocyte marker cd66b+ and the expression of NE and MMP-9, reflecting activated neutrophils. Ulcerated melanoma correlated with a low global E-cadherin score (P = 0.041) and weak-spot score (P = 0.0004). Thus, 28% of the nonulcerated, 42% of the minimally/moderately ulcerated melanoma, and 53% of the excessively ulcerated melanoma presented low scores as opposed to a high E-cadherin score. In addition, the presence of ulceration was correlated with angiotropism (P < 0.0001) and spindle-shaped morphology (P = 0.021). There were no differences in MMP-9 expression or intratumoral vessel density between the ulcerated and nonulcerated group. In conclusion, expression of migratory cell properties showed a highly heterogeneous pattern, which was associated with ulcerated areas and inflammatory cells, in general and with neutrophils in particular. We, therefore, suggest that wound-associated inflammation may be involved in the induction of migratory cell transition and tumor cell dispersal in ulcerated melanoma.