title: 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.
authors.affiliation: Departments of *Oncology, and †Pathology, Aarhus University Hospital, Aarhus, Denmark; ‡Plastic Surgery Research Unit, Department of Plastic Surgery, Aarhus University Hospital, Aarhus, Denmark; §Department of Pathology, Herlev Hospital, Herlev, Denmark; ¶Department of Gastrointestinal Medicine, Hvidovre Hospital, Hvidovre; ‖Department of Oncology, Odense University Hospital, Odense, Denmark; and **Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Marie L
authors.initials: ML
authors.lastname: Bønnelykke-Behrndtz
authors.forename: Torben
authors.initials: T
authors.lastname: Steiniche
authors.forename: Peter
authors.initials: P
authors.lastname: Nørgaard
authors.forename: Allan V
authors.initials: AV
authors.lastname: Danielsen
authors.forename: Tine E
authors.initials: TE
authors.lastname: Damsgaard
authors.forename: Ib J
authors.initials: IJ
authors.lastname: Christensen
authors.forename: Lars
authors.initials: L
authors.lastname: Bastholt
authors.forename: Holger J
authors.initials: HJ
authors.lastname: Møller
authors.forename: Henrik
authors.initials: H
authors.lastname: Schmidt
mesh_terms: D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism*; D002465:Cell Movement; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008545:Melanoma / Q000473:pathology*; D009504:Neutrophils / Q000473:pathology; D010641:Phenotype; D012878:Skin Neoplasms / Q000473:pathology*; D014456:Ulcer / Q000473:pathology*
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins