title: Endothelin-1 in the tumor microenvironment correlates with melanoma invasion.
abstract: Endothelin-1 (ET-1) is a vasoactive peptide that also plays a role in the tanning response of the skin. Animal and cell culture studies have also implicated ET-1 in melanoma progression, but no association studies have been performed to link ET-1 expression and melanoma in humans. Here, we present the first in-vivo study of ET-1 expression in pigmented lesions in humans: an ET-1 immunohistochemical screen of melanocytic nevi, melanoma in situ lesions, invasive melanomas, metastatic melanomas, and blue nevi was performed. Twenty-six percent of melanocytic nevi and 44% of melanoma in situ lesions demonstrate ET-1 expression in the perilesional microenvironment, whereas expression in nevus or melanoma cells was rare to absent. In striking contrast, 100% of moderately to highly pigmented invasive melanomas contained numerous ET-1-positive cells in the tumor microenvironment, with 79% containing ET-1-positive melanoma cells, confirmed by co-staining with melanoma tumor marker HMB45. Hypopigmented invasive melanomas had reduced ET-1 expression, suggesting a correlation between ET-1 expression and pigmented melanomas. ET-1-positive perilesional cells were CD68-positive, indicating macrophage origin. Sixty-two percent of highly pigmented metastatic melanomas demonstrated ET-1 expression in melanoma cells, in contrast to 28.2% of hypopigmented specimens. Eighty-nine percent of benign nevi, known as blue nevi, which have a dermal localization, were associated with numerous ET-1-positive macrophages in the perilesional microenvironment, but no ET-1 expression was detected in the melanocytes. We conclude that ET-1 expression in the microenvironment increases with advancing stages of melanocyte transformation, implicating a critical role for ET-1 in melanoma progression, and the importance of the tumor microenvironment in the melanoma phenotype.
authors.affiliation: Departments of aPathology bDermatopathology cDermatology dPopulation Health eMedicine fMicrobiology gNYU Cancer Center, New York University School of Medicine, New York, New York, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Chiriboga
authors.forename: Shane
authors.initials: S
authors.lastname: Meehan
authors.forename: Iman
authors.initials: I
authors.lastname: Osman
authors.forename: Michael
authors.initials: M
authors.lastname: Glick
authors.forename: Gelo
authors.initials: G
authors.lastname: de la Cruz
authors.forename: Brittny S
authors.initials: BS
authors.lastname: Howell
authors.forename: George
authors.initials: G
authors.lastname: Friedman-Jiménez
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schneider
authors.forename: Sumayah
authors.initials: S
authors.lastname: Jamal
mesh_terms: D000818:Animals; D019332:Endothelin-1 / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009361:Neoplasm Invasiveness; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology*; D059016:Tumor Microenvironment
chemical_list: D019332:Endothelin-1