title: IL-10 expression by primary tumor cells correlates with melanoma progression from radial to vertical growth phase and development of metastatic competence.
abstract: Downregulation of the immune system facilitates tumor progression at different stages of cutaneous melanoma. Sentinel nodes, the first lymph nodes on lymphatics draining directly from a primary melanoma, are immune downregulated by tumor-generated immunosuppressive cytokines, including interleukin-10 (IL-10). To better understand the kinetics of sentinel node suppression, we investigated IL-10 expression by melanoma cells and tumor-associated macrophages and lymphocytes at different stages of primary melanoma evolution. We used reverse-transcriptase in situ PCR to identify the cellular sources of IL-10 mRNA in 39 melanomas. IL-10 mRNA was identified in tumor cells of 2 of 6 melanomas in situ (33%), of 17 of 21 invasive melanomas (81%) and of 11 of 12 metastatic melanomas (92%). Higher IL-10 expression correlates with tumor progression, with differences between melanoma in situ, invasive melanoma and metastatic melanoma. In primary melanomas, the IL-10 mRNA content of tumor cells correlates with Clark's level. There was significantly more IL-10 mRNA in vertical growth-phase melanoma cells than in radial growth-phase cells. In a logistic regression model, moderate-to-high IL-10 mRNA expression by tumor cells was significantly associated with vertical growth-phase melanoma. IL-10 mRNA was detected in melanoma-associated macrophages and lymphocytes. In invasive melanomas, IL-10 mRNA reactivity of macrophages decreased as Clark's level increased. Alterations of immunity by IL-10 derived from melanoma cells and melanoma-associated macrophages and lymphocytes potentially facilitate evolution of the primary melanoma and render regional lymph nodes susceptible to metastases.
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. itakura@ucla.edu
authors.forename: Eijun
authors.initials: E
authors.lastname: Itakura
authors.forename: Rong-Rong
authors.initials: RR
authors.lastname: Huang
authors.forename: Duan-Ren
authors.initials: DR
authors.lastname: Wen
authors.forename: Eberhard
authors.initials: E
authors.lastname: Paul
authors.forename: Peter H
authors.initials: PH
authors.lastname: Wünsch
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Cochran
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism*; D016246:Lymphocytes, Tumor-Infiltrating; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D009361:Neoplasm Invasiveness; D009508:Nevus, Pigmented / Q000175:diagnosis / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; C508609:IL10 protein, human; D012333:RNA, Messenger; D016753:Interleukin-10