• Chronic UV damage of the stroma improves melanoma survival

      Nagore, E; Roeck, Katharina; Budden, Timothy; Smith, SP; Craig, Sarah; Krutmann, J; Lotz, M; Furney, S; Viros, Amaya; Department of Dermatology, Instituto Valenciano Oncologico, Valencia, Spain; (2019)
    • Correction: cutaneous melanoma primary site is linked to nevus density

      Martin-Gorgojo, A; Llinares, M; Viros, Amaya; Requena, C; Garcia-Casado, Z; Traves, V; Kumar, R; Nagore, E; Escuela de Doctorado, Universidad Catolica de Valencia 'San Vicente Martir', Valencia, Spain (2018)
      This corrects the article DOI: 10.18632/oncotarget.22016.Erratum for Cutaneous melanoma primary site is linked to nevus density. [Oncotarget. 2017]
    • Cutaneous melanoma primary site is linked to nevus density.

      Martin-Gorgojo, A; Llinares, M; Virós, Amaya; Requena, C; Garcia-Casado, Z; Traves, V; Kumar, R; Nagore, E; Escuela de Doctorado, Universidad Catolica de Valencia 'San Vicente Martir', Valencia, Spain (2017-11-17)
      There are at least two pathways driving cutaneous melanoma; one is linked to an inherent melanoma susceptibility to nevi development and the second to environmental cumulative ultraviolet light exposure. In this study, we examined the relation between nevus density, accrued sun damage and the site of primary melanoma excision. In a series of 888 consecutive cutaneous melanoma patients, melanomas appearing in skin areas with a high relative nevus density were most prominent in men, with an elevated nevus count, at sites without solar elastosis, but with an epidemiological history of previous sunburn. The present study associates melanoma development to sites with high nevus density. Our study supports more careful surveillance of body areas with increased nevus density in patients with high total body number of nevi, especially when they report a history of sunburns at these sites.
    • Histologic features associated with an invasive component in lentigo maligna lesions

      Moreno, A; Manrique-Silva, E; Viros, Amaya; Requena, C; Sanmartin, O; Traves, V; Nagore, E; School of Medicine, Universidad Catolica de Valencia San Vicente Martir, Valencia, Spain (2019)
      Importance: Lentigo maligna (LM) presents an invasive component in up to 20% of biopsied cases, but to date the histologic features useful in detecting this invasive component have not been described. Some histologic characteristics are hypothesized to contribute to the progression of LM invasion. Objective: To identify the histologic characteristics associated with lentigo maligna melanoma (LMM) in patients with LM diagnosed by a partial diagnostic biopsy. Design, Setting, and Participants: A retrospective cross-sectional study of patients treated between January 1, 2000, and December 31, 2017, was conducted in a referral oncology center in València, Spain. Data and specimens of patients (n?=?96) with a diagnosis of primary cutaneous melanoma in the form of either LM or LMM who had undergone surgical treatment, a complete histologic examination of the whole tumor, and an initial diagnostic partial biopsy of LM were included in the study. Histologic assessment was blinded to the presence of an invasive component. Interventions: All biopsy specimens were evaluated for the presence of certain histologic characteristics. Main Outcomes and Measures: Comparisons between invasive samples and samples without an invasive component were performed. The differences in the distribution of variables between the groups were assessed using the ?2 and Fisher exact tests, and the degree of association of the relevant variables was quantified by logistic regression models. A classification and regression tree analysis was performed to rank the variables by importance. Results: In total, 96 patients had sufficient histologic material that could be evaluated. The patients were predominantly male (56 [58.3%]) and had a mean (SD) age at diagnosis of 72 (12) years. Of these patients, 63 (65.6%) had an LM diagnosis and 33 (34.4%) had an LMM diagnosis (an invasive component). The histologic variables associated with the presence of an invasive component were melanocytes forming rows (odds ratio [OR], 11.5; 95% CI, 1.4-94.1; P?=?.02), subepidermal clefts (OR, 2.8; 95% CI, 1.0-7.9; P?=?.049), nests (OR, 3.0; 95% CI, 1.1-8.6; P?=?.04), and a lesser degree of solar elastosis (OR, 0.4; 95% CI, 0.1-1.1; P?=?.07). A classification and regression tree analysis of the relevant histologic features was able to accurately identify lentigo maligna with an invasive component (LMM) in more than 60% of patients. Conclusions and Relevance: These findings may be useful in classifying early LM specimens at higher risk of invasion, which may eventually be relevant in identifying the most appropriate management for LM.
    • Skin ageing continues long after ultraviolet radiation damage

      Earnshaw, CH; Nagore, E; Roeck, K; Schneider, S; Budden, T; Craig, Sarah; Griffiths, C; Furney, S; Krutmann, J; Viros, Amaya; et al. (2019)
    • Ultraviolet light-induced collagen degradation inhibits melanoma invasion

      Budden, Timothy; Gaudy, C.; Nagore, E; Viros, Amaya; Cancer Research UK Manchester Institute, Nether Alderley, Macclesfield, (2021)
      Ultraviolet radiation (UVR) increases the incidence of cutaneous melanoma. The ageing, sunexposed dermis accumulates UVR damage, and older patients develop more melanomas at UVR-exposed sites. As fibroblasts play key roles in the stromal response to UVR and in cancer progression, we investigated how long term UVR modifies dermal fibroblast function and how this affects melanoma invasion. Chronic UVR exposure on dermal fibroblasts showed that extracellular matrix pathways, particularly those involved in collagen catabolism, were upregulated in the absence of acute UVR. Importantly, the expression of collagen-cleaving matrix metalloprotein-1 (MMP1) was persistently upregulated. This resulted in persistent degradation of collagen 1, and an overall degraded and disorganised matrix. Collagen degradation by MMP1 decreased melanoma invasion in vitro. Conversely, both inhibiting extracellular matrix degradation and MMP1, or higher collagen 1 expression, restored the invasion of melanoma through collagen. Primary cutaneous melanomas of aged humans confirmed these in vitro findings, revealing significantly fewer cancer cells invade as single cells at the invasive front of melanomas arising in chronic sun damaged skin. We show high collagen deposition and melanoma cell invasion in the dermis are robust predictors of poor melanoma-specific survival in 3, international cohorts of primary melanoma. Thus, melanomas arising over UVR-damaged, collagen-poor skin are less invasive, and this reduced invasion improves survival. However, we discovered a subset of melanomas arising over collagen-poor, UVR-damaged dermis have a poor outcome, and found that increased new collagen synthesis by melanoma-associated fibroblasts at the invasive front in these cases restores melanoma single cell invasion and drives poor outcome. Finally, we demonstrate high COL1A1 gene expression is an early stage biomarker of poor outcome across a broad range of primary cancers.
    • Ultraviolet light-induced collagen degradation inhibits melanoma invasion

      Budden, Timothy; Gaudy-Marqueste, C.; Porter, Andrew P; Kay, E.; Gurung, Shilpa; Earnshaw, Charles; Roeck, K.; Craig, S.; Traves, V.; Krutmann, J.; et al. (2021)
      Ultraviolet radiation (UVR) damages the dermis and fibroblasts; and increases melanoma incidence. Fibroblasts and their matrix contribute to cancer, so we studied how UVR modifies dermal fibroblast function, the extracellular matrix (ECM) and melanoma invasion. We confirmed UVR-damaged fibroblasts persistently upregulate collagen-cleaving matrix metalloprotein-1 (MMP1) expression, reducing local collagen (COL1A1), and COL1A1 degradation by MMP1 decreased melanoma invasion. Conversely, inhibiting ECM degradation and MMP1 expression restored melanoma invasion. Primary cutaneous melanomas of aged humans show more cancer cells invade as single cells at the invasive front of melanomas expressing and depositing more collagen, and collagen and single melanoma cell invasion are robust predictors of poor melanoma-specific survival. Thus, primary melanomas arising over collagen-degraded skin are less invasive, and reduced invasion improves survival. However, melanoma-associated fibroblasts can restore invasion by increasing collagen synthesis. Finally, high COL1A1 gene expression is a biomarker of poor outcome across a range of primary cancers.