Vitamin D in melanoma: Controversies and potential role in combination with immune check-point inhibitors

Stucci, Luigia Stefania; D’Oronzo, Stella; Tucci, Marco; Macerollo, Antonella; Ribero, Simone; Spagnolo, Francesco; Marra, Elena; Picasso, Virginia; Orgiano, L.; Marconcini, Riccardo; Rosa, Francesco De; Guardo, Lorenza Di; Galli, Giulia; Gandini, Sara; Palmirotta, Raffaele; Palmieri, Giuseppe; Queirolo, Paola; Silvestris, Franco; Intergroup, Italian Melanoma

doi:10.1016/j.ctrv.2018.05.016

Cited by 34 publications

(47 citation statements)

References 87 publications

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“…3 Further studies are required to investigate the association of severe vitamin D deficiency with BRAF-mutated melanoma, especially as low vitamin D levels may impact and increase the incidence of immune-related adverse events in patients receiving immunotherapy. 4 In this study, over 80% of patients with melanoma were vitamin D deficient; therefore, we recommend testing for all patients with melanoma regardless of stage. However, we note that the authors defined 'tumours arising within a field of cancerization in association with actinic keratosis (AK) as well-differentiated SCC, while those developing in the absence of AK were considered KA'.…”

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confidence: 87%

“…Based on this selection criterion, we searched for the presence of HPV in the two groups of samples and found statistically significant differences between both groups. 4 Furthermore, Taibjee et al highlight the fact that cSCC with KA features may develop from the follicular infundibulum in the absence of actinic keratosis and provide supportive images for this concept. 1 However, the authors do not provide any Fig 1. Clinical and dermatoscopic differences between keratoacanthoma (KA) and squamous cell carcinoma (SCC).…”

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confidence: 98%

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Severe vitamin D deficiency associated with BRAF ‐mutated melanoma

et al. 2019

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DEAR EDITOR, Low levels of vitamin D are associated with poorer prognosis, thicker tumours, ulceration and increased inflammation in primary melanoma. 1 In the U.K., testing is recommended by the National Institute of Clinical Excellence for any new patient diagnosed with melanoma, but not for those with already established or metastatic disease. Driver mutations in BRAF are found in approximately 50% of melanomas and play an important role in cell proliferation and metastases, and also increase inflammation by promoting secretion of proinflammatory cytokines, including interleukin (IL)-6 and IL-8. 2 Inflammation aids proliferation, survival of cancer cells, angiogenesis and metastasis. However, the relationship between BRAF and vitamin D has not been previously examined in patients with melanoma.We conducted a retrospective study to determine levels of 25-hydroxy vitamin D in patients with primary and metastatic melanoma, and make comparisons according to age, sex, stage, season and BRAF status. Classification of vitamin D deficiency (often defined as ≤ 50 nmol L À1 ) remains controversial; however, this is dependent on the type of laboratory testing used. Therefore, we defined deficiency as ≤ 70 nmol L À1 and severe deficiency as ≤ 30 nmol L À1 , as per our laboratory standards. We tested 124 patients (65 men, 59 women; age range 23-85 years) who attended dermatology and oncology clinics from May 2016 to October 2017. Any patients taking vitamin D supplements were excluded. BRAF status was measured in patients with stage III or IV melanoma (American Joint Committee on Cancer, 7th edn). Overall, 104 patients (84%) were vitamin D deficient, 32 of whom (31%) were severely deficient. Four patients were classified as stage 0 melanoma (3%), 18 patients were stage I (14%), seven were stage II (6%), 16 were stage III (13%) and 79 were stage IV (64%). Of the patients with stage IV melanoma, 69 (87%) were vitamin D deficient. There was no variation in patient's levels of vitamin D with regard to the seasons, sex or age. BRAF status was established in 93 patients, 59 of whom (63%) were positive for BRAF mutation. Of these, 22 patients (37%) were severely vitamin D deficient compared with three (9%) BRAF wild-type (P = 0Á006). Of the 43 patients who died, 37 (86%) were vitamin D deficient; 14 of the 43 deceased patients (33%) were severely vitamin D deficient and 11 of these 14 patients (79%) were positive for BRAF mutation.Studies have demonstrated a threefold increased risk of death for higher-risk tumours harbouring NRAS or BRAF mutations compared with wild-type melanomas, after adjusting for other prognostic factors. 3 Further studies are required to investigate the association of severe vitamin D deficiency with BRAF-mutated melanoma, especially as low vitamin D levels may impact and increase the incidence of immune-related adverse events in patients receiving immunotherapy. 4 In this study, over 80% of patients with melanoma were vitamin D deficient; therefore, we recommend testing for all patients with melanoma reg...

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confidence: 87%

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confidence: 98%

Severe vitamin D deficiency associated with BRAF ‐mutated melanoma

et al. 2019

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“…Clinicopathological analyses have shown positive correlations between low or undetectable expression of VD receptor (VDR) in MM with accelerated tumor progression [ 308 , 309 ]. Notably, VD upregulates the expression of programmed death ligand 1 (PD-L1) on both epithelial and immune cells, suggesting an interaction with immune checkpoint inhibitors [ 310 ]. Intriguingly, VDR inhibits the expression of miR-21 [ 54 , 94 , 95 , 311 , 312 ].…”

Section: Environmental Factors Upregulating Mir-21mentioning

confidence: 99%

“…As outlined above, VD deficiency is related to poorer survival in metastatic MM [ 282 , 283 ]. Enhanced VDR signaling may reduce the expression of oncogenic miR-21 [ 54 , 94 , 95 , 307 , 308 , 309 , 310 , 311 , 312 ]. Nevertheless, VD supplementation for MM prevention and adjuvant therapy is still controversial [ 310 , 399 , 400 , 401 , 402 ], but has been recommended in a recent vitamin D symposium [ 403 ].…”

Section: Therapeutic Suppression Of Mir-21mentioning

confidence: 99%

MicroRNA-21-Enriched Exosomes as Epigenetic Regulators in Melanomagenesis and Melanoma Progression: The Impact of Western Lifestyle Factors

Melnik

John

Carrera-Bastos

et al. 2020

Cancers

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DNA mutation-induced activation of RAS-BRAF-MEK-ERK signaling associated with intermittent or chronic ultraviolet (UV) irradiation cannot exclusively explain the excessive increase of malignant melanoma (MM) incidence since the 1950s. Malignant conversion of a melanocyte to an MM cell and metastatic MM is associated with a steady increase in microRNA-21 (miR-21). At the epigenetic level, miR-21 inhibits key tumor suppressors of the RAS-BRAF signaling pathway enhancing proliferation and MM progression. Increased MM cell levels of miR-21 either result from endogenous upregulation of melanocytic miR-21 expression or by uptake of miR-21-enriched exogenous exosomes. Based on epidemiological data and translational evidence, this review provides deeper insights into environmentally and metabolically induced exosomal miR-21 trafficking beyond UV-irradiation in melanomagenesis and MM progression. Sources of miR-21-enriched exosomes include UV-irradiated keratinocytes, adipocyte-derived exosomes in obesity, airway epithelium-derived exosomes generated by smoking and pollution, diet-related exosomes and inflammation-induced exosomes, which may synergistically increase the exosomal miR-21 burden of the melanocyte, the transformed MM cell and its tumor environment. Several therapeutic agents that suppress MM cell growth and proliferation attenuate miR-21 expression. These include miR-21 antagonists, metformin, kinase inhibitors, beta-blockers, vitamin D, and plant-derived bioactive compounds, which may represent new options for the prevention and treatment of MM.

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“…Given the interest in using vitamin D to reduce cancer risk, more research is warranted to establish its role in the control and progression of melanoma, and whether vitamin D supplements can reduce cancer risk and progression and improve outcomes. Interestingly, it has been also shown that vitamin D could be used to control immune-related adverse events mediated by Th-17+ cell expansion occurring during immunotherapy for CMM [111–113].…”

Section: Nutrients/phytochemicals and Melanomamentioning

confidence: 99%

Dietary compounds and cutaneous malignant melanoma: recent advances from a biological perspective

et al. 2019

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Cutaneous malignant melanoma is a heterogeneous disease, being the consequence of specific genetic alterations along several molecular pathways. Despite the increased knowledge about the biology and pathogenesis of melanoma, the incidence has grown markedly worldwide, making it extremely important to develop preventive measures. The beneficial role of correct nutrition and of some natural dietary compounds in preventing malignant melanoma has been widely demonstrated. This led to numerous studies investigating the role of several dietary attitudes, patterns, and supplements in the prevention of melanoma, and ongoing research investigates their impact in the clinical management and outcomes of patients diagnosed with the disease. This article is an overview of recent scientific advances regarding specific dietary compounds and their impact on melanoma development and treatment.

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Vitamin D in melanoma: Controversies and potential role in combination with immune check-point inhibitors

Cited by 34 publications

References 87 publications

Severe vitamin D deficiency associated with BRAF ‐mutated melanoma

Severe vitamin D deficiency associated with BRAF ‐mutated melanoma

MicroRNA-21-Enriched Exosomes as Epigenetic Regulators in Melanomagenesis and Melanoma Progression: The Impact of Western Lifestyle Factors

Dietary compounds and cutaneous malignant melanoma: recent advances from a biological perspective

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