The hypoxic microenvironment of the skin contributes to Akt-mediated melanocyte transformation

Bedogni, Barbara; Welford, Scott M.; Nickoloff, Brian J.; Giaccia, Amato J.; Powell, Marianne Broome

doi:10.1016/j.ccr.2005.11.005

Cited by 166 publications

(159 citation statements)

References 67 publications

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“…31,32 HIF1A, in particular, is largely expressed in human neoplasia, including melanomas, and is linked with metastasis 33,34 and melanocyte transformation, in conjunction with the Akt gene. 35 Furthermore, HIF1A is actively involved in triggering autophagy, a major intracellular pathway promoting the survival of tumor cells under oxygen and nutrient deprivation. [16][17][18] This autophagic process has been documented in human melanomas as early as 1982 by Horikoshi et al, 36 and melanoma cells are known to induce autophagic activity with perinuclear expression after being irradiated with UV light.…”

Section: Discussionmentioning

confidence: 99%

Autophagy patterns and prognosis in uveal melanomas

et al. 2011

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Autophagy is a self-degradation mechanism by which cells recycle their own cytoplasmic constituents. It has been claimed that, under certain conditions, such a process may be associated with tumor progression. In this study, the autophagic activity was investigated in a series of 99 uveal melanomas after immunohistochemical staining for the autophagy-associated proteins MAP1LC3A and BECN1, most commonly known as LC3A and Beclin 1, respectively. These were assessed in parallel with the hypoxia-inducible factor 1a (HIF1A) and its downstream protein lactate dehydrogenase 5 (composed by five LDHA subunits). Increased autophagic reactivity, detected by MAP1LC3A or BECN1, was associated with intense pigmentation and tumor hypoxia. Uveal melanomas with extensive overexpression of BECN1 or those with underexpression of this protein were associated with the worst prognosis, but the former manifested metastases much earlier than the latter; only 58% of patients with extensive BECN1 overexpression were alive at 4 years, compared with 80% of patients with underexpressed patterns. It is concluded that autophagy is commonly upregulated in uveal melanomas, and may be associated with hypoxia and intense pigmentation. There is a strong association between extensive BECN1 overexpression and early metastases/poor prognosis, and between underexpression of this protein and late metastases/better prognosis.

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Section: Discussionmentioning

confidence: 99%

Autophagy patterns and prognosis in uveal melanomas

et al. 2011

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“…Therefore, in order to acquire a proliferation advantage, melanocytes expressing mutated c-Kit require a tissue-specific environment in vivo allowing activation of HIF-1a, such as hypoxia. The presence of a mild hypoxic environment in the skin has already been described (Bedogni et al, 2005), but it remains to be determined whether hypoxia is elevated in the skin located at the extremities of the hands and feet or in the mucosa where acral and mucosal melanoma develop. This strict dependency of c-Kit mutants on the microenvironment could explain the low frequency of c-Kit mutations in cutaneous melanoma (around 2%) Beadling et al, 2008).…”

Section: D576pmentioning

confidence: 99%

“…c-Kit mutants cooperate with HIF-1a to transform melanocytes Although constitutive Akt is not able to transform melanocytes in normoxic conditions (Bedogni et al, 2005) and N Dumaz, unpublished data), it has recently been shown that it can transform melanocytes in a hypoxic environment and that the synergy between Akt and hypoxia is HIF-1a mediated. To investigate the role of hypoxia in melanocyte transformation by c-Kit mutants, we grew melanocytes expressing WT c-Kit or D576 c-Kit in hypoxic conditions and measured the effect on signaling pathways and proliferation.…”

Section: D576pmentioning

confidence: 99%

c-Kit mutants require hypoxia-inducible factor 1α to transform melanocytes

et al. 2009

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Many studies have highlighted the critical role of c-Kit in normal melanocyte development but its role in melanoma development remains unclear. Although c-Kit expression is often lost during melanoma progression, a subset of melanoma has been found to overexpress c-Kit and mutations activating c-Kit have recently been identified in some acral and mucosal melanoma. To address the role of these c-Kit mutants in the transformation of melanocytes, we characterized the physiological responses of melanocytes expressing the most frequent c-Kit mutants found in melanoma (K642E and L576P) and a novel mutant we identified in an acral melanoma. We analysed signaling pathways activated downstream of c-Kit and showed that all three mutants led to a strong activation of the phosphatidyl-inositol-3 kinase (PI3K) pathway but only weak activation of the Ras/Raf/Mek/Erk pathway, which was not sufficient to promote uncontrolled melanocyte proliferation and transformation. However, in hypoxic conditions or coexpressed with a constitutively active form of hypoxia-inducible factor 1a (HIF-1a), c-Kit mutants activate the Ras/Raf/Mek/Erk pathway, stimulate proliferation and transform melanocytes. Proliferation of melanocytes transformed by these mutants was specifically inhibited by imatinib. These results show for the first time that melanocytes require a specific epigenetic environment to be transformed by c-Kit mutants and highlight a distinct molecular mechanism of melanocyte transformation.

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“…13,14), and the timing of HIF-1a inhibition, more active in early rather than late tumor growth (15). Because HIF-1 has not been directly implicated in oncogenic transformation, although evidence has been provided that it can cooperate with AKT in melanomagenesis (16), it has been difficult to translate results from in vitro studies to animal models. Such controversial results reflect, at least in part, the complexity of the involvement of HIF-1 in human cancers and the known limitations of experimental animal models.…”

Section: Introductionmentioning

confidence: 99%