Roads to melanoma: Key pathways and emerging players in melanoma progression and oncogenic signaling

Abstract

Melanoma has markedly increased worldwide during the past several decades in the Caucasian population and is responsible for 80% of skin cancer deaths. Considering that metastatic melanoma is almost completely resistant to most current therapies and is linked with a poor patient prognosis, it is crucial to further investigate potential molecular targets. Major cell-autonomous drivers in the pathogenesis of this disease include the classical MAPK (i.e., RAS-RAF-MEK-ERK), WNT, and PI3K signaling pathways. These pathways play a major role in defining the progression of melanoma, and some have been the subject of recent pharmacological strategies to treat this belligerent disease. This review describes the latest advances in the understanding of melanoma progression and the major molecular pathways involved. In addition, we discuss the roles of emerging molecular players that are involved in melanoma pathogenesis, including the functional role of the melanoma tumor antigen, p97/MFI2 (melanotransferrin).

Developments in targeted therapy in melanoma

“…This cascade concludes in activation of ERK1 and ERK2, which can then translocate to the nucleus and regulate MITF, c-MYC and other transcription factors, resulting in alteration of cell proliferation and senescence. 6 Receptor tyrosine kinases (RTK) or RAS-GTP can activate the PI3K-AKT pathway, while PTEN is a negative regulator, mutation of which leads to constitutive activation of AKT and is followed by changes in cell growth, motility and invasion. 124 wt melanomas analyzed by Krauthammer et al 8 Interestingly, around 60% of these melanomas harbored comutations in RAS-opathy genes (RASA2, PTPN11, SOS1, RAF1 and SPRED1), 8,16 which are known to be linked with Noonan, Leopard and Legius syndromes.…”

“…4 Genetic alterations in melanoma oncogenes and tumor suppressor genes commonly cause constitutive signaling through RAS-RAF-MEK-ERK, also known as the MAPK pathway. 5,6 This cascade concludes in activation of ERK1 and ERK2, which can then translocate to the nucleus and regulate MITF, c-MYC and other transcription factors, resulting in alteration of cell proliferation and senescence ( Fig. 1).…”

“…1). 6 Less frequently identified, yet also relevant are genetic aberrations in other cellular pathways, such as cell cycle control (CDKN2A), apoptosis (PT53) and the PI3K pathway (TERT, PTEN).…”

De-adhesion dynamics of melanoma cells from brain endothelial layer

“…Occurrence of melanoma has increased worldwide, being responsible for over 80% of skin cancer deaths (1). Although metastatic melanoma has relatively low abundance, it shows high resistance to conventional therapies (2,3).…”

O papel da insularina, uma disintegrina recombinante (GST-INS), em processos de progressão tumoral: estudos <i>in vitro</i>.

“…Estas vias desempenham um importante papel na definição da progressão do melanoma, e algumas têm sido objeto de recentes estratégias farmacológicas para tratar esta doença agressiva (PALUNCIC et al, 2016 (APLIN et al, 2011;SMALLEY;SONDAK, 2010).…”