Hypoxia, melanocytes and melanoma - survival and tumor development in the permissive microenvironment of the skin

Abstract

The tissue microenvironment plays a critical role in cell survival and growth and can contribute to cell transformation and tumor development. Cellular interactions with the stroma and with other cells provide key signals that control cellular arrest or division, survival or death, and entrance or exit from a quiescent state. Together, these decisions are essential for maintenance of tissue homeostasis. Tissue oxygenation is an important component of the microenvironment that can acutely alter the behavior of a cell through the direct regulation of genes involved in cell survival, apoptosis, glucose metabolism, and angiogenesis. Loss of tissue homeostasis due to, for example, oncogene activation leads to the disruption of these signals and eventually can lead to cell transformation and tumor development. Here we review the role of tissue oxygenation, and in particular physiologic skin hypoxia, on cell survival and senescence and how it contributes to melanocyte transformation and melanoma development.

Figure 1

O₂ regulates the rate at which HIF-α proteins are degraded. In normoxia, O₂-dependent hydroxylation of proline (P) residues in HIF-α subunits by the enzymes PHD1–3 is required for the binding of the von Hippel-Lindau (VHL) tumour-suppressor protein. HIF-α/VHL complexes are ubiquitylated and targeted to the proteasome for degradation. O₂ also regulates the interaction of HIF-α with transcriptional co-activators. O₂-dependent hydroxylation of asparagine (N) residues by the enzyme FIH-1 (factor inhibiting HIF) blocks the binding of p300 and CBP to HIF-α and therefore inhibits HIF-mediated gene transcription. Under hypoxic conditions, the rate of asparagine and proline hydroxylation decreases. VHL cannot bind to HIF-α subunits that are not prolyl-hydroxylated, resulting in a decreased rate of HIF-α degradation. By contrast, p300 and CBP can bind to HIF-α that are not asparaginyl-hydroxylated, allowing transcriptional activation of HIF-target genes.

Figure 2

HIF-dependent gene regulation. Cells respond to hypoxia by activating HIF transcription factors thereby modulating key target genes which ultimately function to allow survival and to re-establish a normal oxygen supply. In tumors, an imbalanced HIF signaling can contribute to further tumor expansion and progression.

Figure 3

Hypoxia and HIF-1α influence melanocyte growth. (A) Mouse melanocytes expressing Akt or a control vector show a faster growth when placed in 2% O₂. (B) Similarly, melanocytes that express a stable HIF-1α (HIF-1α-_ODD) in atmospheric oxygen (21%) grow faster than controls (pBabe). (C) Melanocytes deficient of HIF-1α (KO) grow at a slower rate in mild hypoxia (2% O₂) than controls (WT).

Figure 4

PI3K/Akt and RAS/BRaf/MEK pathways are frequently altered in melanoma. Akt activation resulting from PTEN loss of function or Akt3 amplification can, to some extent, inhibit the RAS/BRaf/MEK pathway. Ras and BRaf are found mutated in a large number of melanomas and together with Akt they signal to HIF-1. These three signaling pathways can regulate a number of protumorigenic function that can promote melanoma development and progression. Dotted lines indicate normal pathway activation through the interaction of a growth factor (GF) with its receptor.