Malignancy without immortality? Cellular immortalization as a possible late event in melanoma progression

Abstract

Cell senescence is a permanent growth arrest following extended proliferation. Cultured cancer cells including metastatic melanoma cells often appear immortal (proliferate indefinitely), while uncultured benign nevi (moles) show senescence markers. Here, with new explantation methods, we investigated which classes of primary pigmented lesions are typically immortal. Nevi yielded a few proliferating cells, consistent with most nevus cells being senescent. No nevus culture (0/28) appeared immortal. Some thin and thick melanoma cultures proved immortal under these conditions, but surprisingly few (4/37). All arrested cultures displayed three senescence markers in some cells: β-galactosidase, nuclear p16, and heterochromatic foci/aggregates. However, melanoma cultures also showed features of telomeric crisis (arrest because of ultrashort telomeres). Moreover, crisis markers including anaphase bridges were frequent in uncultured vertical growth-phase (VGP) melanomas. Conversely, all immortal melanoma cultures expressed telomerase reverse transcriptase and telomerase, showing aneuploidy. The findings suggest that primary melanomas are typically precrisis, with immortalization/telomere maintenance as a late event.

A prognostic signature of defective p53‐dependent G1 checkpoint function in melanoma cell lines

“…Bypass of the pRB-dependent OIS barrier may permit melanocytes to proliferate until a p53-dependent replicative senescence checkpoint is activated. Normal melanocytes express very low levels of telomerase, as do neval melanocytes (Miracco et al, 2000), and so proliferative clones of oncogene-transformed melanocytes may arrest growth behind a p53-dependent DNA damage response that is triggered when telomeres have eroded to a deprotected state (Simpson et al, 2005; Soo et al, 2011). Thus, p53 serves to arrest the division of oncogene-transformed melanocytes that were not collected behind the pRB barrier.…”

Pathology and genomics of pediatric melanoma: A critical reexamination and new insights

“…However, in the absence of TERT dysregulation, continuous cellular propagation in these cases eventually leads to extreme telomere shortening and eventually telomeric crisis, which is characterized by end‐to‐end chromosomal fusions, chromosome breakage, and anaphase bridges. These cellular events may explain the changes in gene copy number and the morphologic features of malignancy commonly observed in such neoplasms . Although replicative lifespan is limited in these nonimmortal malignant cells, there still remains the potential to acquire the capacity to maintain telomere lengths, either through TERT expression or through a telomerase‐independent alternative lengthening of telomeres mechanism.…”

Melanoma cells in distinct growth phases retain specific invasive qualities during brain metastasis in vivo

“…The switch from RGP to VGP and the metastatic phenotype is associated with increased CD1, loss of E‐Cadherin, c‐KIT and AP‐2, expression of N‐Cadherin, MMP‐2, osteonectin, survivin, βFGF, and αVβ3 integrin (reviewed by Bar‐Eli, 2001; Meier et al., 2000, 2003; Sturm et al., 2002). Further, telomeric crisis is rare in pigmented lesions less progressed than the VGP (Soo et al., 2011).…”