Oral communication, CS19 / C86

Official XXIst International Pigment Cell Conference website - 21-24 Sept 2011, Bordeaux - France | updated: September 04 2011

Markers of telomeric crisis and immortalization in melanoma progression

BACKGROUND AND OBJECTIVES: Abnormal mitoses are characteristic of cancer cells. A common cause of these appears to be telomeric crisis. Crisis occurs in cells that have bypassed cellular senescence (irreversible cell cycle arrest after extended division, mediated by p16 and p53 pathways), and proliferated further. This leads to very short, dysfunctional telomeres, which can be ligated giving dicentric chromosomes. Consequences include large-scale chromosomal rearrangements, anaphase bridges, tripolar and other abnormal mitoses, and apoptosis. Rare cells may overcome crisis and become immortal by re-expressing TERT, a subunit of telomerase, required to maintain telomeres. Primary melanomas appear to have evaded senescence but possibly not crisis, as they often fail to yield immortal cells when explanted. Here we aimed to test whether and when crisis occurs in melanoma progression, and whether immortalization is associated with metastasis. METHODS: Routine paraffin sections of archival lesions from St. George’s Healthcare Trust were used, including approximately 20 each of radial growth phase (RGP), vertical growth phase (VGP), and metastatic melanomas (from lymph nodes and skin). Haematoxylin and eosin-stained sections were viewed for scoring of abnormal mitoses, with emphasis on anaphase bridges (relatively specific for crisis). Also noted were giant and multinucleate cells, and later nuclear blebs and chromatin bridges between nuclei. Currently, unstained sections are being immunostained for TERT, and for additional crisis markers. RESULTS: RGP melanomas showed very few mitoses, with no anaphase bridges, but some multinucleate cells and chromatin bridges. One abnormal mitosis only was observed in one RGP melanoma. In VGP melanomas, multinucleate cells, tripolar mitoses, nuclear blebs and chromatin bridges all appeared common, and anaphase bridges were seen in up to 40% of anaphases. Surprisingly, similar features were seen in most metastatic lesions, with similar percentages of anaphase bridges. CONCLUSIONS: Some RGP melanomas may be entering crisis. VGP melanomas have extensive features of crisis, consistent with the rarity of immortality in culture. Even some metastases show features of crisis, suggesting that melanoma cells may metastasize before full immortalization. Marker expression data should clarify these findings.

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