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.
Highlights
Cell senescence, a form of permanent growth arrest, has emerged as a central mechanism of tumor suppression and a potential source of therapeutic targets for diverse malignancies
Some thin and thick melanoma cultures proved immortal under these conditions, but surprisingly few (4 ⁄ 37)
Crisis markers including anaphase bridges were frequent in uncultured vertical growth-phase (VGP) melanomas
Summary
A form of permanent growth arrest, has emerged as a central mechanism of tumor suppression and a potential source of therapeutic targets for diverse malignancies. Cell senescence is a major tumor suppressor mechanism and a target of familial melanoma genes, while immortality is widely considered a hallmark of cancer. It is unclear whether early cancers are immortal, because most cultured lines arise from advanced cancers. We tested this using improved culture conditions and found unexpectedly that many primary melanomas, despite growing well, eventually arrested. This difference from the previously reported behavior of many metastatic melanomas suggests prognostic value for markers of immortality. We observed that cells from radial growth-phase (RGP) melanomas consistently require keratinocyte products for survival, potentially explaining their thin form
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