Cellular senescence in naevi and immortalisation in melanoma: a role for p16?

Abstract

Cellular senescence, the irreversible proliferative arrest seen in somatic cells after a limited number of divisions, is considered a crucial barrier to cancer, but direct evidence for this in vivo was lacking until recently. The best-known form of human cell senescence is attributed to telomere shortening and a DNA-damage response through p53 and p21. There is also a more rapid form of senescence, dependent on the p16-retinoblastoma pathway. p16 (CDKN2A) is a known melanoma susceptibility gene. Here, we use retrovirally mediated gene transfer to confirm that the normal form of senescence in cultured human melanocytes involves p16, since disruption of the p16/retinoblastoma pathway is required as well as telomerase activation for immortalisation. Expression (immunostaining) patterns of senescence mediators and markers in melanocytic lesions provide strong evidence that cell senescence occurs in benign melanocytic naevi (moles) in vivo and does not involve p53 or p21 upregulation, although p16 is widely expressed. In comparison, dysplastic naevi and early (radial growth-phase, RGP) melanomas show less p16 and some p53 and p21 immunostaining. All RGP melanomas expressed p21, suggesting areas of p53-mediated senescence, while most areas of advanced (vertical growthphase) melanomas lacked both p16 and p21, implying escape from both forms of senescence (immortalisation). Moreover, nuclear p16 but not p21 expression can be induced in human melanocytes by oncogenic BRAF, as found in around 80% of naevi. We conclude that cell senescence can form a barrier to melanoma development. This also provides a potential explanation of why p16 is a melanoma suppressor gene.

p16Ink4a overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors

“…A mutation in a downstream effector of Ras, BRAF (BRAFv600E), is often found in these tumors. BRAFv600E expression in human melanocytes induces cell cycle arrest, accompanied by p16 Ink4a overexpression and senescence-associated acidic b-galactosidase activity (Michaloglou et al, 2005;Gray-Schopfer et al, 2006). Recent evidence has described a similar situation in schwannomas and neurofibromas (Romagosa et al, 2009).…”

“…Supporting this concept, senescent cells have been shown in a number of different benign lesions, including nevi and neurofibromas (Michaloglou et al, 2005;Courtois-Cox et al, 2006), but not in malignant lesions. p16 Ink4a overexpression has been found in premature senescence, and particularly in OIS, and consequently in benign and premalignant lesions with senescent cells (Krishnamurthy et al, 2004;Michaloglou et al, 2005;Gray-Schopfer et al, 2006). Human nevi are benign proliferations of melanocytes, and represent the paradigm of OIS in human tumors.…”

A case of eruptive melanocytic naevi after long-term azathioprine treatment

“…[4] Bu paradoks (melanositik nevüslerde olan BRAF V600E mutantının melanomaya ilerlememesi) 2006'da tümör supresör p16 ve beta galaktozidaz belirtecinin yüksek olmasına ba¤lanmıtır. [5,6] BRAF V600E'nin aırı ekspresyonu primer insan melanositlerinde hücre ço¤almasını bozmaktadır. [6] Spitz nevüslerde (melanoma ile karıabilmekte) ise MAPK aktivitesi fazla, fakat hücre ço¤alması düüktür.…”

“…[5,6] BRAF V600E'nin aırı ekspresyonu primer insan melanositlerinde hücre ço¤almasını bozmaktadır. [6] Spitz nevüslerde (melanoma ile karıabilmekte) ise MAPK aktivitesi fazla, fakat hücre ço¤alması düüktür. [7] Bir çalımada erüptif melanositik nevüs takibi yapılan ve 6-merkaptopürin kullanılan hastaların ekil 1.…”

Erratum: Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas

“…They further demonstrate that, despite the cytostatic nature of the senescence program, senescent cells can turn over in vivo. Whether such turnover is a general feature of senescence in vivo is not clear 14,28 , but when present may reinforce the tumour suppressive action of senescence in pre-malignant settings or in tumours following treatment with senescence-or differentiation-promoting therapies 26,29 . Conversely, our results identify a setting in which the innate immune system is provoked to coordinately attack tumour cells, presumably through both phagocytosis and direct cytotoxic killing, thereby facilitating their elimination.…”