Poster Presentation 25th Lorne Cancer Conference 2013

Absence of senescence traits in human melanocytic nevi (#385)

Sieu L Tran 1 , Sebastian Haferkamp 2 , Lyndee L Scurr 3 , Therese M Becker 3 , Chitra Desilva 4 , John F Thompson 4 5 , Richard A Scolyer 4 5 6 , Richard F Kefford 3 4 5 , Helen Rizos 3
  1. University of Sydney, Sydney, New S, Australia
  2. Dermatology, Venereology and Allergology, University of Würzburg, Würzburg, Germany
  3. Westmead Institute for Cancer Research, Westmead Hospital, Sydney, New South Wales, Australia
  4. Melanoma Institute Australia, Sydney, New South Wales, Australia
  5. Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
  6. Tissue Pathology & Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia

Background:

Cellular senescence permanently restricts cell proliferation in response to various stress signals, including the aberrant activation of oncogenes. The presence of predictive senescence markers in human pre-malignant lesions suggests that senescence may function as a genuine tumor suppressor. However, these markers are not exclusive to the senescence program, and it is possible that their expression in vivo does not discriminate senescence from reversible forms of proliferative arrest.

In this study, we aimed to clarify whether human nevus cells can be distinguished from primary and transformed melanocytes by examining the expression of eight senescence markers, including those previously purported to define nevi as senescent tumors.

Methods:

We assessed the expression of eight senescence markers previously identified in vitro in a series of fresh-frozen and formalin-fixed, paraffin-embedded human benign nevi (n=46) and melanomas (n=46). This panel of markers comprise: p16INK4a, p53 and DNA damage (g-H2AX) and predictive markers of senescence including Ki67, PML, senescence-associated-b-galactosidase activity, heterochromatin foci (H3K9Me, DAPI) and nuclear size.

Results:

The critical markers used to define nevi as senescent tumors in previous studies (namely Ki67 negative, p16INK4a positive and senescence-associated-b-galactosidase positive) did not distinguish nevi from their precursor or transformed melanocyte counterparts. Furthermore, the other markers of this panel also failed to stratify these melanocytic cell types.

Conclusions:

We found that the commonly-accepted senescence markers do not distinguish benign nevus cells from melanoma cells or skin melanocytes and therefore conclude that on the basis of current evidence, it cannot be reasonably concluded that nevi are permanently growth arrested via senescence.

  1. Tran SL, Haferkamp S, Scurr LL, Gowrishankar K, Becker TM, Desilva C, Thompson JF, Scolyer RA, Kefford RF, Rizos H. Absence of distinguishing senescence traits in human melanocytic nevi. J Invest Dermatol. 2012 Sep;132(9):2226-34.