Senescence in premalignant tumours

Abstract

Oncogene-induced senescence is a cellular response that may be crucial for protection against cancer development, but its investigation has so far been restricted to cultured cells that have been manipulated to overexpress an oncogene. Here we analyse tumours initiated by an endogenous oncogene, ras, and show that senescent cells exist in premalignant tumours but not in malignant ones. Senescence is therefore a defining feature of premalignant tumours that could prove valuable in the diagnosis and prognosis of cancer.

Histone macroH2A isoforms predict the risk of lung cancer recurrence

“…This phenomenon has been described for primary cell cultures in vitro (Hayflick, 1965) and is a response to stresses like telomere shortening, accumulation of DNA damage and the overexpression of certain oncogenes (Serrano et al, 1997). It is interesting to note that oncogene-induced senescence has emerged as a potent antitumor mechanism in vivo (Braig et al, 2005;Chen et al, 2005;Collado et al, 2005;Michaloglou et al, 2005;Collado and Serrano, 2006). Here, we also show that macroH2A1.1 is upregulated in senescent cells, consistent with the finding that macroH2A1.1 is more highly expressed in tumors with better prognosis.…”

“…Similar to what we observe in breast cancer arrays, statistical analysis of the lung tumor array reveals that macroH2A1.1 expression is strongly correlated with Ki-67 levels (Po0.001) and decreases with the increase of Ki-67 positive cancer cells (Figure 2a To further test this notion, we analyzed immunohistochemical sections from a mouse model of tumor senescence induced by K-RasG12V (Guerra et al, 2003). Our stainings reveal higher macroH2A1.1 expression in premalignant adenoma lesions, in which hallmark is an abundance of senescent cells (Braig et al, 2005;Chen et al, 2005;Collado et al, 2005), in comparison to the corresponding malignant adenocarcinomas (Figure 3a). In contrast, the splice variant macroH2A1.2 is expressed at similar levels in adenomas and adenocarcinomas.…”

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

“…Like apoptosis, senescence has been proposed as a tumor suppressor mechanism (Braig et al, 2005;Chen et al, 2005;Collado et al, 2005;Lazzerini Denchi et al, 2005;Michaloglou et al, 2005). In normal cells, genotoxic and oncogenic stress activate the p53-p21 and p16-pRB pathways, respectively, leading to transient or permanent growth arrest.…”

p53 isoforms gain functions

“…In addition to the first reported cellular senescence imposed by extensive proliferation and telomere shortening in human fibroblasts, it has become increasingly clear that genetic alterations and cellular stresses or damages linked to cancer development also trigger senescence. Animal models have suggested that preventing senescence can promote more malignant tumour progression and cells carrying characteristics of senescent cells can be found in pre-malignant samples that are lost as the state of transformation of the tumour cells increases (Braig et al, 2005;Collado et al, 2005;Dankort et al, 2007).…”