Sci. STKE, 9 August 2005
CANCER Cell Senescence Occurs in Vivo
Cell senescence, in which stresses such as the expression of activated oncogenes or DNA damage lead to permanent cell cycle arrest, has been postulated to act as a mechanism to prevent the progression of precancerous lesions to malignancy. However, it has been unclear whether senescence, which has been investigated in cultured cells, represents a physiological process (see Sharpless and DePinho). Now four separate groups, investigating various tissues, provide evidence that senescence indeed functions as an in vivo antitumor mechanism.
Chen et al. found that inactivation of the gene encoding the tumor suppressor PTEN in the mouse prostate led to the delayed appearance of nonlethal prostate cancer. Although inactivation in prostate of the gene encoding p53 alone had no apparent effect, the combined loss of PTEN and p53 led to the rapid appearance of lethal prostate cancer. In vitro experiments indicated that loss of PTEN led to decreased cell proliferation, appearance of senescence markers such as senescence-associated β-galactosidase (SA-β-Gal), and increased abundance of p53. Loss of p53 in cells lacking PTEN led to a decrease in senescent cells and an increase in proliferation. Immunohistochemical analysis indicated that, in vivo, loss of PTEN was associated with an increase in senescent cells and in p53 abundance and that the additional loss of p53 was associated with a marked decrease in the number of senescent cells. Thus, in this system, loss of PTEN appears to initiate senescence through a p53-dependent pathway.
Michaloglou et al. investigated moles (benign tumors that can progress to malignant melanoma), which often carry an oncogenic mutation in BRAF, a downstream effector of Ras. Sustained expression of the BRAF mutant (BRAFE600) in isolated human melanocytes led to cell cycle arrest, intense SA-β-Gal activity, and a heterogeneous increase in the abundance of p16INK4a, a tumor suppressor that promotes senescence. Melanocytes in specimens of human moles expressing BRAFE600 were growth-arrested and showed strong SA-β-Gal activity and a heterogeneous increase in the abundance of p16INK4a. Unlike the system investigated by Chen et al., however, moles did not show an increase in p53 abundance.
Activation of senescence by Ras through p16INK4a involves activation of the retinoblastoma (Rb) protein, leading to silencing of growth-promoting genes through heterochromatin formation. Senescence-associated heterochromatin foci are associated with methylation of histone H3 lysine 9 (H3K9me), leading Braig et al. to explore the hypothesis that Rb promotes senescence through the histone methyltransferase Suv39h1. The authors crossed transgenic mice expressing an oncogenic Ras mutation targeted to hematopoietic cells with Suv39h1 knockout mice and found that loss of Suv39h1 in Ras transgenic mice led to the development of lethal T cell lymphomas, whereas Ras mutation alone promoted the much slower development of nonlymphoid malignancies. When activated Ras was expressed in primary splenocytes that expressed Suv39h1, cells showed an increase in H3K9 methylation and intense SA-β-Gal activity and virtually ceased to proliferate, whereas cells lacking Suv39h1 failed to show an increase in H3K9 methylation or SA-β-Gal activity and continued to proliferate. Moreover, when protected from apoptosis, primary cultures of Ras-driven lymphomas underwent senescence in response to the antineoplastic drug adriamycin, whereas Ras-driven lymphomas lacking Suv39h1 did not. Thus, Suv39h1-dependent histone methylation appears to regulate cell senescence in response to oncogenic signaling from Ras.
Finally, Collado et al. analyzed premalignant and malignant tumors of mouse lung and pancreas induced by oncogenic Ras. They monitored a set of novel senescence markers identified through DNA microarray analysis of in vitro oncogene-induced senescence as well as for p16INK4a expression, SA-β-Gal activity, and senescence-associated heterochromatin foci. Immunohistochemical analysis indicated that senescence markers were abundant in premalignant lesions of both lung and pancreas but not in frank cancers. Thus, research from all four groups suggests that senescence functions in vivo to prevent tumor progression.
Z. Chen, L. C. Trotman, D. Shaffer, H.-K. Lin, Z. A. Dotan, M. Niki, J. A. Koutcher, H. I. Scher, T. Ludwig, W. Gerald, C. Cordon-Cardo, P. P. Pandolfi, Crucial role of p53-dependent cellular senescence in suppression of PTEN-deficient tumorigenesis. Nature 436, 725-730 (2005). [PubMed]
C. Michaloglou, L. C. W. Vredeveld, M. S. Soengas, C. Denoyells, T. Kuilman, C. M. A. M. van der Horst, D. M. Majoor, J. W. Shay, W. J. Mooi, BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720-724 (2005). [PubMed]
M. Braig, S. Lee, C. Loddenkemper, C. Rudolph, A. H. F. M. Peters, B. Schlegelberger, H. Stein, B. Dörken, T. Jenuwein, C. A. Schmidt, Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660-665 (2005). [PubMed]
M. Collado, J. Gil, A. Efeyan. C. Guerra, A. J. Schuhmacher, M. Barradas, J. M. Flores, M. Barbacid, D. Beach, M. Serrano, Senescence in premalignant tumors. Nature 436, 642 (2005). [PubMed]
N. E. Sharpless, R. A. DePinho, Crime and punishment. Nature 436, 636-637 (2005). [PubMed]
Citation: Cell Senescence Occurs in Vivo. Sci. STKE 2005, tw288 (2005).
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