[PDF][PDF] Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS

JP Coppé, CK Patil, F Rodier, Y Sun, DP Munoz - 2008 - journals.plos.org
JP Coppé, CK Patil, F Rodier, Y Sun, DP Munoz
2008journals.plos.org
Cancer is a multistep disease in which cells acquire increasingly malignant phenotypes.
These phenotypes are acquired in part by somatic mutations, which derange normal
controls over cell proliferation (growth), survival, invasion, and other processes important for
malignant tumorigenesis [1]. In addition, there is increasing evidence that the tissue
microenvironment is an important determinant of whether and how malignancies develop [2,
3]. Normal tissue environments tend to suppress malignant phenotypes, whereas abnormal …
Cancer is a multistep disease in which cells acquire increasingly malignant phenotypes. These phenotypes are acquired in part by somatic mutations, which derange normal controls over cell proliferation (growth), survival, invasion, and other processes important for malignant tumorigenesis [1]. In addition, there is increasing evidence that the tissue microenvironment is an important determinant of whether and how malignancies develop [2, 3]. Normal tissue environments tend to suppress malignant phenotypes, whereas abnormal tissue environments such at those caused by inflammation can promote cancer progression. Cancer development is restrained by a variety of tumor suppressor genes. Some of these genes permanently arrest the growth of cells at risk for neoplastic transformation, a process termed cellular senescence [4–6]. Two tumor suppressor pathways, controlled by the p53 and p16INK4a/pRB proteins, regulate senescence responses. Both pathways integrate multiple aspects of cellular physiology and direct cell fate towards survival, death, proliferation, or growth arrest, depending on the context [7, 8]. Several lines of evidence indicate that cellular senescence is a potent tumor-suppressive mechanism [4, 9, 10]. Many potentially oncogenic stimuli (eg, dysfunctional telomeres, DNA damage, and certain oncogenes) induce senescence [6, 11]. Moreover, mutations that dampen the p53 or p16INK4a/pRB pathways confer resistance to senescence and greatly increase cancer risk [12, 13]. Most cancers harbor mutations in one or both of these pathways [14, 15]. Lastly, in mice and humans, a senescence response to strong mitogenic signals, such as those delivered by certain oncogenes, prevents premalignant lesions from progressing to malignant cancers [16–19].
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