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As a barrier to metastasis of cancer, cells that lost contact with the neighbouring cells or extracellular matrix(Extracellular matrix, ECM) will be subjected to apoptosis. This cell death process has been termed "anoikis". When normal epithelial cells or solid tumor cells without metastatic potential detach from the primary site, and then enter into the circulatory system, the anoikis mechanism will be activated. The significance of anoikis is to prevent the shedding cells from growing and implanting into other inappropriate sites. Tumor cells, especially several malignant cells that is prone to transfer to distant sites, have properties of anti-anoikis, which facilitates metastasis as well as invasion of tumor cells. The studies found that tumor cells can resist anoikis through multiple mechanisms: the pro-survival pathways are activated by cells autocrine growth factors and paracrine factors derived from neighboring cells; cells change the pattern of integrin expression so that they can receive survival signals from new environment; reactive oxygen species (ROS) activates growth factor receptors in a ligand-independent way to avoid apoptosis; and epithelial-mesenchymal transformation(EMT) is activated etc.. All of these mechanisms lead to activation of survival signals and inhibition of apoptotic pathways, and ultimately cause resistance to anoikis as well as metastasis. This paper summarizes the key mechanisms of the current studies on metastasis, which also suggest important targets for cancer therapy.

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Werner syndrome (WS) is a rare autosomal recessive progeria disease with genetic instability/cancer predisposition, thus a good model in understanding aging related carcinogenesis. Telomere dysfunction induced cellular senescence is essential in the manifestation of the WS phenotype. Our previous data has shown that p21 (encoded by Cdkn1a gene) could induce cellular senescence and suppress cellular growth of ALT (alternative lengthening of telomere) tumors derived from WS, suggested that p21 might play a key role in maintaining senescence of WS cells.To confirm the role of p21 in suppressing telomere dysfunction induced tumorigenesis, we overexpressed dominant negative protein TRF2ΔBΔM in p21-/- mouse embryonic fibroblasts (MEFs). To further stress the cell, we crossed Wrn-/-mice with p21-/- mice to obtained p21-/-Wrn-/- MEFs, and overexpressed TRF2ΔBΔM in these MEFs to induce telomere dysfunction similar to that in WS cells. Our data showed that, in the context of p21-/-TRF2ΔBΔM, loss of p21 function rescued cellular senescence, and induced p53 mutation, but did not induce tumorigenesis. However, in the set of p21-/-Wrn-/-TRF2ΔBΔM, loss of p21 function induced p53 mutation and tumorigenesis.To further verify the role of p21 in suppressing telomere dysfunction related tumorigenesis, we knocked down p21 in non-tumorigenic immortalized cells derived from WS MEFs (mTerc-/-Wrn-/-), and found that loss of p21 could induce ALT tumorigenesis, which displayed typical smear pattern of telomere length and arc-shaped telomeric DNA. In another hand, recovering telomerase activity in these MEFs could also induce tumorigenesis without affecting p21 expression level. Together our data suggested that p21 controlled cell cycle regulation played an essential role in suppressing telomere dysfunction-related tumorigenesis. These data also suggested that the genetic context is essential in determining the role of p21 in cancer prevention. Therefore, targeting p21 in the treatment of human degenerative diseases would require a personalized genetic background screen.