Alternatively, inhibition of specific SASP factors could also be achieved, as is the case for IL-6, IL-8 and TNF. of NRC-AN-019 therapy-induced senescence in cancer and highlight the great promise of two-step strategies in anticancer therapies. showed stem-like features, in which the expression of and was markedly increased. is a master transcription factor of cellular self-renewal.55 Moreover, senescent human and mouse cancer cells could also exhibit proliferation potential and senescence characteristics at the same time.11,19 In epithelial ovarian cancer (EOC), Nacarelli et al NRC-AN-019 found that cisplatin-induced senescence upregulated ALDH1 protein levels and the expression of along with mRNA, which is also the cancer stem-like cell (CSC) signature. When cisplatin-treated EOC cells rather than EOC cells were inhibited, the EOC CSC signature was suppressed and the survival of EOC-bearing mice was improved.56 By lineage tracing the p21+ senescent cells in the p21-CreER mouse model, some of the previously labeled senescent cells were found to re-entered the cell cycle and proliferate rather than being cleared at the late embryonic stage.57 In agreement with previous observations, the researchers from Charit University Medicine found that E-Myc-Bcl2-overexpressing lymphoma cells induced senescence by chemotherapy exhibited both senescence and stem cell-like characteristics. Based on single-cell tracking experiments, SA–gal-positive cells were found to incorporate 5-ethynyl-2-deoxyuridine (EdU), which suggested that senescent cells restarted DNA synthesis. More importantly, the senescent tumor cells of mouse and human origin were allowed to escape cellular senescence and resume sustainable proliferation when senescence-essential mediators such as Suv39 h1 or p53 were acutely inactivated. Strikingly, compared to cells that are never senescent, tumor cells that escape from the senescent state can re-enter the cell cycle with higher aggressive growth and tumor-initiation potential by activating the WNT pathway.19 In addition, Yu et al showed that loss of the H3K9 me3 mark, such as elevate activity of the H3K9 demethylase JMJD2C, could make OIS cell re-entry into Rabbit Polyclonal to OR cell cycle in melanocyte models.58 These findings indicate that senescent cells have the potential to repossess their self-renewal capability. TIS may result in senescence-associated reprogramming, which promotes cells to escape from the arrested condition and cancer recurrence (Figure 1B). However, more direct evidence about the stemness recovery of senescent tumor cells remains to be investigated in the future. Senescence-Associated Signaling Crosstalk Between Tumor Cells and Their Niche Cells Senescent cells can secrete a complex mixture of proinflammatory cytokines, chemokines, growth factors NRC-AN-019 and other cytokines, which is also called as SASP.10 These secretomes might be an important mediator of the cross-talk between senescent cells and nonsenescent cells (Figure 1C). The Effects of Senescent Cancer Cells on Neighboring Cells At the early stage of tumors, SASPs contribute to increased tumor growth control by reinforcing and/or spreading senescence-associated cell cycle exit via autocrine and paracrine signaling. SASPs might be required for stable cell cycle arrest. For example, IL-6 and IL-8, the major components of the SASP, have been NRC-AN-019 shown to restrain the proliferation of malignant cells by reinforcing the senescence growth arrest in an autocrine fashion.59 PAI-1 was also found to be essential for the induction of senescence even in the absence of p53.60 In other studies, senescent MCF-7 breast cancer cells triggered by adriamycin were observed to have an antiproliferative effect in which they induced a senescent state of cell cycle arrest in naive MCF-7 cells by secreting factors in vitro.61 Paracrine-induced senescence by SASPs might be important for the inhibition of tumor progression. Moreover, secreted SASP factors can directly modulate the immune response by signaling to the immune system. As described NRC-AN-019 above, senescent cancer cells recruit immune cells to remove the senescent tumor cells, consequently limiting tumor progression via engagement of the innate and adaptive immune systems. Other than frequently acting as an anticancer mechanism, senescent cells have recently been considered beneficial to cancer progression and relapse in some settings.10,18 Their contribution includes creating an immunosuppressive and protumor tissue microenvironment that protects some cancer cells from being cleared and permits tumor cell residues, thus positively favoring cancer relapse and progression. One of the functions of SASPs is that they can suppress the tumor immune response, which contributes to cancer promotion. For example, a recent study found that chemotherapy-induced senescent cells were able to circumvent immune clearance through concerted MMP-mediated shedding of NKG2D ligands and paracrine.