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The induction of cellular senescence is often seen a beneficial therapeutic strategy for preventing the growth of cancer. This may certainly be the case in the short-term, but the biological impact of senescent cells in the long-term is greatly understudied. Senescent cells are more than just a permanent state of growth arrest; they also display an immune-evoking pro-inflammatory secretory phenotype. However, for some yet unknown reason, senescent cells can evade immune clearance and potentially alter their microenvironment by continuously secreting of pro-inflammatory factors. These pro-inflammatory factors are thus one possible mechanism by which senescent cells could promote the reoccurrence of cancer following senescence therapy.
Prostate cancer (PCa) is one of the most common cancers in American men and a leading cause of cancer- related death. Initial PCa tumours are dependent upon the presence of androgen, such as testosterone, for growth. As such, undergoing androgen deprivation therapy (ADT) is currently the most effective procedure for suppressing tumour progression. ADT not only causes tumour cell death leading to reduction in tumour size, but also induces a proliferative arrest in a large fraction of tumour cells. Within a few years following ADT, the PCa can reemerge, that are no longer dependent on androgen for growth, and for which there are currently no effective therapeutic treatment strategies. Recurrence of nonresponsive or androgen-refractory tumours reduces patient life expectancy to less than two years.
To investigate the mechanisms of PCa reoccurrence, Burton et al focused their efforts on the cells undergoing proliferative arrest in response to ADT. They provide evidence that androgen deprivation-induced proliferative arrest is in fact cellular senescence, termed ADIS (androgen deprivation-induced senescence). The induction of ADIS appears to be due to intracellular up-regulation of ROS and consequently DNA damage. Their data show that continuous exposure of an androgen-sensitive PCa cell line (LNCaP) to the senescent microenvironment, leads to the appearance of cells with androgen-independent characteristics. Further, it is shown that pharmacologic enforcement of the p53-Bax pro-death pathway prior to androgen deprivation (AD) preferentially triggers cellular death rather than cellular senescence. It is thus postulated that the use of drug therapies prior/during ADT that promote cell death rather than cellular senescence may prevent/reduce androgen refractory PCa.
The more difficult question to answer concerns the mechanisms that facilitate the appearance of cells with androgen-refractory characteristics. One possibility is that the secretory phenotype of senescent cells stimulates the proliferation of so called, cancer stem cells (CSCs). The senescent secretory profile is similar to that which occurs during a wound healing response, suggesting CSC may proliferate to facilitate wound repair but in this context facilitates tumour formation. Interestingly, TAp63, a marker of basal prostatic cells, a progenitor population known to survive androgen ablation and is involved in the maintenance of adult stem cells is elevated in the emerging androgen-refractory cells. TAp63 overexpression has also been associated with resistance to premature senescence, suggesting the emerging androgen-refractory cells, at least in part, may be the result of selective pressure favoring the proliferation of cells resistant to ADIS. Further, the secretory phenotype of the surrounding senescent cells may facilitate the expansion of ADIS resistant cells.
This work is important because it addresses the controversial issue of whether AD-induced senescence in cancer cells promotes the progression of the disease; if this is the case, these phenomena can provide therapeutic targets to prevent progression. Additionally, this study provides a method for generating and expanding androgen-refractory cells in a shorter period of time, cells which can be used for further study.
Link to Article: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0068003
Obesity has become more prevalent in most developed countries over the past few decades, and is increasingly recognized as a major risk factor for several common types of cancer1. As the worldwide obesity epidemic has shown no signs of abating, better understanding of the mechanisms underlying obesity-associated cancer is urgently needed. Although several events were proposed to be involved in obesity-associated cancer1, 3, the exact molecular mechanisms that integrate these events have remained largely unclear. Here we show that senescence-associated secretory phenotype (SASP)4, 5has crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice. Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of deoxycholic acid (DCA), a gut bacterial metabolite known to cause DNA damage6. The enterohepatic circulation of DCA provokes SASP phenotype in hepatic stellate cells (HSCs)7, which in turn secretes various inflammatory and tumour-promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogen. Notably, blocking DCA production or reducing gut bacteria efficiently prevents HCC development in obese mice. Similar results were also observed in mice lacking an SASP inducer8 or depleted of senescent HSCs, indicating that the DCA–SASP axis in HSCs has key roles in obesity-associated HCC development. Moreover, signs of SASP were also observed in the HSCs in the area of HCC arising in patients with non-alcoholic steatohepatitis3, indicating that a similar pathway may contribute to at least certain aspects of obesity-associated HCC development in humans as well. These findings provide valuable new insights into the development of obesity-associated cancer and open up new possibilities for its control.
Premature lung aging and cellular senescence in the pathogenesis of idiopathic pulmonary fibrosis and COPD/emphysema
Link to Article: http://www.sciencedirect.com/science/article/pii/S1931524413001825
Androgen Deprivation-Induced Senescence Promotes Outgrowth of Androgen-Refractory Prostate Cancer Cells
Dominick G. A. Burton, Maria G. Giribaldi, Anisleidys Munoz, Katherine Halvorsen, Asmita Patel, Merce Jorda, Carlos Perez-Stable, Priyamvada Rai
- Androgen deprivation (AD) is an effective method for initially suppressing prostate cancer (PC) progression. However, androgen-refractory PC cells inevitably emerge from the androgen-responsive tumor, leading to incurable disease. Recent studies have shown AD induces cellular senescence, a phenomenon that is cell-autonomously tumor-suppressive but which confers tumor-promoting adaptations that can facilitate the advent of senescence-resistant malignant cell populations. Because androgen-refractory PC cells emerge clonally from the originally androgen-responsive tumor, we sought to investigate whether AD-induced senescence (ADIS) affects acquisition of androgen-refractory behavior in androgen-responsive LNCaP and LAPC4 prostate cancer cells. We find that repeated exposure of these androgen-responsive cells to senescence-inducing stimuli via cyclic AD leads to the rapid emergence of ADIS-resistant, androgen-refractory cells from the bulk senescent cell population. Our results show that the ADIS phenotype is associated with tumor-promoting traits, notably chemoresistance and enhanced pro-survival mechanisms such as inhibition of p53-mediated cell death, which encourage persistence of the senescent cells. We further find that pharmacologic enforcement of p53/Bax activation via Nutlin-3 prior to establishment of ADIS is required to overcome the associated pro-survival response and preferentially trigger pervasive cell death instead of senescence during AD. Thus our study demonstrates that ADIS promotes outgrowth of androgen-refractory PC cells and is consequently a suboptimal tumor-suppressor response to AD.
- Androgen deprivation (AD) is an effective method for initially suppressing prostate cancer (PC) progression. However,
- androgen-refractory PC cells inevitably emerge from the androgen-responsive tumor, leading to incurable disease. Recent