Cellular Senescence in Prostate Cancer Reoccurrence

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

DOI: 10.1371/journal.pone.0068003 

Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome


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


Different anatomic and physiological changes occur in the lung of aging people that can affect pulmonary functions and different pulmonary diseases heterogeneously, including deadly diseases such as chronic obstructive pulmonary disease (COPD)/emphysema and idiopathic pulmonary fibrosis (IPF), and can be related to an acceleration of the aging process. The individual genetic background, as well as the exposure to a variety of toxic substances (cigarette smoke in primis) can contribute significantly to accelerating pulmonary senescence. Premature aging can impair lung function by different ways: by interfering specifically with tissue repair mechanisms after damage, thus perturbing the correct crosstalk between mesenchymal and epithelial components; by inducing systemic and/or local alteration of the immune system, thus impairing the complex mechanisms of lung defense against infections; and by stimulating a local and/or systemic inflammatory condition (inflammaging). According to recently proposed pathogenic models in COPD and IPF, premature cellular senescence likely affects distinct progenitors cells, leading to stem cell exhaustion. Mesenchymal stem cells in COPD, alveolar epithelial precursors in IPF. In this review, the large amount of data supporting this pathogenic view are discussed, with emphasis on the possible molecular and cellular mechanisms leading to the severe parenchymal remodeling that characterizes, in different ways, these deadly diseases.

The main focus of ageing research is to prevent/combat age-related disease and disability, allowing everyone to live healthier lives for longer.