Cancer and aging: a model for the cancer promoting effects of the aging stroma

The incidence of cancer rises exponentially with age in humans and many other mammalian species. Malignant tumors are caused by an accumulation of oncogenic mutations. In addition, malignant tumorigenesis requires a permissive tissue environment in which mutant cells can survive, proliferate, and express their neoplastic phenotype. We propose that the age-related increase in cancer results from a synergy between the accumulation of mutations and age-related, pro-oncogenic changes in the tissue milieu. Most age-related cancers derive from the epithelial cells of renewable tissues. An important element of epithelial tissues is the stroma, the sub-epithelial layer composed of extracellular matrix and several cell types. The stroma is maintained, remodeled and repaired by resident fibroblasts, supports and instructs the epithelium, and is essential for epithelial function. One change that occurs in tissues during aging is the accumulation of epithelial cells and fibroblasts that have undergone cellular senescence. Cellular senescence irreversibly arrests proliferation in response to damage or stimuli that put cells at risk for neoplastic transformation. Senescent cells secrete factors that can disrupt tissue architecture and/or stimulate nearby cells to proliferate. We therefore speculate that their presence may create a pro-oncogenic tissue environment that synergizes with oncogenic mutations to drive the rise in cancer incidence with age. Recent evidence lends support to this idea, and suggests that senescent stromal fibroblasts may be particularly adept at creating a tissue environment that can promote the development of age-related epithelial cancers.     

衰老或肿瘤：癌基因诱导的双向性

在大部分的肿瘤中都发现有癌基因的活化,癌基因的活化被认为是导致肿瘤发生的重要原因．然而,在野生型细胞内,癌基因的活化可以诱导细胞衰老,称为癌基因诱导的细胞衰老(oncogene-induced senescence, OIS),从而抑制进一步的肿瘤发生．因而,癌基因的活化具有诱导衰老或肿瘤的双向性．DNA损伤调控反应(DNA damage checkpoint response, DDR)是细胞应对DNA损伤时感应损伤,从而延迟或阻滞细胞周期进程的一种分子信号传递通路,是诱导细胞衰老的重要机制．癌基因的活化可以引发DNA损伤信号的产生,从而激活DDR,诱导细胞衰老．在DDR异常时,癌基因的激活可引发DNA的过度复制与细胞的过度增殖,并导致基因组不稳定性的积累,最终导致肿瘤发生．DDR的完整性决定了癌基因诱导的双向性．DDR在癌基因诱导中的重要作用,提示了保持和恢复DDR的完整性可以作为肿瘤预防和治疗的新方向．     

Arrested development and the great escape – The role of cellular senescence in pancreatic cancer

The outcomes of pancreatic cancer remain dismal due to late clinical presentation and the aggressive nature of the disease. A heterogeneous combination of genetic mutations, including KRAS, INK4a/CDKN2A and p53, underpin the propensity of pancreatic cancer to rapidly invade and disseminate. These oncogenes and tumour suppressors are strongly associated with cellular senescence, therefore suggesting this process as having a key role in malignant transformation. In the context of cancer, oncogenic stimuli trigger the senescent phenotype resulting in cell cycle growth arrest and prevention of progression of premalignant lesions such as PanINs. However mutations of the aforementioned oncogenes or tumour suppressors result in cells escaping senescence and thus allowing tumours to progress. This review presents current evidence regarding both senescence induction and escape with respect to pancreatic cancer, highlighting the key roles of p19ARF, p53, Rb and P16INK4a. The epigenetic regulatory component is also discussed, with relevance to DNA methylation and HDACs. Lastly the role of the tumour microenvironment, and in particular pancreatic stellate cells, is discussed with regards to the induction of a senescence associated secretory phenotype (SASP), with SASP-associated secretory factors contributing to the pro-tumorigenic effects of the surrounding activated stroma. Further work is required in this field to elucidate the most important pathways relating to cellular senescence that contribute to the belligerent nature of this disease, with the aim of discovering therapeutic targets to improve patient outcomes.     

Four faces of cellular senescence

Cellular senescence is an important mechanism for preventing the proliferation of potential cancer cells. Recently, however, it has become apparent that this process entails more than a simple cessation of cell growth. In addition to suppressing tumorigenesis, cellular senescence might also promote tissue repair and fuel inflammation associated with aging and cancer progression. Thus, cellular senescence might participate in four complex biological processes (tumor suppression, tumor promotion, aging, and tissue repair), some of which have apparently opposing effects. The challenge now is to understand the senescence response well enough to harness its benefits while suppressing its drawbacks.     

Aneuploidy,cell delamination and tumorigenesis in Drosophila epithelia

Chromosomal instability (CIN) is a common feature in human cancer, and highly aneuploid tumors are frequently associated with poor prognosis; however, the molecular and cellular mechanisms underlying CIN-induced tumorigenesis are poorly understood. Here we review recent findings about the role of CIN in driving tumor-like growth and host invasiveness in Drosophila epithelia and discuss the commonalities of CIN-induced tumors with other Drosophila-based cancer models. We also discuss possible scenarios that can account for the participation of CIN in tumorigenesis and propose that, alternatively to the classical role of aneuploidy in promoting the accumulation of mutations in cancer cells, aneuploidy can be a source of stress that may contribute to cancer initiation and/or progression.     

Clusterin/apolipoprotein J in human aging and cancer

Clusterin/Apolipoprotein J (ApoJ) is a heterodimeric highly conserved secreted glycoprotein being expressed in a wide variety of tissues and found in all human fluids. Despite being cloned since 1989, no genuine function has been attributed to ApoJ so far. The protein has been reportedly implicated in several diverse physiological processes such as sperm maturation, lipid transportation, complement inhibition, tissue remodeling, membrane recycling, cell-cell and cell-substratum interactions, stabilization of stressed proteins in a folding-competent state and promotion or inhibition of apoptosis. ApoJ gene is differentially regulated by cytokines, growth factors and stress-inducing agents, while another defining prominent and intriguing ApoJ feature is its upregulation in many severe physiological disturbances states and in several neurodegenerative conditions mostly related to advanced aging. Moreover, ApoJ accumulates during the viable growth arrested cellular state of senescence, that is thought to contribute to aging and to tumorigenesis suppression; paradoxically ApoJ is also upregulated in several cases of in vivo cancer progression and tumor formation. This review focuses on the reported data related to ApoJ cell-type and signal specific regulation, function and site of action in normal and cancer cells. We discuss the role of ApoJ during cellular senescence and tumorigenesis, especially under the light of the recently demonstrated various ApoJ intracellular protein forms and their interaction with molecules involved in signal transduction and DNA repair, raising the possibility that its overexpression during cellular senescence might cause a predisposition to cancer.     

Cellular senescence: putting the paradoxes in perspective

Cellular senescence arrests the proliferation of potential cancer cells, and so is a potent tumor suppressive mechanism, akin to apoptosis. Or is it? Why did cells evolve an anti-cancer mechanism that arrests, rather than kills, would-be tumor cells? Recent discoveries that senescent cells secrete growth factors, proteases and cytokines provide a shifting view--from senescence as a cell autonomous suppressor of tumorigenesis to senescence as a means to mobilize the systemic and local tissue milieu for repair. In some instances, this mobilization benefits the organism, but in others it can be detrimental. These discoveries provide potential mechanisms by which cellular senescence might contribute to the diverse, and seemingly incongruent, processes of tumor suppression, tumor promotion, tissue repair, and aging.     

Mitotic catastrophe: a mechanism for avoiding genomic instability

The improper distribution of chromosomes during mitosis compromises cellular functions and can reduce cellular fitness or contribute to malignant transformation. As a countermeasure, higher eukaryotes have developed strategies for eliminating mitosis-incompetent cells, one of which is mitotic catastrophe. Mitotic catastrophe is driven by a complex and poorly understood signalling cascade but, from a functional perspective, it can be defined as an oncosuppressive mechanism that precedes (and is distinct from) apoptosis, necrosis or senescence. Accordingly, the disruption of mitotic catastrophe precipitates tumorigenesis and cancer progression, and its induction constitutes a therapeutic endpoint.     

Recent advances in cellular senescence, cancer and aging

How much do we know about the biology of aging from cell culture studies? Most normal somatic cells have a finite potential to divide due to a process termed cellular or replicative senescence. A growing body of evidence suggests that senescence evolved to protect higher eukaryotes, particularly mammals, from developing cancer. We now know that telomere shortening, due to the biochemistry of DNA replication, induces replicative senescence in human cells. However, in rodent cells, replicative senescence occurs despite very long telomeres. Recent findings suggest that replicative senescence is just the tip of the iceberg of a more general process termed cellular senescence. It appears that cellular senescence is a response to potentially oncogenic insults, including oxidative damage. In young organisms, growth arrest by cell senescence suppresses tumor development, but later in life, due to the accumulation of senescent cells which secret factors that can disrupt tissues during aging, cellular senescence promotes tumorigenesis. Therefore, antagonistic pleiotropy may explain in part, if not in whole, the apparently paradoxical effects of cellular senescence, though this still remains an open question.     

Repair and regeneration: opportunities for carcinogenesis from tissue stem cells

This review will discuss the mechanisms of repair and regeneration in various tissue types and how dysregulation of these mechanisms may lead to cancer. Normal tissue homeostasis involves a careful balance between cell loss and cell renewal. Stem and progenitor cells perform these biologic processes as the functional units of regeneration during both tissue homeostasis and repair. The concept of tissue stem cells capable of giving rise to all differentiated cells within a given tissue led to the concept of a cellular hierarchy in tissues and in tumors. Thus, only a few cells may be necessary and sufficient for tissue repair or tumor regeneration. This is known as the hierarchical model of tumorigenesis. This report will compare this model with the stochastic model of tumorigenesis. Under normal circumstances, the processes of tissue regeneration or homeostasis are tightly regulated by several morphogen pathways to prevent excessive or inappropriate cell growth. This review presents the recent evidence that dysregulation of these processes may provide opportunities for carcinogenesis for the long-lived, highly proliferative tissue stem cell population. New findings of cancer initiating tissue stem cells identified in several solid and circulating cancers including breast, brain and hematopoietic tumors will also be reviewed. Finally, this report reviews the cellular biology of cancer and its relevance to the development of more effective cancer treatment protocols.     

miR-22 represses cancer progression by inducing cellular senescence

Cellular senescence acts as a barrier to cancer progression, and microRNAs (miRNAs) are thought to be potential senescence regulators. However, whether senescence-associated miRNAs (SA-miRNAs) contribute to tumor suppression remains unknown. Here, we report that miR-22, a novel SA-miRNA, has an impact on tumorigenesis. miR-22 is up-regulated in human senescent fibroblasts and epithelial cells but down-regulated in various cancer cell lines. miR-22 overexpression induces growth suppression and acquisition of a senescent phenotype in human normal and cancer cells. miR-22 knockdown in presenescent fibroblasts decreased cell size, and cells became more compact. miR-22-induced senescence also decreases cell motility and inhibits cell invasion in vitro. Synthetic miR-22 delivery suppresses tumor growth and metastasis in vivo by inducing cellular senescence in a mouse model of breast carcinoma. We confirmed that CDK6, SIRT1, and Sp1, genes involved in the senescence program, are direct targets of miR-22. Our study provides the first evidence that miR-22 restores the cellular senescence program in cancer cells and acts as a tumor suppressor.     

Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors

Cells from organisms with renewable tissues can permanently withdraw from the cell cycle in response to diverse stress, including dysfunctional telomeres, DNA damage, strong mitogenic signals, and disrupted chromatin. This response, termed cellular senescence, is controlled by the p53 and RB tumor suppressor proteins and constitutes a potent anticancer mechanism. Nonetheless, senescent cells acquire phenotypic changes that may contribute to aging and certain age-related diseases, including late-life cancer. Thus, the senescence response may be antagonistically pleiotropic, promoting early-life survival by curtailing the development of cancer but eventually limiting longevity as dysfunctional senescent cells accumulate.     

Autophagy and cancer cell metabolism

Autophagy is a catabolic process involving lysosomal turnover of proteins and organelles for maintenance of cellular homeostasis and mitigation of metabolic stress. Autophagy defects are linked to diseases, such as liver failure, neurodegeneration, inflammatory bowel disease, aging and cancer. The role of autophagy in tumorigenesis is complex and likely context-dependent. Human breast, ovarian and prostate cancers have allelic deletions of the essential autophagy regulator BECN1 and Becn1(+/-) and other autophagy-deficient transgenic mice are tumor-prone, whereas tumors with constitutive Ras activation, including human pancreatic cancers, upregulate basal autophagy and are commonly addicted to this pathway for survival and growth; furthermore, autophagy suppression by Fip200 deletion compromises PyMT-induced mammary tumorigenesis. The double-edged sword function of autophagy in cancer has been attributed to both cell- and non-cell-autonomous mechanisms, as autophagy defects promote cancer progression in association with oxidative and ER stress, DNA damage accumulation, genomic instability and persistence of inflammation, while functional autophagy enables cancer cell survival under stress and likely contributes to treatment resistance. In this review, we will focus on the intimate link between autophagy and cancer cell metabolism, a topic of growing interest in recent years, which has been recognized as highly clinically relevant and has become the focus of intense investigation in translational cancer research. Many tumor-associated conditions, including intermittent oxygen and nutrient deprivation, oxidative stress, fast growth and cell death suppression, modulate, in parallel and in interconnected ways, both cellular metabolism and autophagy to enable cancer cells to rapidly adapt to environmental stressors, maintain uncontrolled proliferation and evade the toxic effects of radiation and/or chemotherapy. Elucidating the interplay between autophagy and tumor cell metabolism will provide unique opportunities to identify new therapeutic targets and develop synthetically lethal treatment strategies that preferentially target cancer cells, while sparing normal tissues.     

Rb function in the apoptosis and senescence of non-neuronal and neuronal cells: role in oncogenesis

Regulators of the cell cycle machinery play a major role in modulating a variety of cellular phenomena including proliferation, quiescence, differentiation, senescence and apoptosis. Studies in the past decade have clearly established a role for the retinoblastoma tumor suppressor protein, Rb, and its primary downstream target E2F1, in the above processes. While the role of the Rb protein in the regulation of cell cycle progression has been analyzed in great detail, its potential roles in apoptosis as well as senescence are relatively less studied. It has become increasingly clear that the anti-apoptotic functions of Rb contribute significantly to the genesis and progression of tumors. This is especially relevant in neuronal systems, since terminally differentiated neurons do not proliferate; therefore the normal anti-proliferative functions of Rb in neurons are not very dominant. This chapter describes the current thoughts on the role of Rb function in the apoptosis and senescence of cells, both of neuronal and non-neuronal origin. Recent studies have also addressed how Rb function is differentially modulated by proliferative and apoptotic signals received at the cell surface, though both lead to Rb inactivation. The contribution of Rb to inducing cellular senescence has been long recognized, but the underlying molecular mechanisms are being elucidated only recently; the contribution of this function of Rb to tumor suppression remains to be understood in detail. It can be expected that an understanding of Rb function in cellular apoptosis and senescence will enhance our ability to develop novel agents and strategies to combat cancer.     

Inactivation of heat shock factor Hsf4 induces cellular senescence and suppresses tumorigenesis in vivo

Studies suggest that Hsf4 expression correlates with its role in cell growth and differentiation. However, the role of Hsf4 in tumorigenesis in vivo remains unexplored. In this article, we provide evidence that absence of the Hsf4 gene suppresses evolution of spontaneous tumors arising in p53- or Arf-deficient mice. Furthermore, deletion of hsf4 alters the tumor spectrum by significantly inhibiting development of lymphomas that are normally observed in the majority of mice lacking p53 or Arf tumor suppressor genes. Using mouse embryo fibroblasts deficient in the hsf4 gene, we have found that these cells exhibit reduced proliferation that is associated with induction of senescence and senescence-associated β-galactosidase (SA-β-gal). Cellular senescence in hsf4-deficient cells is associated with the increased expression of the cyclin-dependent kinase inhibitors, p21 and p27 proteins. Consistent with the cellular senescence observed in vitro, specific normal tissues of hsf4(-/-) mice and tumors that arose in mice deficient in both hsf4 and p53 genes exhibit increased SA-β-gal activity and elevated levels of p27 compared with wild-type mice. These results suggest that hsf4 deletion-induced senescence is also present in vivo. Our results therefore indicate that Hsf4 is involved in modulation of cellular senescence, which can be exploited during cancer therapy.     

Chromatin: a molecular interface between cancer and aging

To prevent cancer, mammals have evolved potent tumor suppression mechanisms, including senescence and apoptosis. These processes depend on regulation of chromatin. Chromatin-dependent tumor suppressor pathways are activated in premalignant cells and tissues harboring cancer-causing genetic alterations, and also in normal aged tissue, the latter likely due to accumulation of genetic and cellular damage. Paradoxically, however, disruption of chromatin structure may also promote cancer. Apparent defects in chromatin structure accumulate with age, the biggest single risk factor for cancer. Evidence suggests that these age-associated perturbations in chromatin structure contribute to the age-associated increase in incidence of cancer. Thus, alterations in chromatin structure can both suppress and promote the onset of cancer, and both activities are inextricably linked to aging.     

Regulation of cGAS-STING signalling in cancer: Approach for combination therapy

Innate immunity plays an important role not only during infection but also homeostatic role during stress conditions. Activation of the immune system including innate immune response plays a critical role in the initiation and progression of tumorigenesis. The innate immune sensor recognizes pathogen-associated molecular patterns (PAMPs) and activates cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) (cGAS-STING) and induces type-1 immune response during viral and bacterial infection. cGAS-STING is regulated differently in conditions like cellular senescence and DNA damage in normal and tumor cells and is implicated in the progression of tumors from different origins. cGAS binds to cytoplasmic dsDNA and synthesize cyclic GMP-AMP (2’3’-cGAMP), which selectively activates STING and downstream IFN and NF-κB activation. We here reviewed the cGAS-STING signalling pathway and its cross-talk with other pathways to modulate tumorigenesis. Further, the review also focused on emerging studies that targeted the cGAS-STING pathway for developing targeted therapeutics and combinatorial regimens for cancer of different origins.     

上皮间质转化和细胞衰老在肿瘤发生中的共同调节分子

上皮间质转化(epithelial-mesenchymal transition,EMT)和细胞衰老是与肿瘤发生密切相关的两个重要事件。在肿瘤发展过程中,上皮间质转化是促进迁移和侵袭的重要机制。细胞衰老作为一个重要的细胞自主的肿瘤预防机制,可以抑制细胞转化和肿瘤发生。虽然EMT和细胞衰老发生在肿瘤发展过程中的不同时间段,但众多研究发现,多种介导EMT发生的关键信号通路和转录因子能调节细胞衰老过程;同时,参与细胞衰老的经典信号通路也影响着EMT进程。就联系这两种细胞生物学事件的调控因素作一综述。