The extracellular matrix modulates the hallmarks of cancer

The extracellular matrix regulates tissue development and homeostasis, and its dysregulation contributes to neoplastic progression. The extracellular matrix serves not only as the scaffold upon which tissues are organized but provides critical biochemical and biomechanical cues that direct cell growth, survival, migration and differentiation and modulate vascular development and immune function. Thus, while genetic modifications in tumor cells undoubtedly initiate and drive malignancy, cancer progresses within a dynamically evolving extracellular matrix that modulates virtually every behavioral facet of the tumor cells and cancer‐associated stromal cells. Hanahan and Weinberg defined the hallmarks of cancer to encompass key biological capabilities that are acquired and essential for the development, growth and dissemination of all human cancers. These capabilities include sustained proliferation, evasion of growth suppression, death resistance, replicative immortality, induced angiogenesis, initiation of invasion, dysregulation of cellular energetics, avoidance of immune destruction and chronic inflammation. Here, we argue that biophysical and biochemical cues from the tumor‐associated extracellular matrix influence each of these cancer hallmarks and are therefore critical for malignancy. We suggest that the success of cancer prevention and therapy programs requires an intimate understanding of the reciprocal feedback between the evolving extracellular matrix, the tumor cells and its cancer‐associated cellular stroma.     

Control of mitochondrial integrity in ageing and disease

Various molecular and cellular pathways are active in eukaryotes to control the quality and integrity of mitochondria. These pathways are involved in keeping a ‘healthy’ population of this essential organelle during the lifetime of the organism. Quality control (QC) systems counteract processes that lead to organellar dysfunction manifesting as degenerative diseases and ageing. We discuss disease- and ageing-related pathways involved in mitochondrial QC: mtDNA repair and reorganization, regeneration of oxidized amino acids, refolding and degradation of severely damaged proteins, degradation of whole mitochondria by mitophagy and finally programmed cell death. The control of the integrity of mtDNA and regulation of its expression is essential to remodel single proteins as well as mitochondrial complexes that determine mitochondrial functions. The redundancy of components, such as proteases, and the hierarchies of the QC raise questions about crosstalk between systems and their precise regulation. The understanding of the underlying mechanisms on the genomic, proteomic, organellar and cellular levels holds the key for the development of interventions for mitochondrial dysfunctions, degenerative processes, ageing and age-related diseases resulting from impairments of mitochondria.     

Targeting the SASP to combat ageing: Mitochondria as possible intracellular allies?

Anti‐senescence therapies, such as drugs that specifically kill senescent cells, to stave off ageing are currently under investigation. While these interventions show promise, their potential pitfalls are discussed herein. We have shown that the mitochondria are essential for development of senescence and many of the associated phenotypes, including the often detrimental senescence‐associated secretory phenotype (SASP). Here, we disentangle many ways in which the mitochondria may influence senescence and development of the SASP and focus on possible pathways that could be exploited for future generation of anti‐senescence therapies with a clear aim; to specifically eliminate the problematic features of senescent cells, while maintaining their beneficial characteristics.     

Human ageing: A cellular phenomenon or evolutionary determinant?

During the course of the last twenty years scientific interest in the ageing process in man gradually has assumed a position of considerable importance. The situation has arisen largely because of the realization that, at least in industrialized countries, the elderly comprise an ever-increasing proportion of the population and diseases associated directly or indirectly with old age already account for a significant percentage of total health care expenditure. A particular problem to be faced in the investigation of human ageing lies in the selection of a suitable model. While various invertebrates and small mammals have been extensively utilized for this purpose, human diploid cells culturedin vitro offer many advantages, not least removal of the necessity for inter-specific extrapolations. Numerous cellular organelles and processes have been suggested as primary «targets» in ageing. Detailed investigations into a variety of such «targets» are described including cell membrane composition and structure, protein catabolism and integrity of the free aminoacid pool, and cellular energy flux. The data indicate a central role for mitochondrial senescence. The significance of the findings is discussed in terms of the role of ageing as an adaptive or non-adaptive process.     

Target of rapamycin activation predicts lifespan in fruit flies

Aging and age-related diseases are one of the most important health issues that the world will confront during the 21^st century. Only by understanding the proximal causes will we be able to find treatments to reduce or delay the onset of degenerative diseases associated with aging. Currently, the prevalent paradigm in the field is the accumulation of damage. However, a new theory that proposes an alternative explanation is gaining momentum. The hyperfunction theory proposes that aging is not a consequence of a wear and tear process, but a result of the continuation of developmental programs during adulthood. Here we use Drosophila melanogaster, where evidence supporting both paradigms has been reported, to identify which parameters that have been previously related with lifespan best predict the rate of aging in wild type flies cultured at different temperatures. We find that mitochondrial function and mitochondrial reactive oxygen species (mtROS) generation correlates with metabolic rate, but not with the rate of aging. Importantly, we find that activation of nutrient sensing pathways (i.e. insulin-PI3K/Target of rapamycin (Tor) pathway) correlates with lifespan, but not with metabolic rate. Our results, dissociate metabolic rate and lifespan in wild type flies and instead link nutrient sensing signaling with longevity as predicted by the hyperfunction theory.     

Oxidants, metabolism, and stem cell biology

Adult stem cells persist throughout the lifetime of the organism and may therefore require specific mechanisms to limit the effects of chronic oxidative stress. Recently, several instructive genetic mouse models have demonstrated the unique susceptibility of stem cells to perturbations in metabolic or redox homeostasis. These results have implications not only for stem cell biology but also suggest a mechanistic link between intracellular oxidants and the decline in regenerative function that occurs as a normal consequence of aging.