Showing papers in "Annual Review of Pathology-mechanisms of Disease in 2010"
TL;DR: A senescence-associated secretory phenotype (SASP) is acquired that turns senescent fibroblasts into proinflammatory cells that have the ability to promote tumor progression.
Abstract: Cellular senescence is a tumor-suppressive mechanism that permanently arrests cells at risk for malignant transformation. However, accumulating evidence shows that senescent cells can have deleterious effects on the tissue microenvironment. The most significant of these effects is the acquisition of a senescence-associated secretory phenotype (SASP) that turns senescent fibroblasts into proinflammatory cells that have the ability to promote tumor progression.
3,332 citations
TL;DR: There have been major advances in the understanding of the enzymology of sirtuins, their regulation, and their ability to broadly improve mammalian physiology and health span, and the challenges that will confront the field in the coming years are discussed.
Abstract: Aging is accompanied by a decline in the healthy function of multiple organ systems, leading to increased incidence and mortality from diseases such as type II diabetes mellitus, neurodegenerative diseases, cancer, and cardiovascular disease. Historically, researchers have focused on investigating individual pathways in isolated organs as a strategy to identify the root cause of a disease, with hopes of designing better drugs. Studies of aging in yeast led to the discovery of a family of conserved enzymes known as the sirtuins, which affect multiple pathways that increase the life span and the overall health of organisms. Since the discovery of the first known mammalian sirtuin, SIRT1, 10 years ago, there have been major advances in our understanding of the enzymology of sirtuins, their regulation, and their ability to broadly improve mammalian physiology and health span. This review summarizes and discusses the advances of the past decade and the challenges that will confront the field in the coming years.
1,765 citations
TL;DR: Nonalcoholic fatty liver disease is recognized as the leading cause of chronic liver disease in adults and children and is most closely linked with insulin resistance; the current Western diet, high in saturated fats and fructose, plays a significant role.
Abstract: Nonalcoholic fatty liver disease (NAFLD) is recognized as the leading cause of chronic liver disease in adults and children. NAFLD encompasses a spectrum of liver injuries ranging from steatosis to steatohepatitis with or without fibrosis. Fibrosis may progress to cirrhosis and complications including hepatocellular carcinoma. Histologic findings represent the complexity of pathophysiology. NAFLD is closely associated with obesity and is most closely linked with insulin resistance; the current Western diet, high in saturated fats and fructose, plays a significant role. There are several mechanisms by which excess triglycerides are acquired and accumulate in hepatocytes. Formation of steatotic droplets may be disordered in NAFLD. Visceral adipose tissue dysfunction in obesity and insulin resistance results in aberrant cytokine expression; many cytokines have a role in liver injury in NAFLD. Cellular stress and immune reactions, as well as the endocannabinoid system, have been implicated in animal models and in some human studies.
746 citations
TL;DR: Analysis of the many ways that a shift from carbohydrate glycolytic metabolism to fatty acid and ketone oxidative metabolism may modulate metabolism, signal transduction pathways, and the epigenome gives an appreciation of the ketogenic diet and the potential for bioenergetic therapeutics.
Abstract: Mitochondrial dysfunction has been linked to a wide range of degenerative and metabolic diseases, cancer, and aging. All these clinical manifestations arise from the central role of bioenergetics in cell biology. Although genetic therapies are maturing as the rules of bioenergetic genetics are clarified, metabolic therapies have been ineffectual. This failure results from our limited appreciation of the role of bioenergetics as the interface between the environment and the cell. A systems approach, which, ironically, was first successfully applied over 80 years ago with the introduction of the ketogenic diet, is required. Analysis of the many ways that a shift from carbohydrate glycolytic metabolism to fatty acid and ketone oxidative metabolism may modulate metabolism, signal transduction pathways, and the epigenome gives us an appreciation of the ketogenic diet and the potential for bioenergetic therapeutics.
609 citations
TL;DR: The recent discoveries of upregulated antiangiogenic factors provide promise for future testing to predict and diagnose preeclampsia as well as therapeutic targets for amelioration of the clinical disease.
Abstract: Preeclampsia is a systemic syndrome that occurs in 3 to 5% of pregnant women and classically manifests as new-onset hypertension and proteinuria after 20 weeks of gestation. Preeclampsia is a leading cause of maternal and neonatal morbidity and mortality. The only known cure is delivery of the placenta. Recent discoveries, however, have led to important advances in understanding the pathogenesis of the condition. Placental antiangiogenic factors are upregulated and disrupt the maternal endothelium. This change in the normal angiogenic balance toward an antiangiogenic state can result in hypertension, proteinuria, glomerular endotheliosis, HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, and cerebral edema—the clinical signs of preeclampsia and eclampsia. The regulation of these antiangiogenic factors in the placenta is unknown. The recent discoveries of upregulated antiangiogenic factors provide promise for future testing to predict and diagnose preeclampsia as well as therapeutic ta...
571 citations
TL;DR: The critical roles of the tight junction in health and the contributions of barrier dysfunction to disease pathogenesis are discussed and the role of immune cells and luminal microbiota is explored.
Abstract: Epithelia form barriers that are essential to life. This is particularly true in the intestine, where the epithelial barrier supports nutrient and water transport while preventing microbial contamination of the interstitial tissues. Along with plasma membranes, the intercellular tight junction is the primary cellular determinant of epithelial barrier function. Disruption of tight junction structure, as a result of specific protein mutations or aberrant regulatory signals, can be both a cause and an effect of disease. Recent advances have provided new insights into the extracellular signals and intracellular mediators of tight junction regulation in disease states as well as into the interactions of intestinal barrier function with mucosal immune cells and luminal microbiota. In this review, we discuss the critical roles of the tight junction in health and explore the contributions of barrier dysfunction to disease pathogenesis.
518 citations
TL;DR: Detailed information is gathered on the nucleotide sequence changes in a number of human cancers to help identify key rate-limiting genes for tumor growth that could serve as potential targets for directed therapies.
Abstract: Cancer recapitulates Darwinian evolution. Mutations acquired during life that provide cells with a growth or survival advantage will preferentially multiply to form a tumor. As a result of The Cancer Genome Atlas Project, we have gathered detailed information on the nucleotide sequence changes in a number of human cancers. The sources of mutations in cancer are diverse, and the complexity of those found to be clonally present in tumors has increasingly made it difficult to identify key rate-limiting genes for tumor growth that could serve as potential targets for directed therapies. The impact of DNA sequencing on future cancer research and personalized therapy is likely to be profound and merits critical evaluation.
209 citations
TL;DR: The mechanisms that have been implicated in the pathogenesis of the gliomas are reviewed and examples of the cooperative nature of the pathways involved are provided, which may influence the initial therapeutic response and the potential for development of resistance.
Abstract: The ongoing characterization of the genetic and epigenetic alterations in the gliomas has already improved the classification of these heterogeneous tumors and enabled the development of rodent models for analysis of the molecular pathways underlying their proliferative and invasive behavior. Effective application of the targeted therapies that are now in development will depend on pathologists’ ability to provide accurate information regarding the genetic alterations and the expression of key receptors and ligands in the tumors. Here we review the mechanisms that have been implicated in the pathogenesis of the gliomas and provide examples of the cooperative nature of the pathways involved, which may influence the initial therapeutic response and the potential for development of resistance.
206 citations
TL;DR: Although the p53homolog p63 has emerged as a gene with an enormously complex function that is distinct from that of p53, it encodes two distinct transcript isoforms that have a dramatic impact on replenishment of cutaneous epithelial stem cells and on ovarian germ cell survival.
Abstract: The p53homolog p63has emerged as a gene with an enormously complex function that is distinct from that of p53. It encodes two distinct transcript isoforms that have a dramatic impact on replenishment of cutaneous epithelial stem cells and on ovarian germ cell survival. However, although these two fundamental roles of p63 attest to its powerful place in development, its other functions-specifically the apparent capacity of p63, when induced, to supervise the emergence of new cell populations in the breast, prostate, cervix, and upper reproductive tract-are shared by embryo and adult. These observed functions may only scratch the surface of a repertoire that has been postulated to encompass a range of cellular activities, as evidenced by the fact that p63 proteins have been shown to potentially bind to over 5800 target sites. Whether tumorigenic pathways are also involved, and to what extent, is a subject of both promise and controversy that remains to be resolved.
205 citations
TL;DR: It is known that GAS organisms secrete a variety of proteases that disrupt host tissue and that these proteolytic enzymes are regulated by multiple transcriptional and posttranslational processes, which will be crucial to supporting downstream efforts that seek to develop novel vaccines and therapeutic agents for this serious human infection.
Abstract: Necrotizing fasciitis, also known as the flesh-eating disease, is a severe invasive infection associated with very high rates of human morbidity and mortality. It is most commonly caused by group A Streptococcus(GAS), a versatile human pathogen that causes diseases ranging in severity from uncomplicated pharyngitis (or strep throat) to life-threatening infections such as necrotizing fasciitis. Herein, we review recent discoveries bearing on the molecular pathogenesis of GAS necrotizing fasciitis. Importantly, the integration of new technologies and the development of human-relevant animal models have markedly expanded our understanding of the key pathogen-host interactions underlying GAS necrotizing fasciitis. For example, we now know that GAS organisms secrete a variety of proteases that disrupt host tissue and that these proteolytic enzymes are regulated by multiple transcriptional and posttranslational processes. This pathogenesis knowledge will be crucial to supporting downstream efforts that seek to ...
140 citations
TL;DR: High-throughput genetic, epigenetic, and gene-expression analyses have enhanced the understanding of the relationship of these early neoplastic lesions to normal breast tissue, and they strongly suggest that preinvasive breast cancer develops and evolves along two distinct molecular genetic and biological pathways that correlate with tumor grade.
Abstract: Preinvasive breast cancer accounts for approximately one-third of all newly diagnosed breast cancer cases in the United States and constitutes a spectrum of neoplastic lesions with varying degrees of differentiation and clinical behavior. High-throughput genetic, epigenetic, and gene-expression analyses have enhanced our understanding of the relationship of these early neoplastic lesions to normal breast tissue, and they strongly suggest that preinvasive breast cancer develops and evolves along two distinct molecular genetic and biological pathways that correlate with tumor grade. Although unique epigenetic and gene-expression changes are not observed in the tumor epithelial compartment during the transition from preinvasive to invasive disease, distinct molecular alterations are observed in the tumor-stromal and myoepithelial cells. This suggests that the stromal and myoepithelial microenvironment of preinvasive breast cancer actively participates in the transition from preinvasive to invasive disease. An improved understanding of the transition from preinvasive to invasive breast cancer will pave the way for novel preventative and therapeutic strategies.
TL;DR: A large body of evidence converges on a single common theme: the central importance of the transforming growth factor beta (TGF-beta) pathway, which has the therapeutic potential to treat all fibrogenic responses in the lung.
Abstract: Fibrogenic lung reactions occur as a common phenotype shared among disorders of heterogeneous etiologies. Even with a common etiology, the extent and pattern of fibrosis vary greatly among individuals, even within families, suggesting complex gene-environment interactions. The search for mechanisms shared among all fibrotic lung diseases would represent a major advance in the identification of therapeutic targets that could have a broad impact on lung health. Although it is difficult to grasp all of the complexities of the varied cell types and cytokine networks involved in lung fibrogenic responses, and to predict the biologic responses to the overexpression or deficiency of individual cytokines, a large body of evidence converges on a single common theme: the central importance of the transforming growth factor beta (TGF-β) pathway. Therapies that act upstream or downstream of TGF-β activation have the therapeutic potential to treat all fibrogenic responses in the lung.
TL;DR: Understanding of innate and adaptive immune mechanisms in the lower respiratory tract is summarized and how animal models for selected pulmonary pathogens can contribute to the understanding of the pathogenesis of lung infections and to the search for new vaccines and therapies is discussed.
Abstract: Acute viral and bacterial infections in the lower respiratory tract are major causes of morbidity and mortality worldwide. The proper study of pulmonary infections requires interdisciplinary collaboration among physicians and biomedical scientists to develop rational hypotheses based on clinical studies and to test these hypotheses in relevant animal models. Animal models for common lung infections are essential to understand pathogenic mechanisms and to clarify general mechanisms for host protection in pulmonary infections, as well as to develop vaccines and therapeutics. Animal models for uncommon pulmonary infections, such as those that can be caused by category A biothreat agents, are also very important because the infrequency of these infections in humans limits in-depth clinical studies. This review summarizes our understanding of innate and adaptive immune mechanisms in the lower respiratory tract and discusses how animal models for selected pulmonary pathogens can contribute to our understanding of the pathogenesis of lung infections and to the search for new vaccines and therapies.