Annual Review of Pathology: Mechanisms of Disease - Volume 1, 2006

I am honored to write the prefatory chapter for the inaugural volume of the Annual Review of Pathology: Mechanisms of Disease. This publishing venture signals that pathology takes its rightful place alongside the other biomedical sciences.

I thought it may be of interest to some to delineate how a circuitous path led me into a career in experimental pathology and to give some of the flavor of a past era in experimental approaches. Thus, my title.

Among the many viruses that are known to infect the human liver, hepatitis B virus (HBV) and hepatitis C virus (HCV) are unique because of their prodigious capacity to cause persistent infection, cirrhosis, and liver cancer. HBV and HCV are noncytopathic viruses and, thus, immunologically mediated events play an important role in the pathogenesis and outcome of these infections. The adaptive immune response mediates virtually all of the liver disease associated with viral hepatitis. However, it is becoming increasingly clear that antigen-nonspecific inflammatory cells exacerbate cytotoxic T lymphocyte (CTL)-induced immunopathology and that platelets enhance the accumulation of CTLs in the liver. Chronic hepatitis is characterized by an inefficient T cell response unable to completely clear HBV or HCV from the liver, which consequently sustains continuous cycles of low-level cell destruction. Over long periods of time, recurrent immune-mediated liver damage contributes to the development of cirrhosis and hepatocellular carcinoma.

Helicobacter pylori is the main cause of peptic ulceration, distal gastric adenocarcinoma, and gastric lymphoma. Only 15% of those colonized develop disease, and pathogenesis depends upon strain virulence, host genetic susceptibility, and environmental cofactors. Virulence factors include the cag pathogenicity island, which induces proinflammatory, pro-proliferative epithelial cell signaling; the cytotoxin VacA, which causes epithelial damage; and an adhesin, BabA. Host genetic polymorphisms that lead to high-level pro-inflammatory cytokine release in response to infection increase cancer risk. Pathogenesis is dependent upon inflammation, a Th-1 acquired immune response and hormonal changes including hypergastrinaemia. Antral-predominant inflammation leads to increased acid production from the uninflamed corpus and predisposes to duodenal ulceration; corpus-predominant gastritis leads to hypochlorhydria and predisposes to gastric ulceration and adenocarcinoma. Falling prevalence of H. pylori in developed countries has led to a falling incidence of associated diseases. However, whether there are disadvantages of an H. pylori-free stomach, for example increased risk of esosphageal adenocarcinoma, remains unclear.

Malignant gliomas, the most common type of primary brain tumor, are a spectrum of tumors of varying differentiation and malignancy grades. These tumors may arise from neural stem cells and appear to contain tumor stem cells. Early genetic events differ between astrocytic and oligodendroglial tumors, but all tumors have an initially invasive phenotype, which complicates therapy. Progression-associated genetic alterations are common to different tumor types, targeting growth-promoting and cell cycle control pathways and resulting in focal hypoxia, necrosis, and angiogenesis. Knowledge of malignant glioma genetics has already impacted clinical management of these tumors, and researchers hope that further knowledge of the molecular pathology of malignant gliomas will result in novel therapies.

In the past 25 years, a majority of cancer studies have focused on examining functional consequences of activating and/or inactivating mutations in critical genes implicated in cell cycle control. These studies have taught us a great deal about the functions of oncogenes and tumor suppressor genes and the signaling pathways regulating cell proliferation and/or cell death. However, such studies have largely ignored the fact that cancers are heterogeneous cellular entities whose growth is dependent upon reciprocal interactions between genetically altered “initiated” cells and the dynamic microenvironment in which they live. This review highlights the aspects of cancer development that, like organogenesis during embryonic development and tissue repair in adult mammals, are regulated by interactions between epithelial cells, activated stromal cells, and soluble and insoluble components of the extracellular matrix.

Neurodegenerative diseases as diverse as Alzheimer's, Parkinson's, and Creutzfeldt-Jakob disease share a common pathogenetic mechanism involving aggregation and deposition of misfolded proteins, which leads to progressive central nervous system disease. Although the type of aggregated protein and the regional and cellular distribution of deposition vary from disease to disease, these disorders may all be linked by similar pathways of protein aggregation with fibril formation and amyloid deposition. This perspective on pathogenesis suggests that a wide variety of neurodegenerative diseases can be grouped mechanistically as brain amyloidoses, an outlook that yields novel insights into potential therapeutic approaches that may be applicable across the broad spectrum of neurodegenerative disease.

The endothelial cells lining vascular and lymphatic vessels are targets of several infectious agents, including viruses and bacteria, that lead to dramatic changes in their functions. Understanding the pathophysiological mechanisms that cause the clinical manifestations of those infections has been advanced through the use of animal models and in vitro systems; however, there are also abundant studies that explore the consequences of endothelial infection in vitro without supporting evidence that endothelial cells are actual in vivo targets of infection in human diseases. This article defines criteria for considering an infection as truly endothelium-targeted and reviews the literature that offers insights into the pathogenesis of human endothelial-target infections.

Developmental heart disorders are the most common of all human birth defects and occur in nearly one percent of the population. Survivors of congenital heart malformations are an increasing population, and it is becoming clear that genetic mutations that cause developmental anomalies may result in cardiac dysfunction later in life. This review highlights the progress in understanding the underlying molecular basis for cardiac formation and how disruption of the intricate steps of cardiogenesis can lead to congenital heart defects. The lessons learned from examining the early steps of heart formation are essential for informing the prevention of malformations and their long-term consequences, as well as for approaches to guide stem cells into cardiac lineages.

Modern techniques of cell and molecular biology have rapidly uncovered the mechanisms underlying inflammatory injury of the lung. This expanding knowledge (which includes an understanding of complement, cell surface receptors, cytokines and chemokines, transcription factors, oxidants, proteinases, and endogenous inhibitors, as well as the role of leukocyte adhesion-promoting molecules) has provided new insights into the inflammatory system in general, as well as in the context of lung injury. In this review, we summarize recent progress in understanding the regulation of lung inflammation by using immunoglobulin G (IgG) immune complex–induced lung injury as a model. These studies have provided information on the role of various inflammatory mediators and their sequence of engagement. Insights into potential interventional approaches for the suppression of inflammatory processes in humans have emerged from those studies.

Prostate cancer displays considerable clinical, morphological, and biological heterogeneity. Classical genetic techniques have provided only limited information about the pathogenesis of prostate cancer progression. Nevertheless, several candidate genes and pathways have been implicated in prostate cancer development. High-throughput techniques have exponentially expanded the number of candidate genes, including some whose role in prostate cancer pathogenesis has been studied. However, the techniques used to study the prostate cancer genome, transcriptome, and proteome generate massive amounts of data that have yet to be integrated and explored. To move beyond candidate gene identification and develop a comprehensive understanding of cancer pathogenesis, integrative approaches need to analyze this data on a global level. This review addresses candidate genes involved in prostate cancer pathogenesis in a biological and clinical context and demonstrates how integrated analysis of high-throughput data augments our understanding of prostate cancer.

Kaposi's sarcoma (KS) has long been suspected of having an infectious etiology on the basis of its unusual epidemiology, histopathology, and natural history. Nearly a decade ago, a novel herpesviral genome was discovered in KS biopsies, and since that time strong epidemiologic evidence has accumulated correlating infection with this KS-associated herpesvirus (KSHV, also known as human herpesvirus 8) with the development of the disease. Here we review the evidence linking KSHV infection to KS risk and discuss current notions of how KSHV gene expression promotes the development of this remarkable neoplasm. These studies show that both latent and lytic viral replicative cycles contribute significantly—but differently—to KS development. The studies also highlight mechanistic differences between oncogenesis caused by KSHV and that caused by its distant relative Epstein-Barr virus.

Atherosclerosis, the cause of myocardial infarction, stroke, and ischemic gangrene, is an inflammatory disease. The atherosclerotic process is initiated when cholesterol-containing low-density lipoproteins accumulate in the intima and activate the endothelium. Leukocyte adhesion molecules and chemokines promote recruitment of monocytes and T cells. Monocytes differentiate into macrophages and upregulate pattern recognition receptors, including scavenger receptors and toll-like receptors. Scavenger receptors mediate lipoprotein internalization, which leads to foam-cell formation. Toll-like receptors transmit activating signals that lead to the release of cytokines, proteases, and vasoactive molecules. T cells in lesions recognize local antigens and mount T helper-1 responses with secretion of pro-inflammatory cytokines that contribute to local inflammation and growth of the plaque. Intensified inflammatory activation may lead to local proteolysis, plaque rupture, and thrombus formation, which causes ischemia and infarction. Inflammatory markers are already used to monitor the disease process and anti-inflammatory therapy may be useful to control disease activity.

From histological and biological perspectives, lung cancer is a complex neoplasm. Although the sequential preneoplastic changes have been defined for centrally arising squamous carcinomas of the lung, they have been poorly documented for the other major forms of lung cancers, including small cell lung carcinoma and adenocarcinomas. There are three main morphologic forms of preneoplastic lesions recognized in the lung: squamous dysplasias, atypical adenomatous hyperplasia, and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. However, these lesions account for the development of only a subset of lung cancers. Several studies have provided information regarding the molecular characterization of lung preneoplastic changes, especially for squamous cell carcinoma. These molecular changes have been detected in the histologically normal and abnormal respiratory epithelium of smokers. Two different molecular pathways have been detected in lung adenocarcinoma pathogenesis: smoking-associated activation of RAS signaling, and nonsmoking-associated activation of EGFR signaling; the latter is detected in histologically normal respiratory epithelium.

Nonimmune glomerulopathies are an area of significant research. This review discusses the development of focal segmental glomerulosclerosis, with particular attention to the role of the podocyte in the initiation of glomerulosclerosis and the contribution to glomerulosclerosis from capillary hypertension and soluble factors such as transforming growth factor beta, platelet-derived growth factor, vascular endothelial growth factor, and angiotensin. The effects of these factors on endothelial and mesangial cells are also discussed. In addition, we review our current understanding of the slit diaphragm (a specialized cell junction found in the kidney), slit diaphragm–associated proteins (including nephrin, podocin, α-actinin-4, CD2-associated protein, and transient receptor potential channel 6), and the role of these proteins in glomerular disease. We also discuss the most recent research on the pathogenesis of collapsing glomerulosclerosis, human immunodeficiency virus associated nephropathy, Denys-Drash, diabetic nephropathy, Alport syndrome, and other diseases related to the interaction between the podocyte and the glomerular basement membrane.

The association between Epstein-Barr virus (EBV) and a large number of benign and malignant diseases is unique among DNA viruses. Within infected tissues, proteins that are expressed during the normal lytic and latent viral life cycle lead to cellular alterations that contribute to these EBV-associated diseases. Although the early events of EBV infection are poorly understood, increasing knowledge of the viral processes that govern viral latency has shed light upon the potential mechanisms by which EBV infection can lead to cellular transformation. Our current understanding of the role of EBV in the development of Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, and other EBV-associated diseases is discussed.

Loss of Ca²⁺ homeostasis, often in the form of cytoplasmic increases, leads to cell injury. Depending upon cell type and the intensity of Ca²⁺ toxicity, the ensuing pathology can be reversible or irreversible. Although multiple destructive processes are activated by Ca²⁺, lethal outcomes are determined largely by Ca²⁺-induced mitochondrial permeability transition. This form of damage is primarily dependent upon mitochondrial Ca²⁺ accumulation, which is regulated by the mitochondrial membrane potential. Retention of the mitochondrial membrane potential during Ca²⁺ increases favors mitochondrial Ca²⁺ uptake and overload, resulting in mitochondrial permeability transition and cell death. In contrast, dissipation of mitochondrial membrane potential reduces mitochondrial Ca²⁺ uptake, retards mitochondrial permeability transition, and delays death, even in cells with large Ca²⁺ increases. The rates of mitochondrial membrane potential dissipation and mitochondrial Ca²⁺ uptake may determine cellular sensitivity to Ca²⁺ toxicity under pathological conditions, including ischemic injury.

Sarcomas form a highly diverse group of rare tumors that are derived from connective tissue. More than 100 different malignant and benign soft tissue neoplasms can be recognized by histologic examination. Few diagnostic markers exist, and the cell of origin for many soft tissue tumors is unknown. The accurate diagnosis of many of these tumors therefore remains a challenge. The study of sarcomas has yielded many insights that can be applied to other neoplasms such as carcinoma. For example, the success of the treatment of gastrointestinal stromal tumor with Imatinib has led to an increased effort to find targeted therapies for other malignancies. Here we describe the known molecular changes in a number of sarcomas and focus on novel scientific approaches that can be expected to lead to improved diagnosis, prognostication, and therapy of sarcoma.

Although Gram-negative bacteria have often been implicated in the pathogenesis of severe sepsis and septic shock, how they trigger these often lethal syndromes is uncertain. In particular, the role played by blood-borne bacteria is controversial. This review considers two alternatives. In the first, circulating Gram-negative bacteria induce toxic reactions directly within the vasculature; in the second, the major inflammatory stimulus occurs in local extravascular sites of infection and circulating bacteria contribute little to inducing toxic responses. Evidence for each alternative is found in the literature. Bacteremia and severe sepsis are not so closely linked that the most striking cases can be a model for the rest. Intravascular and extravascular triggers may warrant different approaches to prevention and therapy.

Parasitic diseases represent major global health problems of immense proportion. Schistosomiasis, malaria, leishmaniasis, Chagas disease, and African sleeping sickness affect hundreds of millions of people worldwide, cause millions of deaths annually, and present an immense social and economic burden. Recent advances in genomic analysis of several of the major global parasites have revealed key factors involved in the pathogenesis of parasite diseases. Among the major virulence factors identified are parasite-derived proteases. This review focuses on the direct role of proteases in disease pathogenesis. Well-characterized examples of the roles proteases play in pathogenesis include their involvement in invasion of the host by parasite migration through tissue barriers, degradation of hemoglobin and other blood proteins, immune evasion, and activation of inflammation.