Annual Review of Pathology: Mechanisms of Disease - Volume 9, 2014

Glioblastoma (GBM) is one of the most lethal human cancers. Genomic analyses are defining the molecular architecture of GBM, uncovering relevant subsets of patients whose disease may require different treatments. Many pharmacological targets have been revealed, promising to transform patient care through targeted therapies. However, for most patients, clinical responses to targeted inhibitors are either not apparent or not durable. In this review, we address the challenge of developing more effective, molecularly guided approaches for the treatment of GBM patients. We summarize the current state of knowledge regarding molecular classifiers and examine their benefit for stratifying patients for treatment. We survey the molecular landscape of the disease, discussing the challenges raised by acquired drug resistance. Furthermore, we analyze the biochemical features of GBM, suggesting a next generation of drug targets, and we examine the contribution of tumor heterogeneity and its implications. We conclude with an analysis of the experimental approaches and their potential benefit to patients.

A new paradigm for the pathogenesis of female pelvic cancer helps explain persistent problems in describing the development and diverse morphology of these neoplasms. This paradigm incorporates recent advances in the molecular pathogenesis of epithelial ovarian cancer (EOC) with new insights into the origin of these tumors. Correlated clinicopathologic and molecular genetic studies gave rise to a dualistic model that divides the various histologic types of EOCs into two broad categories designated type I and type II. Because serous carcinomas are the most common EOC and account for the vast majority of deaths, they form the subject of this review. Recent studies indicate that the precursor of ovarian high-grade serous carcinoma appears to develop from an occult intraepithelial carcinoma in the fimbria of the fallopian tube and involves the ovary secondarily. Another possible mechanism is implantation of normal fimbrial epithelium on the denuded ovarian surface at the site of rupture when ovulation occurs, causing the development of cortical inclusion cysts. The dualistic model serves as a framework for the study of ovarian cancer and can help investigators organize this complex group of neoplasms. It also facilitates the development of novel approaches to prevention, screening, and treatment of this devastating disease.

Hypoxia-inducible factors (HIFs) are transcriptional activators that function as master regulators of oxygen homeostasis, which is disrupted in disorders affecting the circulatory system and in cancer. The role of HIFs in these diseases has been elucidated by clinical studies and by analyses of mouse models. HIFs play a protective role in the pathophysiology of myocardial ischemia due to coronary artery disease, limb ischemia due to peripheral arterial disease, pressure-overload heart failure, wound healing, and chronic rejection of organ transplants. In contrast, HIFs contribute to the pathogenesis of pulmonary arterial hypertension, systemic hypertension associated with sleep apnea, ocular neovascularization, hereditary erythrocytosis, and cancer.

Both the chronic development of atherosclerotic lesions and the acute changes in lesion phenotype that lead to clinical cardiovascular events are significantly influenced by the innate and adaptive immune responses to lipoprotein deposition and oxidation in the arterial wall. The rapid pace of discovery of mechanisms of immunologic recognition, effector functions, and regulation has significantly influenced the study of atherosclerosis, and our new knowledge is beginning to affect how we treat this ubiquitous disease. In this review, we discuss recent advances in our understanding of how innate and adaptive immunity contribute to atherosclerosis, as well as therapeutic opportunities that arise from this knowledge.

Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of CD5⁺CD23⁺ B cells in blood, marrow, and second lymphoid tissues. Gene-expression profiling and phenotypic studies suggest that CLL is probably derived from CD5⁺ B cells similar to those found in the blood of healthy adults. Next-generation sequencing has revealed recurrent genetic lesions that are implicated in CLL pathogenesis and/or disease progression. The biology of CLL is entwined with its microenvironment, in which accessory cells can promote leukemia cell growth and/or survival. Recently, much attention has been focused on the CLL B cell receptor (BCR) and on chemokine receptors that enable CLL cells to home to lymphoid tissues and to establish the leukemia microenvironment. Agents that can interfere with BCR signaling or chemokine–receptor signaling, or that target surface antigens selectively expressed on CLL cells, promise to have significant therapeutic benefit in patients with this disease.

Reactive oxygen species (ROS) are a chemical class of molecules that have generally been conceptualized as deleterious entities, albeit ones whose destructive properties could be harnessed as antimicrobial effector functions to benefit the whole organism. This appealingly simplistic notion has been turned on its head in recent years with the discovery of the NADPH oxidases, or Noxes, a family of enzymes dedicated to the production of ROS in a variety of cells and tissues. The Nox-dependent, physiological generation of ROS is highly conserved across virtually all multicellular life, often as a generalized response to microbes and/or other exogenous stressors. This review discusses the current knowledge of the role of physiologically generated ROS and the enzymes that form them in both normal biology and disease.

Recent advances in our understanding of genetic-epigenetic interactions have unraveled new mechanisms underlying the etiology of complex autoimmune diseases. Autoimmune thyroid diseases (AITDs) are highly prevalent, affecting 1% to 5% of the population. The major AITDs include Graves disease (GD) and Hashimoto's thyroiditis (HT); although these diseases contrast clinically, their pathogenesis involves shared immunogenetic mechanisms. Genetic data point to the involvement of both shared and unique genes. Among the shared susceptibility genes, HLA-DRβ1-Arg74 (human leukocyte antigen DR containing an arginine at position β74) confers the strongest risk. Recent genome-wide analyses have revealed new putative candidate genes. Epigenetic modulation is emerging as a major mechanism by which environmental factors interact with AITD susceptibility genes. Dissecting the genetic-epigenetic interactions underlying the pathogenesis of AITD is essential to uncover new therapeutic targets.

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease associated with aging that is characterized by the histopathological pattern of usual interstitial pneumonia. Although an understanding of the pathogenesis of IPF is incomplete, recent advances delineating specific clinical and pathologic features of IPF have led to better definition of the molecular pathways that are pathologically activated in the disease. In this review we highlight several of these advances, with a focus on genetic predisposition to IPF and how genetic changes, which occur primarily in epithelial cells, lead to activation of profibrotic pathways in epithelial cells. We then discuss the pathologic changes within IPF fibroblasts and the extracellular matrix, and we conclude with a summary of how these profibrotic pathways may be interrelated.

Neutrophils and neutrophil-like cells are the major pathogen-fighting immune cells in organisms ranging from slime molds to mammals. Central to their function is their ability to be recruited to sites of infection, to recognize and phagocytose microbes, and then to kill pathogens through a combination of cytotoxic mechanisms. These include the production of reactive oxygen species, the release of antimicrobial peptides, and the recently discovered expulsion of their nuclear contents to form neutrophil extracellular traps. Here we discuss these primordial neutrophil functions, which also play key roles in tissue injury, by providing details of neutrophil cytotoxic functions and congenital disorders of neutrophils. In addition, we present more recent evidence that interactions between neutrophils and adaptive immune cells establish a feed-forward mechanism that amplifies pathologic inflammation. These newly appreciated contributions of neutrophils are described in the setting of several inflammatory and autoimmune diseases.

Cryptococcus neoformans is a fungal pathogen with worldwide distribution. Serological studies of human populations show a high prevalence of human infection, which rarely progresses to disease in immunocompetent hosts. However, decreased host immunity places individuals at high risk for cryptococcal disease. The disease can result from acute infection or reactivation of latent infection, in which yeasts within granulomas and host macrophages emerge to cause disease. In this review, we summarize what is known about the cellular recognition, ingestion, and killing of C. neoformans and discuss the unique and remarkable features of its intracellular life, including the proposed mechanisms for fungal persistence and killing in phagocytic cells.

Melanomas comprise multiple biologically distinct categories, which differ in cell of origin, age of onset, clinical and histologic presentation, pattern of metastasis, ethnic distribution, causative role of UV radiation, predisposing germ-line alterations, mutational processes, and patterns of somatic mutations. Neoplasms are initiated by gain-of-function mutations in one of several primary oncogenes, which typically lead to benign melanocytic nevi with characteristic histologic features. The progression of nevi is restrained by multiple tumor-suppressive mechanisms. Secondary genetic alterations override these barriers and promote intermediate or overtly malignant tumors along distinct progression trajectories. The current knowledge about the pathogenesis and clinical, histologic, and genetic features of primary melanocytic neoplasms is reviewed and integrated into a taxonomic framework.

Sjögren's syndrome (SS) is a chronic autoimmune disorder that typically affects exocrine glands—mainly labial and lacrimal—leading to complaints of dry mouth and eyes. Given that periepithelial mononuclear cell infiltrates, both in exocrine glands and in other parenchymal organs (kidney, lung, and liver), are the histopathological disease hallmark, the term autoimmune epithelitis has been proposed. B cell hyperactivity is another cardinal SS feature manifested by the presence of autoantibodies and hypergammaglobulinemia, as well as clinical/serological phenotypes mediated by immune complexes, such as peripheral neuropathy, vasculitic lesions, and hypocomplementemia. These have been designated adverse predictors for lymphoma development in approximately 5% to 10% of patients. Activation of the type I interferon/B cell–activating factor axis in SS has recently attracted particular attention. Inappropriate overexpression of endogenous nucleic acids in a genetically susceptible individual might provide a plausible scenario for the immune activation observed in SS.

MicroRNAs (miRNAs) are small noncoding RNAs that typically inhibit the translation and stability of messenger RNAs (mRNAs), controlling genes involved in cellular processes such as inflammation, cell-cycle regulation, stress response, differentiation, apoptosis, and migration. Thus, miRNAs have been implicated in the regulation of virtually all signaling circuits within a cell, and their dysregulation has been shown to play an essential role in the development and progression of cancer. Here, after a brief description of miRNA genomics, biogenesis, and function, we discuss the effects of miRNA dysregulation in the cellular pathways that lead to the progressive conversion of normal cells into cancer cells and the potential to develop new molecular miRNA-targeted therapies.

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is an immune-mediated condition that can affect almost any organ and is now being recognized with increasing frequency. IgG4-RD is characterized by a lymphoplasmacytic infiltrate composed of IgG4⁺ plasma cells, storiform fibrosis, obliterative phlebitis, and mild to moderate eosinophilia. The diagnosis of IgG4-RD unifies many eponymous fibroinflammatory conditions that had previously been thought to be confined to single organs. IgG4-RD lesions are infiltrated by T helper cells, which likely cause progressive fibrosis and organ damage. IgG4 antibodies are generally regarded as noninflammatory. Although autoreactive IgG4 antibodies are observed in IgG4-RD, there is no evidence that they are directly pathogenic. Rituximab-induced B cell depletion in IgG4-RD leads to rapid clinical and histological improvement accompanied by swift declines in serum IgG4 concentrations. Although IgG autoantibodies against various exocrine gland antigens have been described in IgG4-RD, whether they are members of the IgG4 subclass is unknown. The contribution of autoantibodies to IgG4-RD remains unclear.

Epstein–Barr virus (EBV) and Kaposi's sarcoma herpesvirus (KSHV), formally designated human herpesvirus 4 (HHV-4) and 8 (HHV-8), respectively, are viruses that can cause a variety of cancers in humans. EBV is found in non-Hodgkin and Hodgkin lymphomas, as well as in lymphoproliferative disorders, which occur more commonly but not exclusively in individuals with immunodeficiency. EBV also causes nonlymphoid malignancies such as nasopharyngeal carcinoma. KSHV causes primary effusion lymphomas, multicentric Castleman's disease, and Kaposi's sarcoma. The frequency of lymphoid malignancies related to infection by one of these two herpesviruses is greatly increased in individuals with immunodeficiency, whether primary or acquired, for example, as a consequence of HIV infection and AIDS or in the case of therapeutic immunosuppression for organ transplantation. Our current understanding indicates that EBV and KSHV contribute to lymphomagenesis by affecting genomic stability and by subverting the cellular molecular signaling machinery and metabolism to avoid immune surveillance and enhance tumor cell growth and survival. Understanding the viral associations in specific lymphoproliferative disorders and the molecular mechanisms of viral oncogenesis will lead to better prevention, diagnosis, and treatment strategies for these diseases.