Review
Abstract
Breast cancer is a heterogeneous disease. There is a high degree of diversity between and within tumors as well as among cancer-bearing individuals, and all of these factors together determine the risk of disease progression and therapeutic resistance. Advances in technologies such as whole-genome sequencing and functional viability screens now allow us to analyze tumors at unprecedented depths. However, translating this increasing knowledge into clinical practice remains a challenge in part due to tumor evolution driven by the diversity of cancer cell populations and their microenvironment. The articles in this Review series discuss recent advances in our understanding of breast tumor heterogeneity, therapies tailored based on this knowledge, and future ways of assessing and treating heterogeneous tumors.
Authors
Kornelia Polyak
Abstract
Many tumors, including breast cancer, are maintained by a subpopulation of cells that display stem cell properties, mediate metastasis, and contribute to treatment resistance. These cancer stem cells (CSCs) are regulated by complex interactions with the components of the tumor microenvironment — including mesenchymal stem cells, adipocytes, tumor associated fibroblasts, endothelial cells, and immune cells — through networks of cytokines and growth factors. Since these components have a direct influence on CSC properties, they represent attractive targets for therapeutic development.
Authors
Hasan Korkaya, Suling Liu, Max S. Wicha
Abstract
Breast cancer, rather than constituting a monolithic entity, comprises heterogeneous tumors with different clinical characteristics, disease courses, and responses to specific treatments. Tumor-intrinsic features, including classical histological and immunopathological classifications as well as more recently described molecular subtypes, separate breast tumors into multiple groups. Tumor-extrinsic features, including microenvironmental configuration, also have prognostic significance and further expand the list of tumor-defining variables. A better understanding of the features underlying heterogeneity, as well as of the mechanisms and consequences of their interactions, is essential to improve targeting of existing therapies and to develop novel agents addressing specific combinations of features.
Authors
Nicholas R. Bertos, Morag Park
Abstract
In recent years the description of well-defined molecular subtypes of breast cancer, together with the identification of the driving genetic alterations and signaling pathways, has led to the clinical development of a number of successful molecular targeted agents. This is best exemplified in the subset of HER2-amplified breast cancers, in which an increasing number of active agents are changing the natural history of this aggressive disease. Other targets are under exploration, and the clinical development of these agents will require a change from the current large, randomized trials in unselected patient populations to smaller trials in groups with a molecularly defined tumor type. In addition, combinatorial approaches that act on the secondary mutations and/or compensatory pathways in resistant tumors may markedly improve on the effects of targeted agents used alone.
Authors
Michaela J. Higgins, José Baselga
Abstract
The successful treatment of certain autoimmune conditions with the humanized anti–IL-6 receptor (IL-6R) antibody tocilizumab has emphasized the clinical importance of cytokines that signal through the β-receptor subunit glycoprotein 130 (gp130). In this Review, we explore how gp130 signaling controls disease progression and examine why IL-6 has a special role among these cytokines as an inflammatory regulator. Attention will be given to the role of the soluble IL-6R, and we will provide a perspective into the clinical blockade of IL-6 activity in autoimmunity, inflammation, and cancer.
Authors
Simon A. Jones, Jürgen Scheller, Stefan Rose-John
Abstract
Chronic kidney disease (CKD) results from a wide array of processes that impair the kidney’s ability to perform its major functions. As many as 20 million Americans suffer from CKD and nearly a half million from end-stage renal disease, but there are also examples of centenarians with adequate renal function. Family-based and genome-wide studies suggest that genetic differences substantially influence an individual’s lifetime risk for kidney disease. One emerging theme is that evolution of genes related to host defense against pathogens may limit kidney longevity. The identification of these genetic factors will be critical for expanding our understanding of renal development and function as well as for the design of novel therapeutics for kidney disease.
Authors
David J. Friedman, Martin R. Pollak
Abstract
Atrial fibrillation (AF) is an extremely common cardiac rhythm disorder that causes substantial morbidity and contributes to mortality. The mechanisms underlying AF are complex, involving both increased spontaneous ectopic firing of atrial cells and impulse reentry through atrial tissue. Over the past ten years, there has been enormous progress in understanding the underlying molecular pathobiology. This article reviews the basic mechanisms and molecular processes causing AF. We discuss the ways in which cardiac disease states, extracardiac factors, and abnormal genetic control lead to the arrhythmia. We conclude with a discussion of the potential therapeutic implications that might arise from an improved mechanistic understanding.
Authors
Reza Wakili, Niels Voigt, Stefan Kääb, Dobromir Dobrev, Stanley Nattel
Abstract
Over the past decade and a half, the biomedical community has uncovered a previously unappreciated reciprocal relationship between cells of the immune and skeletal systems. Work in this field, which has been termed “osteoimmunology,” has resulted in the development of clinical therapeutics for seemingly disparate diseases linked by the common themes of inflammation and bone remodeling. Here, the important concepts and discoveries in osteoimmunology are discussed in the context of the diseases bridging these two organ systems, including arthritis, osteoporosis, cancer, and infection, and the targeted treatments used by clinicians to combat them.
Authors
Dallas Jones, Laurie H. Glimcher, Antonios O. Aliprantis
Abstract
All tissues and organs can be classified according to their ability to repair and regenerate during adult homeostasis and after injury. Some exhibit a high rate of constant cell turnover, while others, such as the lung, exhibit only low-level cell regeneration during normal adult homeostasis but have the ability to rapidly regenerate new cells after injury. Lung regeneration likely involves both activation of progenitor cells as well as cell replacement through proliferation of remaining undamaged cells. The pathways and factors that control this process and its role in disease are only now being explored. In this Review, we will discuss the connection between pathways required for lung development and how the lung responds to injury and disease, with a particular emphasis on recent studies describing the role for the epithelium in repair and regeneration.
Authors
Michael F. Beers, Edward E. Morrisey
Abstract
Cloned in 1994, the ob gene encodes the protein hormone leptin, which is produced and secreted by white adipose tissue. Since its discovery, leptin has been found to have profound effects on behavior, metabolic rate, endocrine axes, and glucose fluxes. Leptin deficiency in mice and humans causes morbid obesity, diabetes, and various neuroendocrine anomalies, and replacement leads to decreased food intake, normalized glucose homeostasis, and increased energy expenditure. Here, we provide an update on the most current understanding of leptin-sensitive neural pathways in terms of both anatomical organization and physiological roles.
Authors
Laurent Gautron, Joel K. Elmquist
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