Brekken Rolf A., Stupack Dwayne (eds.) Extracellular Matrix in Tumor Biology

Springer, 2017. — 121 p. — ISBN: 978-3-319-60906-5.One of the first “mantras” encountered by non-matrix biologists, as they enter the field of matrix biology, is that the extracellular matrix (ECM) is not simply the glue that holds tissues together. To many matrix biologists, this notion is self-evident; after all, biologists have understood for more than eight decades that there is a unique molecular complexity to the ECM and, moreover, have known that different histological tissues exhibit different ECM components. The concept that the complexities and variances in ECM deposition are critical to the unique mechanical and adhesive structures of a given tissue is appreciated and validates the current collection of chapters focused on the contribution of the ECM to cancer biology. Why should it be a surprise that the ECM would be critical to guide, inform, sustain, and signal under essentially every physiologically relevant condition, including cancer? In a world where we are witnessing an increasing average life span, age-related diseases have greater incidence and impact. Chief among these is cancer. A disease known from the beginnings of medicine, it was assigned its modern name in ancient Greece but remains poorly understood even today. As we develop and implement new approaches to treat cancer, life spans are being extended, yet de facto cures are rare. The disease remains enigmatic, and we are increasingly appreciating that it is a plastic disease, changing as it moves from oncogenesis to late stage. Cancer cells evolve within a patient to adjust to changing selection conditions, whether to escape the homeostatic limits imposed by normal cells, evade immune detection, compete with neighboring tissues and cancer cells for expansion, or resist the challenge of therapy. The ECM is critical for this plasticity and to tumor pathology in general. A study of the literature over the last two decades can give a reader an indication of the normal function of individual components of the ECM and how they participate in development, wound healing, and tissue homeostasis. We have a good understanding of what the normal functions of ECM components tend to be from human genetic diseases and from mouse models. However, during neoplasia, all normal rules of development and cellular regulation are subject to change. The normal patterns of ECM expression can be altered; the organization of the ECM can change due to alternative and even rare splicing patterns of ECM components, which may be exposed to proteases not normally encountered during development and homeostasis, or even due to the co-expression of ECM components that are not normally co-expressed within a given tissue. These new and different possible combinations conspire to increase tumor plasticity. Such combinations offer the opportunity to provide new signals or alter the interpretation of normal signals. Such alterations offer new ways for a tumor to sustain itself during critical challenges. Indeed, many of the most famous and impactful oncogenes, such as Ras proteins, P53, and phosphoinositide 3-kinases, are known to be intimately impacted via cell interaction with the ECM. Moreover, receptor tyrosine kinases, which are also key oncogenic drivers, typically depend upon cellular contact with an ECM to function. It is therefore not unexpected that the overexpression of these proteins in cancer, or expression of their oncogenic forms, would be impacted by the very nature of cell contact with the ECM. This dystopic ECM can ultimately contribute to the pathology of cancer in a number of different ways. Signals received from the ECM can guide tumor cells, encouraging tissue invasion or intravasation and the subsequent local or distant metastases. The distribution and componentry of the ECM guides the relative types of cell migration that are required or advantaged during these processes. These include mesenchymal migration along fibrils of ECM or amoeboid types of movement that proceed by leveraging cell movement through pores in the ECM. Thus, the migration of cancer cells through the brain, or along the bone or along blood vessels, provides unique scenarios that favor cell invasion via different mechanisms. The density of the ECM directs the mechanical and structural support of a tumor, thus dictating how migration is best accomplished. Such density can also influence other determinants of outcome, such as the capacity of chemotherapy to penetrate, and ultimately impact, a tumor. As a result, highly desmoplastic cancers, such as pancreatic cancer, impose special challenges for therapy. The influence of a dysregulated ECM extends to normal, nonmalignant cells in the tumor microenvironment. The impact of exposure to wound-like ECM components can induce changes in normal tissue that facilitate tumor cell invasion. Further, ECM-induced reprogramming of fibroblasts, selective modulation of immune cell activation, and local metabolic reprogramming can all impact tumor pathology. The precise signaling nature of these events, however, is unique and varies from cell to cell. Recent efforts have begun to quantify and characterize the vast number of ECM proteins in the tumor microenvironment, but equally important will be an understanding of their relative distribution and their interactions with each other and the surface of cancer cells. Understanding these differences is very likely to impact our comprehension of the local drivers of a given cancer. The recent appreciation of a subpopulation of tumor cells, tumor-initiating cells, and cancer stemlike cells (CSCs) and the concept of tumor dormancy offer new dimensions to our understanding of the tumor ECM. CSCs flourish in a tumor stemlike cell niche that consists in part of a specialized ECM that provides mechanical cues to tumor-initiating cells. Many of the known CSC markers are adhesion receptors. It is easy for matrix biologists to forget or ignore the fact that markers such as CD49f is α6 integrin or that CD44S is also HCAM (the major receptor for hyaluronan). Matrix biologists interested in cancer biology should use this and many other well-documented examples of how ECM biology affects cancer development and progression to highlight the critical importance of ECM biology in cancer. Matrix biologists need to be the flagbearers for key questions, such as whether the elevated expression of these receptors on the surface is functionally relevant and whether they are in constant use or simply poised to give strong and immediate signals when a permissive environment is encountered. The goal of this volume is to better integrate our understanding of the contribution of the ECM to tumor progression. While it is not possible to assemble a tome that encompasses all our advances in an exhaustive fashion, this volume represents a survey of recent advances that have significantly added to our concept of the tumor microenvironment and the function of the ECM in it. The chapters cover topics that range from classic matrix components such as fibronectin, to proteoglycans, to proteinases and hybrid molecules that bridge the protease/matrix field. Such molecules, as well as non-protease matricellular proteins that dance in and out of a rigid assembled matrix, all dramatically alter ECM dynamics and function. Indeed, even as we consider tumor heterogeneity, we have to appreciate that this will be accompanied by ECM heterogeneity. Local ECM distribution might be influenced by programmed or stochastic factors. In either case, such alterations can elicit different behaviors, even among genetically similar cells. It is hoped that beyond being a simple aggregation of data and a review of the current state of knowledge, the similarities and differences in signaling listed in these chapters will support the next level of matrix dissection: that of additive and modulating effects. Understanding this complexity will be important to the comprehension of the complexity of the underlying disease.