Introduction to Cancer Metastasis

Aamir Ahmad, Aamir Ahmad

• Verlag: Academic Press
• Jahr: 2016
• ISBN:
  9780128040331
• Thema: Medicine
• Thema: Oncology

Introduction to Cancer Metastasis provides, in one place, an overview of organ-specific cancer metastasis and the most common sites of cancer metastasis. Through specific chapters on individual primary cancers, their metastasis, and chapters on common metastatic sites, this volume comprehensively informs readers about the broader knowledge base in cancer metastasis. The process of metastasis is particularly responsible for making cancer so lethal. This volume explores both metastasis from sites of origin and common metastatic sites, thus increasing understanding of both perspectives.

• Includes basic biology and translational approaches to organ-specific cancer sites
• Provides readers with information on emerging therapeutic targets for cancer metastasis
• Contains contributions from leading researchers around the globe

Part I

Cancer Metastasis From Primary Organs

Outline

Chapter 1. Cancer Metastasis: An Introduction

Chapter 2. Breast Cancer Metastasis

Chapter 3. Prostate Cancer Metastasis

Chapter 4. Lung Cancer Metastasis

Chapter 5. Cervical Cancer Metastasis

Chapter 6. Colorectal Cancer Metastasis

Chapter 7. Metastatic Pancreatic Cancer: Current State and Future Directions

Chapter 8. Gastric Cancer Metastasis

Chapter 9. Hepatocellular Carcinoma: Metastatic Disease

Chapter 10. Metastatic Bladder Cancer

Chapter 11. Metastatic Cutaneous Squamous Cell Carcinomas

Chapter 12. Osteosarcoma Metastasis—Prognostic Factors and Treatment Strategies

Chapter 1

Cancer Metastasis

An Introduction

H. Zubair, and A. Ahmad University of South Alabama, Mobile, AL, United States

Abstract

Cancer is a deadly disease that affects millions of people worldwide. The one factor that makes cancer particularly lethal is its ability to metastasize. Cancer, localized at primary site, is generally associated with good prognosis, however, its escape from the confines of primary organ and onto distant organs is largely untreatable. A number of molecular factors are under investigation for their role in cancer metastasis. In the introductory chapter of this volume, our goal is to summarize the process of metastasis and provide an updated information on what is known about the general process of cancer metastasis. Other chapters in this volume will provide a more detailed overview of metastasis from, and to, specific organs.

Keywords

Cancer metastasis; Epithelial–mesenchymal transition; Matrix metallo proteinases

1. Introduction

Cancer remains a leading cause of death worldwide, resulting in about 8.2 million deaths in 2012 (Stewart and Wild, 2014). Metastases of cancer account for a vast majority of morbidity and mortality of cancer patients and is associated with about 90% of all cancer-associated deaths (Mehlen and Puisieux, 2006). Cancer metastasis is defined as the formation of new tumors (secondary and tertiary tumor nests) in tissues and organs away from the primary site of tumor origin. Although significant strides have been made in understanding the mechanism of metastasis, vital information on the process of metastasis, the factors responsible for the cancer spread and establishment at distal secondary locations are still relatively unknown (Hunter et al., 2008). Nearly half of all cancer patients present clinically detectable metastatic disease (Martin et al., 2000), whereas a larger number of clinically diagnosed cancer patients also have micrometastasis that is beyond detection limit of techniques currently employed (Winter et al., 2015).

Cancer is the result of the accumulation of multiple genetic aberrations and epigenetic modifications which can be considered as the basis of metastasis as well (Vogelstein and Kinzler, 2004; Jaenisch and Bird, 2003). Metastasis requires a careful choreography of chain-of-events to be completed for successful colonization; which otherwise can lead to the elimination of emigrating cells at any stage of metastasis (van et al., 2011). The major events involved in the “metastatic cascade” include loss of cell–cell adhesion, detachment from the extracellular matrix and invasion in to the basement membrane, intravasation to blood stream and survival in circulation, identification of organ suitable for secondary growth, extravasation from circulation and establishment of distant colony followed by angiogenesis to overcome dormancy (Wan et al., 2013) (Fig. 1.1). Identification of underlying mechanism(s) during these crucial events can lead to design of novel targeted therapies that can limit cancer invasion and result in better management and treatment of cancer.

2. Disruption of Cell Adhesion: Initiation of Metastasis

Initiation of the metastatic cascade in cancers derived from the epithelium primarily requires the detachment of cells from the tumor mass with changes in the extracellular matrix and the surrounding basement membrane, relieving the cells of cell–cell interactions (Palmer et al., 2011; Bersini et al., 2014). Adhesiveness between cells is maintained by adherens junctions (AJs), tight junctions (TJs), and gap junctions (GPs).

Figure 1.1 An overview of the metastatic cascade.

In metastasis, tumor cells from the primary site initiate loss of cell–cell adhesion and detach from the extracellular matrix to invade the basement membrane from where they intravasate to blood stream. The tumor cells survive in circulation and they seek an organ suitable for their secondary growth, and extravasate from circulation to establish distant colony. Alternatively, these cells may propagate to the lymph nodes from which they can move to distant lymph nodes and other organs.

2.1. Adherens Junctions

The AJs are the source of the strongest adhesion in the epithelium, followed by TJs and GJs that provide a modest adhesion (Coopman and Djiane, 2016). AJs are cell–cell interacting microdomains (Giepmans and van Ijzendoorn, 2009). Cadherin protein family represents the widely studied AJs and E-cadherin is one of the very well-characterized family member. E-cadherin, apart from maintaining cell–cell adhesion, has also been demonstrated to maintain the levels of cell cycle regulator p27^kip1(Massarelli et al., 2005). Loss of E-cadherin in cancer cells leads to a simultaneous loss of these cell cycle inhibitors leading to disruption of contact inhibition (Motti et al., 2005). Moreover, the cadherins also have catenin-binding domains that interact with and bind to β-catenin or γ-catenin (plakogobin), which forms a link with the actin cytoskeleton (Conacci-Sorrell et al., 2002). Thus, in relation to cancer, E-cadherins have been delineated as potent tumor suppressors due to their essential role in maintaining cell–cell interactions. E-cadherin’s downregulation is also one of the initial step in initiation of epithelial to mesenchymal transition (EMT). However, soluble E-cadherin has been demonstrated to activate multiple signaling pathways enhancing tumor progression (Hu et al., 2016). Furthermore, somatic and germline E-cadherin mutations have been observed in a number of cancers (Berx et al., 1998a,b). Lobular breast cancers, among other cancer types, have been observed to harbor somatic mutations that correlate with tumor progression toward highly invasive and metastatic phenotype of the cancer. Some cases of familial gastric carcinoma have been reported to present germline mutations (Black et al., 2014). However, most tumor cases demonstrate E-cadherin reduction by transcriptional silencing through direct targeting of the promoter sequence (Venza et al., 2016; Han et al., 2016; Liu et al., 2016). Thus, there seems to be overwhelming evidence supporting metastasis-suppressive action of E-cadherin, and the loss or downregulation of E-cadherin is one of the early event in cancer metastasis.

2.2. Tight Junctions

TJ complexes are located at the apical membranes of epithelial and endothelial cells and are subdivided into integral membrane proteins, junctional adhesion molecules, the claudin family of proteins, and the cytoplasmic adaptor proteins (Balda and Matter, 2016). These complexes line the plasma membranes between adjacent cells and create an intercellular barrier, occludin...