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Puzzle-shaped cells and the mechanical response of tobacco (Nicotiana tabacum L.) seed coats
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- Silvia Bonfanti, Mario Beretta, Simone Milan, Cinzia Ferrario, Carlo Alberto Biffi, Oleksandr Chepizhko, Caterina A. M. La Porta, Ausonio Tuissi, Stefano Zapperi
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- Programmable Materials / Volume 2 / 2024
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- 16 February 2024, e1
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The seed coat of tobacco displays an intriguing cellular pattern characterised by puzzle-like shapes whose specific function is unknown. Here, we perform a detailed investigation of the structure of tobacco seeds by electron microscopy and then follow the germination process by time lapse optical microscopy. We use particle image velocimetry to reveal the local deformation fields and perform compression experiments to study the mechanical properties of the seeds as a function of their hydration. To understand the mechanical role of the observed coat structure, we perform finite element calculations comparing structure with puzzle-shaped cells with similar structures lacking re-entrant features. The results indicate that puzzle-shaped cells act as stress suppressors and reduce the Poisson’s ratio of the seed coat structure. We thus conclude that the peculiar cellular structure of these seed coats serves a mechanical purpose that could be relevant to control germination.
6 - Biomechanics of Cancer
- Caterina A. M. La Porta, Università degli Studi di Milano, Stefano Zapperi, Università degli Studi di Milano
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- The Physics of Cancer
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- 04 May 2017
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- 20 April 2017, pp 81-91
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11 - Outlook on the Physics of Cancer: A New Interdisciplinary Area
- Caterina A. M. La Porta, Università degli Studi di Milano, Stefano Zapperi, Università degli Studi di Milano
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- The Physics of Cancer
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- 04 May 2017
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- 20 April 2017, pp 138-140
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Summary
In this book, we have tried to define the expanding boundaries of the relatively new field of the physics of cancer. Traditionally, physicists have contributed to cancer research mostly through the development of novel diagnostic and imaging tools. Things started to change in the last few years when physicists became more and more involved in trying to understand the roots of cancer and its development, bringing to the field their experience with quantitative modeling and data analysis. The basic idea is that cellular processes should ultimately obey the laws of physics: cell migration or mitosis occurs thanks to physical forces; tumors grow into tissues and are thus subject to mechanical and hydrodynamic forces. To understand these issues one needs to perform quantitative measurements and develop theoretical models as physicists have been doing for centuries.
In the last few years, cancer research witnessed the emergence of several promising new avenues deserving further investigation. Biology is currently undergoing a real revolution brought by the sheer growth of readily available quantitative data on all kind of biological processes in general and on cancer in particular. A considerable international effort is currently underway to assemble large databases of genetic mutations, transcriptomes and miRNA for all kinds of tumors from hundreds or sometimes thousands of patients. The ultimate goal of these efforts is to pave the way to a new type of personalized or precision medicine in which treatment will be tailored to the specific genetic and epigenetic features of each patient. Traditional training in biology is, however, often insufficient to deal with the mathematical and computational complexity associated with big data, which are instead the bread-and-butter of physicists. So while these big projects are not driven by physics, many of the people involved were trained in physics.
While genetic, transcriptomic, proteomic and metabolomic data are steadily accumulating in public databases, their interpretation is still a pressing challenge. The first problem stems from the fact that often data in different experiments are recorded using various methods with differences in normalization, formatting and notation. Hence it is often hard to treat and compare different data sets at the same time.
2 - The Biology of Cancer
- Caterina A. M. La Porta, Università degli Studi di Milano, Stefano Zapperi, Università degli Studi di Milano
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- The Physics of Cancer
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- 04 May 2017
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- 20 April 2017, pp 23-37
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Cancer results from abnormal cellular growth. It is considered to be benign when localised in situ while it is defined to be malign and metastatic when it is invasive and spreads inside the body through blood or lymphatic vessels. Cancer progression can be interpreted as an evolutionary process, as we discuss in Section 2.1. In spite of the increasing knowledge gained on the molecular mechanisms involved in the deregulation of cancer cells, such as the identification of many oncogenes and oncosuppressors (discussed in Section 2.2), many open questions still exist about the origin of cancer cells. In Section 2.3, we introduce a key oncosuppressor gene which is of fundamental importance for cancer development: P53, also known as the “guardian of the genome.” While important oncogenes and oncosuppressors clearly exist, cancer involves a multitude of different genes requiring an integrative data-based approach (Section 2.4).
Another important issue that is still under investigation is the presence of a subpopulation of more aggressive cancer cells, usually described as cancer stem cells (Section 2.5) (CSCs). The molecular aspects related to the capability of cancer cells to receive nutrients from the environment through existing vessels, and the ability of the same cancer cells to induce vessel formation (angiogenesis), are two critical aspects of the biology of cancer that we illustrate in Section 2.6. Furthermore, in Section 2.7, we illustrate the spread of cancer cells inside the body in the metastatic process. All together these aspects will be discussed here, combining biological and physical viewpoints. In this perspective, the cancer ecosystem is the combination of physical forces and biochemical ingredients. Finally, the new diagnostic tools for the identification of a cancer cell are also discussed and critically reviewed (Section 2.8).
Cancer Origin and Evolution
It is now commonly accepted that cancer is the consequence of random mutations in cells. This general idea dates back to the pioneering observations of chromosomal abnormalities in cancer made by Boveri at the beginning of the twentieth century (Boveri, 1903). The concept gained further traction with the discovery, made by Muller in the twenties, that ionizing radiation is mutagenic (Muller, 1930). In the forties, Berenblum and Shubik discovered that chemical carcinogenesis was described by two stages: initiation by carcinogens and promotion by other chemicals (Berenblum and Shubik, 1949).
Dedication
- Caterina A. M. La Porta, Università degli Studi di Milano, Stefano Zapperi, Università degli Studi di Milano
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- The Physics of Cancer
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The Physics of Cancer
- Caterina A. M. La Porta, Stefano Zapperi
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- 04 May 2017
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- 20 April 2017
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Recent years have witnessed an increasing number of theoretical and experimental contributions to cancer research from different fields of physics, from biomechanics and soft-condensed matter physics to the statistical mechanics of complex systems. Reviewing these contributions and providing a sophisticated overview of the topic, this is the first book devoted to the emerging interdisciplinary field of cancer physics. Systematically integrating approaches from physics and biology, it includes topics such as cancer initiation and progression, metastasis, angiogenesis, cancer stem cells, tumor immunology, cancer cell mechanics and migration. Biological hallmarks of cancer are presented in an intuitive yet comprehensive way, providing graduate-level students and researchers in physics with a thorough introduction to this important subject. The impact of the physical mechanisms of cancer are explained through analytical and computational models, making this an essential reference for cancer biologists interested in cutting-edge quantitative tools and approaches coming from physics.
Contents
- Caterina A. M. La Porta, Università degli Studi di Milano, Stefano Zapperi, Università degli Studi di Milano
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- The Physics of Cancer
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Frontmatter
- Caterina A. M. La Porta, Università degli Studi di Milano, Stefano Zapperi, Università degli Studi di Milano
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- The Physics of Cancer
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7 - Cancer Cell Migration
- Caterina A. M. La Porta, Università degli Studi di Milano, Stefano Zapperi, Università degli Studi di Milano
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- The Physics of Cancer
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- 04 May 2017
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- 20 April 2017, pp 92-111
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Cell migration plays a fundamental role in cancer, being at the basis of the metastatic process, where cancer cells detach from the primary tumor, invade neighboring tissues and finally spread to distant organs. In this chapter we discuss the main biological and physical aspects of migration, starting from the motion of individual cells (Section 7.1) and the statistical characterization of their trajectories in terms of stochastic processes. Cells respond to chemical signals, in a process known as chemotaxis (Section 7.2), and then polarize and move in the direction of the chemical gradient. In order to move, cells make use of a vast class of cell adhesion molecules, which we review in Section 7.3.Motion results from the application of traction forces to the ECM, which can be quantified experimentally, as we discuss in Section 7.4. Cell adhesion molecules also play an important role in the interaction between cells, leading to collective effects. Experiments and models of collective cell migration are discussed in Section 7.5. Finally, in Section 7.6, all the fundamental steps giving rise to cell migration are summarized and discussed in the framework of the metastatic process.
Individual Cell Motion
Cell migration plays a key role in many physiological processes such as embryogenesis and morphogenesis, immune response, wound healing and tissue repair, but it is also a crucial determinant for cancer invasion and metastasis (Rørth, 2009; Friedl and Gilmour, 2009; Ilina and Friedl, 2009). Cellular migration is regulated at the biochemical level by the coordinated action of a multitude of factors involved in the response to external chemical stimuli, in the remodeling of the actin cytoskeleton and in the regulation of adhesion molecules needed to apply traction forces to the surrounding ECM and to neighboring cells. While discussing these processes in more detail in the coming sections, we focus here on the movement resulting from their integration.
3 - A Modeling Toolbox for Cancer Growth
- Caterina A. M. La Porta, Università degli Studi di Milano, Stefano Zapperi, Università degli Studi di Milano
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- The Physics of Cancer
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In this chapter we review a set of basic mathematical models and tools that have been widely applied to study cancer growth.We start in Section 3.1 with branching processes, simple probabilistic mean-field models for the evolution of a population. Branching processes represent the most widely used approach to model population dynamics of cancer cells. In Section 3.2 we consider probabilistic models for the evolution of mutations in cancer development. These models are sometimes related to branching processes we need to take into account for mutations in expanding clonal populations. In Section 3.3 we discuss models’ gene regulatory networks and signaling networks relevant for cancer, and in particular models for the p53 network. Mean-field models are not adequate to take into account the spatial localization of a tumor or of cancer cell population. To this end, one should introduce individual cell models in which we can follow the dynamics of a set of interacting active cells (Section 3.4). At a more coarse-grained level, the growth dynamics of a tumor can be represented by lattice cellular automata or by continuum phase-field models as discussed in Section 3.5.
Branching Processes
Branching processes (Harris, 1989; Kimmel and Axelrod, 2002) are a class of simple models that have been used extensively to model growth dynamics of stem cells (Vogel et al., 1968; Matioli et al., 1970; Potten and Morris, 1988; Clayton et al., 2007; Antal and Krapivsky, 2010; Itzkovitz et al., 2012) and cancer cells (Kimmel and Axelrod, 1991; Michor et al., 2005; Ashkenazi et al., 2008; Michor, 2008; Tomasetti and Levy, 2010; La Porta et al., 2012). Branching processes can be defined in discrete or continuous time and with evolution rules that may or may not depend on time. A detailed review of the mathematical theory of the branching process is given by Harris (1989) and applications to biology are discussed in Kimmel and Axelrod (2002).
Index
- Caterina A. M. La Porta, Università degli Studi di Milano, Stefano Zapperi, Università degli Studi di Milano
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- The Physics of Cancer
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4 - Vascular Hydrodynamics and Tumor Angiogenesis
- Caterina A. M. La Porta, Università degli Studi di Milano, Stefano Zapperi, Università degli Studi di Milano
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- The Physics of Cancer
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Tumors need nutrients and oxygen to grow and, at the same time, must evacuate metabolic waste and carbon dioxide. To this end, tumor cells induce the sprout of new vessels from the pre-existing ones through a process known as angiogenesis, introduced in Section 4.1, where we mostly focus on the main biological aspects. In Section 4.2, we discuss how tumor cells can form vessels directly, a process known as vasculogenic mimicry. The physical aspects of angiogenesis, such as the constraints posed by the hydrodynamics of blood flow, are reviewed in Section 4.3. Finally, Section 4.4 is devoted to a discussion of the physics-based computational models for angiogenesis. These models are interesting since they allow therapeutic strategies in silico to be tested by simulating the release of drugs through the blood flow.
Biological Aspects of Angiogenesis
The growth of a tumor and its capacity to invade and give rise to metastasis crucially depend on angiogenesis, which is thus considered one of the hallmarks of cancer (Hanahan and Weinberg, 2000). Whereas blood vessel growth is tightly regulated under physiological conditions, the vasculature produced by angiogenesis in tumors typically displays aberrant structure, geometry and organization (see Figure 4.1), showing an excess of branching and modifications in the shape and size of vessels, which is reflected in defective blood flow and leakage (McDonald and Choyke, 2003; Nagy et al., 2010).
The acquisition of an angiogenic phenotype in tumors is associated to a switch in the balance between pro- and anti-angiogenic factors (Baeriswyl and Christofori, 2009; Bergers and Benjamin, 2003). This switch can be specific to distinct tumor types and localizations, and might also be altered during tumor progression (Folkman, 2002).
9 - Control of Tumor Growth by the Immune System
- Caterina A. M. La Porta, Università degli Studi di Milano, Stefano Zapperi, Università degli Studi di Milano
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- The Physics of Cancer
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- 04 May 2017
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- 20 April 2017, pp 123-131
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The immune system is the primary defense of the organism against diseases, but cancer is often able to evade its response. Many advanced therapeutic strategies nowadays aim to redirect the immune response against the tumor. In Section 9.1, we introduce the immune system, discussing innate and adaptive immunity. The ability of cancer cells to escape the immune response is discussed in Section 9.2. The communication between cells during the immune response is coordinated by cytokines, as we discuss in 9.3. The organism responds to external pathogens by a process of inflammation that we review in Section 9.4, where we also discuss its relevance for tumors. Finally, in Section 9.5, we illustrate simple mathematical models for the interactions between cancer cells and the immune system.
The Immune System
The immune system plays the crucial role of defending organisms against not only pathogens but also tumor cells. In mammals, immuno-surveillance is a combination of innate and adaptive immunity (Figure 9.1). The main feature of innate immunity is to activate an immediate response making use of pre-existing mechanisms: mechanical barriers, enzymes, complementary systems and cells, such as neutrophils that can phagocyte pathogens, or like the natural killer (NK) that can kill them. Adaptive immunity is provided by lymphocytes B and T that require first to be activated by pathogens and only then proliferate, finally inducing terminal factors needed to eliminate the pathogens. The whole process of adaptive immunity requires more time than innate immunity, but once the system is immunized, the response is much faster and stronger thanks to the release of memory cells (Figure 9.2). In the adaptive immunity, the antigen should be presented by Major Histocompatibility Complex (MHC) expressed or on the plasma membrane of all the nucleated cells (MHC type I) or on the surface of the antigen presenting cells (MHCII) at the lymphocyte T that recognize the complex MHC-peptide through the T Cell Receptor (TCR). In contrast, B cells recognize directly the antigen through the antibody expressed on the plasma membrane (B Cell Receptor, BCR).
References
- Caterina A. M. La Porta, Università degli Studi di Milano, Stefano Zapperi, Università degli Studi di Milano
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- The Physics of Cancer
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- 20 April 2017, pp 141-170
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Preface
- Caterina A. M. La Porta, Università degli Studi di Milano, Stefano Zapperi, Università degli Studi di Milano
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- The Physics of Cancer
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- 20 April 2017, pp xi-xiv
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Understanding how cancer initiates, grows and migrates has been a fundamental topic of biomedical research in the past decades and is still the object of intense scientific activity. Cancer is a complex disease where many factors cooperate. According to the 2000 seminal paper by Hanahan and Weinberg, six biological capabilities (the hallmarks of cancer) encapsulate the key features describing the remarkable variability displayed by cancer: sustaining proliferative signaling, evading growth suppression, activating invasion and metastasis, inducing angiogenesis, resisting cell death, activating invasion and metastasis, enabling replicative immortality (Hanahan and Weinberg, 2000). In a more recent review, the same authors take into account the observations that emerged in the previous ten years and add four new hallmarks: avoiding immune destruction, promoting inflammation, genome instability and mutation, deregulating cellular energetics (Hanahan and Weinberg, 2011). Hence, after ten years the hallmarks of cancer are still to be understood and have even increased in number! This is a signal in our opinion that traditional approaches need new strings in their bows. Tumors are extremely heterogeneous and their growth depends on dynamical interactions among cancer cells and between cells and the constantly changing microenvironment. All these interactive processes act together to control cell proliferation, apoptosis and migration. There is an increasing consensus that these dynamical interactions cannot be investigated purely through single biological experiments because experimental complexity usually restricts the accessible spatial and temporal scales of observations. Therefore it is necessary to study cancer as a complex system.
Advances in systems biology are already beginning to have an impact on medicine through the use of computer simulations for drug discovery. The integration of new experimental physics techniques in cancer research may help improve, for example, the capability to design more efficient cancer therapies. Understanding the biology of cancer cells and the impact of physical mechanisms, such as cell and tissue mechanics, on their biological functions could help validate biomarkers and develop more accurate diagnostic tools and individualized cancer therapies. In the past years, clinical studies have relied heavily on conventional population-based randomized clinical trials that try to identify favorable outcomes as an average over the population. Cancers are, however, extremely heterogeneous even within the same tumor class, so that an average positive outcome does not necessarily translate to a positive outcome in individual cases.
1 - Introduction to the Cell
- Caterina A. M. La Porta, Università degli Studi di Milano, Stefano Zapperi, Università degli Studi di Milano
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- The Physics of Cancer
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In this chapter we will introduce the main properties of the eukaryotic cell, starting from its characterization in terms of its organelles, such as the nucleus, and its structural components, such as the cytoskeleton and the membrane (see Section 1.1). In Section 1.2, we discuss in detail how DNA is organized, and we introduce different chromatin structures such as B-DNA and Z-DNA and their condensation into chromosomes. Section 1.3 discusses how DNA is replicated so that the genetic information it encodes can be passed over to daughter cells. We also explain how DNA is repaired when damage due to external perturbation occurs. Next, in Section 1.4, we explain how the genetic information encoded in the DNA is transcribed into RNA and then translated into proteins, a process that has been termed the “central dogma” of molecular biology. Cells are surrounded by the plasma membrane formed by lipid bilayers, which also enclose the organelles and have a key role in intracellular and extracellular transport. This issue is illustrated in Section 1.5. Section 1.6 discusses the regulation of gene expression in the cell, and in particular that performed by miRNAs, a set of small RNA molecules. Finally, Section 1.7 illustrates the process of cell division and Section 1.8 discusses cell death and cell senescence.
Architecture of the Eukaryotic Cell
A cell is a small organized machine where DNA stores information, RNAs translate the message in protein language and proteins are the effectors. The ingredients needed to control the behavior of a cell are a mixture of biochemical and physical factors. Before discussing in detail how the machine functions, we first describe its general architecture. Cells in the human body can differ widely in terms of shape, size and function, but some general features are common to all cell types and are illustrated in Figure 1.1.
Eukaryotic cells are enclosed by the plasma membrane, a semi-permeable membrane in the form of a lipid bilayer that we will discuss in detail in Section 1.5. In contrast to bacterial cells, eukaryotic cells contain a set of membrane bound structures, known as organelles, that perform specialized functions.
5 - Cancer Stem Cells and the Population Dynamics of Tumors
- Caterina A. M. La Porta, Università degli Studi di Milano, Stefano Zapperi, Università degli Studi di Milano
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- The Physics of Cancer
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According to the CSC hypothesis, tumor growth is driven by a small population of cancer stem cells which can self-renew and differentiate into cancer cells with a long but limited lifespan. The experimental challenges in the identification of CSCs are discussed in Section 5.1 where we review the relevant biological markers. In Section 5.2, we discuss the population dynamics within the tumor, composed by CSCs and other tumor cells. To this end, we introduce a mathematical model for the evolution of the populations and compare its results with experiments. In Section 5.3, we deal with the possibility that cancer cells can occasionally switch back to the CSC state, discussing relevant experiments and models. Section 5.4 is devoted to the issue of cell sorting. While one would like to define the CSC population in a sharp way, in practice the boundary is fuzzy, being based on the expression of biological markers which are by their nature imperfect. This opens an interesting issue about the interpretation of the experimental results.
Experimental Identification of Cancer Stem Cells
Tumor growth can either be described by the conventional model or by the CSC theory. According to the first model, cancer cells are heterogeneous but are all tumorigenic, while the CSC hypothesis states that in the tumor there is a subpopulation sustaining the tumor growth (La Porta, 2009). Cancer stem cells (CSCs) are a subpopulation of tumor cells that possess the stem cell properties of selfrenewal and differentiation. Therefore, a CSC is a cell within the tumor that has the capacity of self-renewing and generating a heterogeneous population of cancer cells composing the tumor. Contrary to normal stem cells, however, which control very strictly their proliferation capability and try to carefully maintain their genomic integrity, CSCs typically lack any control of those processes. Identifying differences between normal stem cells and CSCs is important for understanding how cancers progress and could possibly result in new therapies to fight cancer. In practice, CSCs can only be defined experimentally by their ability to recapitulate the generation of a continuously growing tumor. To this end, putative CSCs are identified according to the expression of surface markers (e.g., factors expressed by normal stem cells) and isolated through fluorescence-activated cell sorting (FACS).
10 - Pharmacological Approaches: Old and New
- Caterina A. M. La Porta, Università degli Studi di Milano, Stefano Zapperi, Università degli Studi di Milano
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- The Physics of Cancer
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- 20 April 2017, pp 132-137
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Traditional approaches to treat cancer rely on surgery, radiotherapy and chemotherapy. There is a current effort to improve the efficacy of drug delivery by using nanotechnology, encapsulating drugs inside nanoparticles. We discuss these methods in Section 10.1. Evidence of the relationship between cancer and nutrition has been accumulating over the years. We discuss this point in Section 10.2.
The Traditional Approaches and Nanomedicine
Current cancer treatments consist of surgery, radiotherapy and chemotherapy. Removal of the bulk of the tumor by surgery still remains the most effective treatment for cancer. Evidence exists, however, that surgery may induce an acceleration of tumor and metastatic growth due to the inflammatory response associated with wound healing (Coffey et al., 2003). Radio- and chemotherapy are often used to eliminate possible peripheral cells that are not completely eradicated by surgery and to control cancer growth activated by wound healing. Some tumors such as melanoma are radio-resistant, and therefore chemotherapy is the only possible alternative strategy apart from surgery.
Chemotherapy is not always effective due to problems in drug delivery, drug resistance and toxicity for the patients. Resistance to chemotherapy can have various causes in which a big role could be played by the large cell-to-cell variability inside a tumor, even within the same patient (Kessler et al., 2014). The current strategy is to use a combination chemotherapy, referring to the simultaneous administration of two or multiple therapeutic agents (Greco and Vicent, 2009; Dai and Tan, 2015; Xu et al., 2015; Pacardo et al., 2015). The main idea is that choosing an appropriate drug combination can help prevent cancer drug resistance and improve target selection and therapeutic action. An important limitation of combination chemotherapy stems from the different kinetics associated with each drug, making it difficult to obtain a simultaneous combined action. Furthermore, it is important to remark that the systemic toxicity of combination chemotherapy might be significantly enhanced due to the sum of side effects of separated drugs, which could enormously limit the effectiveness of combination therapy in the clinic.
Nanotechnology represents a promising strategy to improve drug delivery, allowing for easy drug administration, improved accumulation at the tumor site and at the same time minimization of side effects for the patient (Langer, 1998; Saltzman and Olbricht, 2002; Peer et al., 2007; LaVan et al., 2003; Farokhzad and Langer, 2009).
8 - Chromosome and Chromatin Dynamics in Cancer
- Caterina A. M. La Porta, Università degli Studi di Milano, Stefano Zapperi, Università degli Studi di Milano
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- The Physics of Cancer
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- 20 April 2017, pp 112-122
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Cancer typically displays alterations in the number of chromosomes, often the result of incorrect segregation during cell division, as we discuss in Section 8.1. Faithful chromosome segregation relies on the combined action of motor proteins and microtubules which must first align all the chromosomes on the cell central plate. This complex process can be described realistically by computational models which allow the effect of several biological factors on cell division to be tested, as we discuss in Section 8.2. In addition to chromosomal alterations, cancer cells often display other defects in nuclear architecture and chromatin organization, as we review in Section 8.3.
Chromosomal Instability
As discussed previously, cancer results from the accumulation of genetic mutations, but how these mutations are generated is debated. A high frequency of mutations, known as genetic instability, is believed to be a key property, if not a requirement, of most tumors (Lengauer et al., 1998). Genetic instability exists at the level of the nucleotides, resulting from their insertions, delations or substitutions, or at the level of the entire chromosome. Indeed, most cancers display an altered number of chromosomes, a state known as aneuploidy, and mis-segregated chromosomes at high rates, a condition known as chromosomal instability (CIN) (see Figure 8.1). Aneuploidy is simply detected by counting chromosome numbers, a task that can easily be achieved by several experimental techniques (Thompson et al., 2010). Detection of CIN requires instead the measurement of chromosome mis-segregation rates, which involves counting the number of chromosomes at different times in clonal populations.
CIN is a characteristic feature of human solid tumors and of many hematological malignancies (Boveri, 1903), a principal contributor to genetic heterogeneity in cancer (Burrell et al., 2013a) and an important determinant of clinical prognosis and therapeutic resistance (Lee et al., 2011; Bakhoum and Compton, 2012). While the link between aneuploidy and cancer was recognized already over a century ago (Boveri, 1903), general understanding of the mechanisms leading to CIN, as well as appreciation of its consequences on cellular viability and tumor evolution, has grown considerably over the past two decades (Bakhoum and Compton, 2012; Thompson et al., 2010).