**1.1. History, definition and classification**

Life and death are essential parts of the natural cycle of all multicellular organisms. In metazoans, somatic cells divide normally during the process known as mitosis. Cell proliferation is tightly controlled, according to the organism needs. An increase in the number of cells takes place during growth and when one of these cells finishes its physiological function or detects DNA or cell damage, it undergoes a physiological process known as apoptosis that induces its own death. In humans about a hundred thousand cells are formed every second through mitosis, while a similar number is destroyed by apoptosis [1]. This dynamic balance between proliferation and cell death is known as homeostasis. If altered, different pathologic processes such as carcinogenesis can take place. Besides its role in embryonic development, homeostasis maintenance and aging, apoptosis is also a defence mechanism by which infected, injured or mutated cells as a result of irradiation or chemotherapeutic drugs are eliminated. This type of cell death involves the activation of an evolutionary conserved and tightly regulated intracellular machinery that requires energy consumption [2]. An important feature of apoptosis is that the cell is eliminated without triggering an immune response, avoiding thus tissue damage [3].

The term **apoptosis** to describe cell death was introduced by Kerr and colleagues in 1972 [4], from the Greek term "appo-teo-sis" which means "falling off" (as in leaves from a tree or petals from a flower). Apoptosis has been used as a synonym of programmed cell death and

© 2012 Martínez-Lacaci et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 Martínez-Lacaci et al., licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

refers to a suicidal type of death. However, as more mechanisms of programmed cell death are being elucidated, the Nomenclature Committee on Cell Death (NCCD) recommends caution when using the term apoptosis [5]. Historically, the classical methods to define cell death rely on morphological criteria. Thus, apoptosis was termed programmed cell death type I, autophagy named as programmed cell death type II and necrosis as a type of death lacking characteristics of both type I and type II. As more biochemical methods become available over the last decades, a more definite and concise classification of types of cell death has become necessary. Therefore, cell death types can be classified according to morphological appearance, biochemical features, functional criteria or immunological aspects. In the following figure (Figure 1) the classification of different types of cell death, in accordance with to the NCCD are described:

Cell Death and Cancer, Novel Therapeutic Strategies 69

round-up, b) chromatin condensation (picnosis) and fragmentation and nuclear breakdown, c) overall cell shrinkage and cytoskeleton alterations although the majority of the cell organelles remain intact, d) membrane blebbing and formation of the membrane-enclosed particles called apoptotic bodies that contain nuclear or cytoplasmic material and will be

Because apoptotic cells are eaten so quickly, there are few dead cells left on tissue sections. This is the reason why apoptosis was neglected by pathologists for a long time, even though apoptosis is the main mechanism for discarding of harmful or unwanted cells in

Along with the morphological transformation described, there are several biochemical alterations that take place. For instance, activation of endonucleases, some of them dependent on Ca2+ and Mg2+ channels, that cleaves genomic DNA. In the apoptotic process, this event gives rise to internucleosomal DNA double-strand breaks with fragments of multiples of 180 bp, resulting in the typical pattern of *DNA ladder* that can be detected by electrophoresis on agarose gels. Other changes include loss of the inner mitochondrial transmembrane potential [7] and exposure of the phospholipid phosphatidylserine to the outer cell membrane, which allows phagocytes to detect and

**Figure 2.** Features of Apoptosis, Oncosis and Necrosis (taken from Hail et al., 2006)

The most distinguishable feature of apoptosis is the formation of apoptotic bodies. On the other hand, oncosis is characterized by cytoplasmic swelling, dilation of organelles and vacuolization and plasma membrane blebbing. The cell will finally die by cytolysis, which is a typical hallmark of necrosis [9]. Apoptotic cells can also lose their plasma membrane and eventually undergo a secondary necrosis. However, this phenomenon has only been observed *in vitro*. According to Majno and Joris, necrosis is not a type of cell death, but

engulfed by phagocytes or neighbouring cells [6].

multicellular organisms.

engulf these apoptotic cells [8].

**Figure 1.** Classification of different types of cell death according to the NCCD (modified from Galluzzi et al. 2012)

It is important to mention that a single stimulus can trigger more than one mechanism of cell death simultaneously within a cell. However, only the most efficacious mechanism will be prevalent.
