Page 57 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

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Tumor Biology and Metastasis

DAVID J. ARGYLE, CHAND KHANNA, AND NICOLE GIANCRISTOFARO

Cells of multicellular organisms form part of a specialized soci- the M (mitosis) and S (DNA synthesis) phases and are referred to
ety that cooperate to promote survival of the organism. In this as G0 (quiescent) cells. Most cells in normal tissues are in G0. Cells
society, cell division, proliferation, and differentiation are strictly are stimulated to enter the cell cycle in response to external factors,
controlled, and a balance exists between normal cell birth and the including growth factors and cell adhesion. During the G1 phase
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natural cell death rate. Derangement of these normal homeo- of the cell cycle, cells are responsive to mitogenic signals. Once the
static mechanisms can lead to uncontrolled proliferation or loss of cell cycle has traversed the restriction point (R) in the G1 phase,
the ability to die, which may contribute to a normal cell taking on cell cycle transitions become autonomous.
a malignant phenotype. Interphase (G1, S, and G2 phases) is the longest phase of the
Cancer in animals is well documented throughout history but cell cycle. During interphase the chromatin is very long and slen-
has taken on significance over the past hundred years for a num- der; however, it shortens and thickens as interphase progresses.
ber of reasons. Studies on chicken, feline, and bovine retroviruses The M phase is further subdivided into four phases. The first phase
have made significant contributions to our overall understanding is referred to as prophase and sees the first appearance of the chro-
of carcinogenesis through the discovery of oncogenes and tumor mosomes. As the phase progresses, the chromosomes appear as
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suppressor (TS) genes. Further contributions to the understand- two identical sister chromatids joined at the centromere. As the
ing of viral oncogenesis have come from studies of the papilloma- nuclear membrane disappears, spindle fibers form and radiate
viruses in cattle and horses, complementing research into cervical from the two centrioles, each located at opposite poles of the cell.
cancer in women. 3–10 This complementary cancer research has The spindle fibers serve to pull the chromosomes to opposite sides
paved the way for the development of programs of research in of the cell.
comparative medicine that has benefits for both humans and vet- During metaphase the spindle fibers pull the centromeres of the
erinary species. This chapter summarizes the current understand- chromosomes, which become aligned to the middle of the spindle,
ing of the molecular mechanisms of cancer development and often referred to as the equatorial plate. During anaphase the cen-
metastasis. tromeres split and the sister chromatids are pulled apart by the
contraction of the spindle fibers. The final stage of cell division is
Normal Cell Division telophase, characterized by the formation of a nuclear membrane
around each group of chromosomes, followed by cytokinesis or
To understand the genesis of cancer, it is important to first under- separation of the cytoplasm to produce two identical diploid cells.
stand the basic biology of normal cell division (i.e., normal cel- Progression through the cell cycle lasts approximately 12 to 24
lular homeostasis). Within an animal all cells are subject to wear hours.
and tear, making cellular reproduction a necessity for maintenance
of the individual. Reproduction of the gametes occurs by the pro- Control of the Cell Cycle
cess of meiosis, whereas reproduction of somatic cells involves
two sequential phases known as mitosis and cytokinesis. Mitosis Progression through the cell cycle is mediated by the sequential
is nuclear division (karyokinesis), and cytokinesis involves the activation and inactivation of a class of proteins called cyclin-
division of the cytoplasm, the two occurring in close succession. dependent kinases (CDKs). 11–16 CDKs are enzymes that catalyze
Nuclear division is preceded by a doubling of the genetic mate- the addition of phosphate groups onto target substrates involved in
rial of the cell during a period known as interphase. In addition the processes of DNA replication, protein synthesis, and cell divi-
to copying of the chromosomes, this period is characterized by sion. CDKs act as “fine tuning” for cell cycle control and so must
marked cellular activity in terms of RNA, protein, and lipid syn- themselves be controlled in a strict and temporal fashion. CDK
thesis. The alternation between mitosis and interphase in all tis- activity is controlled by regulatory subunits known as cyclins. 11,13
sues is often referred to as the cell cycle. Although the levels of CDKs remain constant throughout the
cell cycle, the concentration of cyclins varies in a phase-specific
The Cell Cycle manner during the cell cycle. The periodic synthesis and destruc-
tion of cyclins provides the primary level of cell cycle control
The cell cycle comprises four phases (M phase, G1, S phase, and (see Fig. 2.1). The activity of cyclin/CDK complexes is also regu-
G2) (Fig. 2.1). Nonproliferating cells are usually arrested between lated by phosphorylation. Activation of CDK/cyclin complexes

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