Page 66 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 2 Tumor Biology and Metastasis 45

in cancer biology is further endorsed by the fact that all normal As described previously, cancer is a very common disease in
cells, irrespective of origin and phenotype, carry similar molecular animals and humans; however, the development of cancer is, in
fact, a rare event. Despite the number of cells in the body, the
machineries that regulate cell proliferation, differentiation, aging,
VetBooks.ir and cell death. proliferation and regulation of these cells, and the potential for
malignant transformation, the development of a single cancer is
Tumorigenesis is a multistep process, and these steps reflect
genetic alterations that drive the progression of a normal cell into rare. This is because of the cell’s own natural defenses against pro-
a highly malignant cancer cell. This is supported by the finding gression toward the malignant phenotype. The ability of the cell
that genomes of tumor cells are invariably altered at multiple to effect DNA repair or initiate cell death is a defense mechanism
sites. The spectrum of changes ranges from subtle point mutations against malignant transformation and serves to maintain cellular
in growth regulatory genes to obvious changes in chromosomal homeostasis. Each of the acquired capabilities described previously
complement. represents a breach in a cell’s homeostatic mechanisms. However,
Cancer cells have defects in regulatory circuits that govern cel- the biology of cancer cannot be understood by simply considering
lular proliferation, homeostasis, and survival. A model has been the phenotypic traits of the cancer cell. Rather, the cancer phe-
proposed that suggests that the vast array of genetic abnormalities notype is defined by the interactions between the cancer cell, the
associated with cancer is a manifestation of eight alterations in cel- TME, and the enabling effects of fundamental genomic instability
lular physiology that collectively contribute to malignant growth. and chronic inflammation.
First proposed in 2000 and updated in 2011, these “hallmarks”
of cancer constitute an organizing principle for rationalizing the Self-Sufficiency in Growth Signals
complexities of cancer and are underpinned by two overarching
themes: genome instability and chronic inflammation. 69,70 The eight Normal cells require mitogenic stimuli for growth and prolifera-
acquired characteristics can be summarized under these headings tion. These signals are transmitted to the nucleus by the binding of
(see Fig. 2.6): signaling molecules to specific receptors, the diffusion of growth
• Self-sufficient growth factors into the cell, extracellular matrix (ECM) components, or
• Insensitivity to antigrowth signals cell-to-cell adhesions or interactions. 73,74 As previously discussed,
• Evasion of programmed cell death (apoptosis) many oncogenes act by mimicking normal growth signals. Tumor
• Limitless replicative potential cells are not dependent on external mitogenic stimuli for prolif-
• Sustained angiogenesis eration and sustained growth, but rather are self-sufficient. The
• Reprogramming energy metabolism liberation from dependency on exogenous signals severely disrupts
• Evading immune destruction normal cellular homeostasis. Arguably the most fundamental trait
• Tissue invasion and metastasis of cancer cells is their ability to sustain chronic proliferation. By
Cancer exhibits another dimension of complexity in that it deregulating these signals, cancer cells become masters of their
contains an array of “normal” cells that contribute to the acqui- own destinies, promoting signaling (typically through intracel-
sition and maintenance of the cancer hallmarks by creating the lular kinase domains) to promote progression through the cell
tumor microenvironment (TME). The next section is an overview cycle, increases in cell size, increases in cell survival, and changes
of these traits and the strategies by which they are acquired in in energy metabolism.
cancer cells. The process of metastasis requires angiogenesis and The cancer cell can acquire this capability in a number of ways:
invasion; therefore the traits of sustained angiogenesis and tissue • They may produce growth factor ligands themselves.
invasion and metastasis are collectively reviewed under a final sec- • They may induce stromal cells to produce such ligands.
tion on metastasis. • Receptor concentration on the cell surface may increase, lead-
ing to receptor homodimerization or heterodimerization, mak-
The Hallmarks of Cancer ing the cell hyperresponsive to ligands.
• Structural alterations in the receptor may take place that cause
In the preceding section we described the normal cell and the ligand-independent “firing.”
role of oncogenes and TS genes in cell cycle control and regula- • Constitutive activation of the signaling pathway (downstream
tion. Directly or indirectly all components of the cancer phe- of the receptor) may occur. A good example of this is the con-
notype (i.e., hallmarks of cancer) emerge from dysregulation stitutive activation of the PI3K-Akt pathway, through muta-
of genes or the regulation of gene expression. Cancer-associ- tions in the catalytic subunit of the PI3 kinase.
ated changes in the regulation of gene expression (epigenom- • Disruptions in negative feedback mechanisms that attenuate
ics) have increasingly become the focus of cancer research. proliferative signaling may occur; for example:
Amplifying this study of the regulation of gene expression has o Mutations in the Ras gene compromise the Ras GTPase
been a new understanding of therapeutic interventions that activity, which acts as a negative feedback mechanism to
target various aspects of gene regulation (e.g., bromodomain ensure the effects of Ras are only transitory.
inhibitors). 71 o PTEN is a tumor suppressor protein that counteracts
Furthermore, understanding of the targets of the regulation of PI3K signaling. PTEN loss has an effect similar to con-
gene expression has expanded from the conventional view of epi- stitutive PI3K activation and promotes tumorigenesis.
genetic regulation of promoter activity to a new understanding Although the acquisition of growth signaling autonomy by can-
of enhancer epigenomics and the description of “super enhanc- cer cells is conceptually satisfying, it is in fact too simplistic. One
ers.” As suggested by the name, super enhancers may be consid- of the major problems of cancer research has been focusing on the
ered to be have a broad control of a transcriptional signature. As cancer cell in isolation. It is now apparent that we must also con-
such, the alteration in the activity of a single super enhancer may sider the contribution of the TME to the survival of cancer cells.
yield a change in many transcriptional components of the cancer Within normal tissues paracrine and endocrine signals contribute
phenotype. 72 greatly to growth and proliferation. Cell-to-cell growth signaling is