Page 70 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 2 Tumor Biology and Metastasis 49

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• Fig. 2.8 In normal tissues, cellular respiration in the presence of oxygen allows the production of a net
gain in energy through metabolism of glucose to pyruvate. The Warburg effect in cancer cells refers to
a metabolic switch that causes cancer cells to preferentially metabolize glucose to lactate irrespective of
oxygen status, leading to a net loss of energy in the form of adenosine triphosphate (ATP).
Genome Instability • The production of reactive oxygen species that are mutagenic
Most acquired hallmarks of cancer require changes in the genome Many of the cells that contribute to this are components of the
through mutation, amplification, or chromosomal translocation. innate immune system, particularly macrophages with a specific,
However, the process of random mutation is inefficient because of cancer-promoting phenotype. Specifically, they form part of the
the complex and fastidious maintenance mechanisms of the nor- TME that supports the maintenance of the cancer phenotype.
mal cell that monitor DNA damage and regulate repair enzymes.
As such, it is actually difficult to explain why cancers arise in ani- The Pathways to Cancer
mals at all, because the acquisition of all traits would seem an
impossible task. To explain this, it may be argued that genomes The eight acquired capabilities of cancer cells and the two over-
must attain increased mutability or genome instability to over- arching enabling characteristics of genome instability and tumor
come the redundant homeostatic mechanisms that ordinarily pre- inflammation have been outlined. It is important to stress that the
vent the emergence of a cancer cell. 1,2 pathways by which cells become malignant are highly variable.
A number of mechanisms have been suggested that may sup- Mutations in certain oncogenes can occur early in the progression
port the development of genomic instability. 70 of some tumors and late in others. As a consequence, acquisition
• Defects that affect various components of the DNA-main- of the essential cancer characteristics may appear at different times
tenance machinery (caretakers of the genome), which may in the progression of different cancers. Furthermore, in certain
involve mutations in caretaker genes tumors a specific genetic event may, on its own, contribute only
• The loss of telomeric DNA, which may cause karyotypic partially to the acquisition of a single capability, whereas in oth-
instability and chromosomal changes (amplification/dele- ers it may contribute to the simultaneous acquisition of multiple
tion) capabilities. Regardless of the path taken, the hallmark capa-
• Inactivation of TS genes through genetic (mutation) or epi- bilities of cancer remain common for multiple cancer types and
genetic (DNA methylation/histone modifications) mecha- help clarify mechanisms, prognosis, and the development of new
nisms treatments.
The highly complex signaling circuitry in cells is highly inte-
Tumor-Promoting Inflammation grated and aligned with function. In the formation of a cancer cell,
It has been recognized for decades that tumors contain inflam- these circuits are “reprogrammed” to regulate the acquired capa-
matory and immune cell infiltrates, which classically have been bilities of the cancer cell, or hallmarks of malignancy. The change
considered an attempt by the immune system to eradicate the is not simplistic, and considerable cross-talk occurs between cir-
tumor. However, recent evidence suggests that tumor-associated cuits to support these hallmarks. This is in addition to a connec-
inflammation paradoxically may have a tumor-promoting effect. tion and signaling between the cancer cell and the TME
Inflammation can contribute to neoplastic progression through
one of several mechanisms. 70, 80, 102,103
• The supply of growth factors and growth signals to the TME The Role of Tumor Microenvironment and
that promote angiogenesis, cell proliferation, and invasion Cancer Stem Cells
• Induction signals that support the process of EMT
• Fostering of the progression of premalignant lesions to overt Over the past 10 years tumors have been increasingly considered
malignancy as organ systems similar to the tissues from which they derive. This