Page 61 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

40 PART I The Biology and Pathogenesis of Cancer

Gene Amplification Point Mutation

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Mechanisms of Oncogene Activation

Ph
Myc
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Viral Insertion Chromosomal Translocation
• Fig. 2.4 Methods of oncogene activation. Oncogenes can be activated by chromosomal rearrange-
ments (e.g., BCR/ABL–induced leukemia), gene amplification (e.g., amplification of mouse double minute
2 oncogene [MDM2] in some sarcomas), point mutations (e.g., changes in nucleotide sequence that alter
protein production), or by viral insertions (e.g., the insertion of feline leukemia virus [FeLV] at the myc locus
in FeLV-induced lymphomas).
• The process of DNA replication is also subject to the intro- • Cancer: This often refers to a malignant tumor, characterized
duction of errors, and this is closely monitored by a class of by unchecked cellular division and the capacity for both local
enzymes called DNA repair enzymes. Consequently, a number invasion and distant metastasis.
of safeguards within the cell cycle ensure that normal cells are
produced during division and that the DNA is replicated accu- Multistep Carcinogenesis
rately. The next section describes how these systems are over-
come to produce a malignant cancer cell. Cancer has been defined as the phenotypic end result of a whole
series of changes that may have taken a long period of time to
From Normal Cell to Cancer Cell develop. Indeed, recent studies that have sequenced the genome
of pancreatic and brain tumors have identified 63 and 60 genetic
It is difficult to define a cancer cell in absolute terms. Tumors are alterations on average in each cancer, respectively. From this large
usually phenotypically recognized by the fact that their cells show list of genetic alterations, a small number of commonly mutated
abnormal growth patterns and are no longer under the control genes are “drivers” of the cancer phenotype. 27,28
of normal homeostatic growth-controlling mechanisms, includ- The application of a cancer-producing agent (carcinogen) to tis-
ing apoptosis. Although the range of mechanisms involved in the sues does not lead to the immediate production of a cancer cell. After
development of tumors and the spectrum of tissues from which an initiation step produced by the agent, a period of tumor promo-
tumors are derived are diverse, they can be classified into three tion follows. This promotion may be caused by the same initiating
broad types: agent or by other substances, such as normal growth promoters or
• Benign tumors: Broadly speaking, these tumors arise in any of hormones. The initiating step is a rapid event and affects the genetic
the tissues of the body and grow locally. Their clinical signifi- material of the cell. If the cell does not repair this damage, then
cance is the ability to cause local pressure, cause obstruction, or promoting factors may progress the cell toward a malignant pheno-
form a space-occupying lesion, such as a benign brain tumor. type. In contrast to initiation, progression (the stochastic accumula-
Benign tumors do not metastasize. tion of mutations that impose a survival advantage on the daughter
• In situ tumors: These are often small tumors that arise in the epi- cells) may be a very slow process and may not even manifest in the
thelium. Histologically, the lesion appears to contain cancer cells, lifetime of the animal. Each stage of multistep carcinogenesis collec-
but the tumor remains within the epithelial layer and does not tively results in an accumulation of genetic changes in the cell that
invade the basement membrane or the supporting mesenchyme. ultimately provide a selection advantage that drives the progression
A typical example of this is preinvasive squamous cell carcinoma toward a highly malignant cell. The age-dependent incidence of
(SCC) affecting the skin of cats, which is often referred to as cancer suggests that between four and seven rate-limiting, stochastic
Bowen’s disease. events are required to produce the malignant phenotype. 29