Page 65 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

44 PART I The Biology and Pathogenesis of Cancer

Genome Instability

VetBooks.ir

Self-Sufficient in Growth Insensitive to Antigrowth Signals

Limitless Replicative Potential Sustained Angiogenesis

CANCER

Evasion of Programmed Cell Death Evading Immune Destruction

Reprogramming Energy Metabolism Tissue Invasion and Metastasis

Tumor-Promoting Inflammation
• Fig. 2.6 The hallmarks of cancer. Cancer can be considered the end product of acquisition of eight
fundamental characteristics. Underpinning these capabilities are the common denominator enabling char-
acteristics of genome instability and tumor-promoting inflammation.

for tumor suppression and prevent accumulation of poten- • In this process of natural selection, the acquired characteris-
tially oncogenic mutations and genomic instability. Failure of tics that are advantageous to the cancer phenotype are often
p53 to activate such cellular functions may ultimately result referred to as the hallmarks of cancer.
in abnormal uncontrolled cell growth, leading to tumorigenic • Studies on viral carcinogenesis and/or monogenic cancer syn-
transformation. 58–62 dromes have facilitated the dissection of cancer biology and the
p53 is the most frequently inactivated gene in human neo- identification of cancer-causing genes (oncogenes and tumor
plasia, with functional loss commonly occurring through gene suppressor genes). However, most cancers encountered in clini-
mutational events, including nonsense, missense and splice site cal practice are sporadic (occurring as a result of changes in
mutations, allelic loss, rearrangements, and deletions. However, adult somatic cells) and not inherited.
p53 function can also be abrogated by several nonmutational • Proto-oncogenes are normal genes involved in growth and pro-
mechanisms, including nuclear exclusion, complex formation liferation and can be “activated” to promote malignancy.
with a number of viral proteins, and through overexpression of • Tumor supressor genes are normal genes expressing proteins
the cellular oncogene MDM2. 63 that inhibit growth and proliferation.
The homologs of p53 and MDM2 have both been identified • If proto-oncogenes are the “accelerator pedal” in a cell, then
in domestic animal species, and a number of studies indicate that tumor supressor genes are the “brakes.”
this gene also has a central role in the progression of veterinary • Gain of function in oncogenes and/or loss of function in tumor
cancers. 64–68 suppressor genes promotes the malignant phenotype.

Key Points Cancer Arises through Multiple Molecular
Fig. 2.6; also see Table 2.1. Mechanisms
• Cancer is a genetic disease characterized by aberrant molecular The advances in understanding of normal cell biology and the
changes in the genetic material of the cell. processes that lead to malignancy have increased dramatically over
• Cancer arises through mutations in DNA and/or changes in the past 30 years. The last decade has shown that transformation
gene expression (epigenetic events). of a normal cell into a malignant cell requires very few molecu-
• Cancer is a clonal disease resulting from the accumulation of lar, biochemical, and cellular changes that can be considered as
mutations in oncogenes or tumor suppressor genes. Each suc- acquired capabilities. 42,43 Furthermore, despite the wide diversity
cessive change leads to a survival advantage for the cell, akin to of cancer types, these acquired capabilities appear to be common
darwinian natural selection. to all types of cancer. An optimistic view of increasing simplicity