Page 1269 - Clinical Small Animal Internal Medicine

130 Biology of Cancer and Cancer Genetics 1207

An alternative mechanism of resisting cell death by due to multiple mutations in oncogenes and tumor sup-
VetBooks.ir cancer cells is through manipulating antiapoptotic path- pressor genes, varying environmental conditions, and
inherited germline variations. The combination of these
ways. These antiapoptotic pathways are intended to
maintain the natural homeostasis of cellular prolifera-
tion and deletion within tissues. Widely studied inhibi- factors leads to immense natural heterogeneity in tumor
phenotypes, disease outcomes, and response to thera-
tors of apoptosis include members of the Bcl‐2 family pies. The development of new molecular biological tools
and survivin. The distribution of Bcl‐2 protein in normal has expanded the understanding of genetics and the
and neoplastic feline tissues has been studied, as well as pathophysiology of tumorigenesis.
the expression of survivin in canine urinary bladder Gene expression profiling with the use of microarray
transitional cell carcinoma. technology has greatly improved our ability to classify
In general, mitotic catastrophe is the primary method tumors by generating unique molecular fingerprints that
of cellular killing by radiation exposure and a significant have delineated tumor subtypes. DNA microarray tech-
component of cell death by certain chemotherapy nology allows the study of gene activity and gene func-
agents. A major mode of action of chemotherapy‐ tion at the genome level as a means to analyze the
induced death is the activation of apoptosis. To provide molecular phenotypes and clinical heterogeneity of
a clinical example, a class of drugs incorporated in tumors. The emergence of genome sequences for a vari-
cancer therapy protocols which induces apoptosis in a ety of veterinary species has allowed for the develop-
specific cellular population are the bisphosphonates. ment of new microarray‐based technologies that
Bisphosphonate drugs used in veterinary oncology facilitate whole genome, or gene‐targeted, profiling to be
include pamidronate and zoledronate, and these are pre- performed at a considerably higher resolution and
scribed for patients that have developed malignancies throughput.
which involve the destruction of bone. Bone undergoes The use of microarray‐based technology in the veteri-
constant turnover. Homeostasis of the tissue is main- nary field has become more prevalent. Recently, the
tained by the activity of osteoblasts, which create bone, utility of gene expression analysis using a cDNA micro-
and osteoclasts, which destroy bone. Bisphosphonates array to differentiate metastatic and nonmetastatic soft
inhibit the destruction of bone by reducing osteoclast tissue sarcomas in dogs was investigated. Further,
activities and stimulating these cells to undergo apopto- microarray technology was used to characterize the
sis. The therapeutic effect of osteoclast inhibition is to gene expression profile of tumors in a population of
slow the malignant destruction of the affected bone, dogs with soft tissue sarcomas being treated with radia-
which results in alleviation of pain and improvement of tion therapy and hyperthermia to predict therapeutic
quality of life. Recent examples of clinical research uti- response. Comparisons were made between the gene
lizing bisphosphonate drugs for the treatment of veteri- changes that occurred, tumor volume, and functional
nary cancer patients include the use of pamidronate in MRI parameters. Significant correlations were identi-
the management of canine appendicular osteosarcoma fied between tumor responses and genes involved in tel-
and zoledronate for treatment of oral squamous cell omerase activity, DNA repair, inflammation, and growth
carcinoma in cats. factor signaling. In this cohort of canine sarcomas, the
gene expression of tumors was affected significantly,
but not uniformly, by the combination of radiation and
Genome Instability and Mutation hyperthermia.

In an established neoplasm, mutations have evolved to
circumvent effective cell cycle checkpoints and DNA Tumor Promoting Inflammation
repair mechanisms. This allows the tumor to reproduce
in a state of genetic instability, further driving an aggres- While it is important to understand the cellular charac-
sive phenotype. In veterinary oncology, such genetic teristics of a tumor, we must consider that the cells exist
instability has recently been studied in canine mammary in a complex microenvironment. Tumor cells are inti-
tumors, where variable rates of microsatellite sequence mately associated with supporting stromal cells, immune
aberrations were documented among the mammary cells, and microvasculature. Solid tumors exist in a state
cancer samples. of active inflammation, and conventional cancer therapy
A given population of tumor cells is heterogenous by can both promote and reduce inflammation. Tumor
nature, with variable distributions of genetic mutations tissue reacts as a unit to therapeutic interventions;
and phenotypic manifestations of these abnormalities. however, responses to treatments are not limited to the
Genetic and pathologic evaluations of tumors with the neoplasm. There are unique localized and systemic
same clinical diagnosis exhibit intertumoral heterogeneity responses to chemotherapy, radiation therapy, and other