Page 1271 - Clinical Small Animal Internal Medicine

130 Biology of Cancer and Cancer Genetics 1209

prognostic marker for a number of tumors, such as possible therapeutic targets in canine mammary cancer,
VetBooks.ir canine intracranial meningiomas, osteosarcoma, lym- glial brain tumors, nasal carcinomas, and feline oral
squamous cell carcinoma.
phoma, oral malignant melanoma, and feline invasive
Epidermal growth factor receptor belongs to a group
mammary carcinoma.
Abnormal tumor vessel morphology includes aberrant of proteins that form the receptor tyrosine kinase (RTK)
architecture and function of blood vessels which often superfamily. Tyrosine kinases are transmembrane recep-
leads to low oxygenation within the tumor, known as tors that regulate normal cell signal transduction and
intratumoral hypoxia. Tumor hypoxia may stimulate maintain cell growth and differentiation. Additional
angiogenesis through expression of the transcription examples of receptor tyrosine kinases include Kit, Met,
factor hypoxia inducible factor‐1 (HIF‐1). HIF‐1 induces VEGFR, PDGFR, and FGFR. RTKs are commonly
several proangiogenic factors such as VEGF. Hypoxic abnormally activated and dysregulated in human and
regions within tumors are a significant issue in radiation veterinary cancer. For instance, Kit is a receptor found
therapy because hypoxic cells are more resistant than on mast cells, and mutations to Kit in canine mast cell
oxygenated cells to treatment. Hypoxic cells are also tumors (MCTs) have been shown to drive unregulated
more resistant to chemotherapy as hypoxic cells are far- proliferative signaling. Up to 30% of all canine MCTs are
ther from the vasculature and may not be exposed to affected with Kit mutations, and these have been shown
lethal drug concentrations. Importantly, hypoxia may to be significantly associated with tumor grade, as the
increase the biologic aggressiveness of a tumor by HIF‐1 more malignant tumors are more likely to have abnormal
activation of several neoplastic pathways. Kit receptors. Further, canine gastrointestinal stromal
Targeted therapeutic approaches have been developed tumors (GIST) have also been characterized as carrying
recently which are intended to disrupt tumor angiogen- Kit mutations.
esis. The use of continuous, low‐dose chemotherapy is Recently, a variety of small molecule inhibitors that
commonly referred to as “metronomic chemotherapy.” target tyrosine kinases, known as tyrosine kinase inhib-
Three aspects of angiogenesis that are affected by metro- itors (TKIs), have been approved for the treatment of
nomic chemotherapy are direct cytotoxic effects on the human cancer. The use of these inhibitors has resulted
endothelial cells of the tumor blood vessels indirect in significant clinical efficacy, being used as sole
effect of tipping the influence from proangiogeneic therapeutics or in combination therapy protocols.
growth factors to inhibitors, thus preventing further Importantly, TKIs have now been incorporated into
vessel expansion, and reducing the recruitment of bone veterinary oncology care. Examples of these drugs
marrow‐derived endothelial progenitor cells. The effi- include Palladia™ (toceranib), and Gleevec® (imatinib).
cacy of metronomic chemotherapy protocols has been Gleevec has been used to treat cancers in dogs and cats,
studied in veterinary oncology through clinical trials and Palladia has undergone registrational studies in
with canine patients treated for splenic hemangiosar- dogs with MCTs. The molecular targets inhibited by
coma and soft tissue sarcoma with the drug combination these drugs consist of Kit, VEGF, and PDGFR and
of cyclophosphamide and piroxicam. they have been used to treat MCTs and sarcomas in
dogs and cats, as well as carcinomas, melanoma, and
myeloma in dogs.
Sustaining Proliferative Signaling

In normal tissues, growth factors regulate cellular prolif- Deregulating Cellular Energetics
eration and differentiation. Cancer cells, however,
develop a reduced requirement for exogenous growth It has been discussed with the preceding hallmarks that
factors as they become capable of autonomous activation tumors adapt and proliferate despite harsh conditions of
of autocrine and paracrine growth pathways. As the inflammatory stress and disorganized, ineffective micro-
goals for cancer therapy include tumor regression and circulation. The tumor microenvironment is not only
eradication, this aberrant proliferation must be inhibited characterized by varying degrees of hypoxia, but also
to prevent resistance and recurrence. nutrient deprivation and low extracellular pH. The unu-
Some of the key proteins regulating cell survival and sual metabolism of cancer cells is intimately involved in
proliferation are the transmembrane epidermal growth creating such an abnormal physiologic state.
factor receptor (EGFR) and ligand epidermal growth fac- Normal tissues are able to sustain routine cellular
tor (EGF). EGFR is overexpressed in many tumor types functions through the oxidation of nutrients to provide
and is associated with aggressiveness and resistance to energy in the form of adenosine triphosphate (ATP).
therapies. EGFR and EGF have been studied in veteri- Glucose metabolism is regulated in response to changes
nary medicine as potential prognostic indicators and in cellular oxygen levels. Initially, glucose is converted to