Page 279 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

258 PART III Therapeutic Modalities for the Cancer Patient

VetBooks.ir CRD AB IgD LRD EGFD CadhD

EPHA AXL TIE RET ALK
EGFR MET IGF-1R TRKA EPHB TYRO3 TEK
ERBB2 FGFR PDGFR VEGFR RON TRKB MER
ERBB3 KIT TRKC
ERBB4 FLT3
• Fig. 15.5 Structure of receptor tyrosine kinases. The structures of receptor tyrosine kinase families impli-
cated in a variety of malignancies are shown. AB, Acid box; ALK, anaplastic lymphoma kinase; CadhD,
cadherin-like domain; CRD, cysteine-rich domain; EGFD, epidermal growth factor-like domain; EGFR,
epidermal growth factor receptor; Eph, member of ephrin receptor family; FGFR, fibroblast growth factor
receptor; IgD, immunoglobulin-like domain; LRD, leucine-rich domain; IGF-1R, insulin like growth factor
receptor 1; PDGFR, platelet-derived growth factor receptor; TIE, tyrosine kinase receptor on endothelial
cells; TRK, member of nerve growth factor receptor family; VEGFR, vascular endothelial growth factor
receptor. The symbols α and β indicate specific RTK subunits. (Reprinted with permission from Blackwell
Publishing, London CA, Vet Comp Oncol 2:177–193, 2004.)

(GFs) or other stimuli that initiate the cascade. Protein kinases are -beta are expressed in stroma and pericytes that are critical for the
classified as tyrosine kinases (TKs) if they phosphorylate proteins maintenance of newly formed blood vessels. 81,82 FGFR-1 and -2
on tyrosine residues or serine/threonine kinases if they phosphory- are expressed on vascular endothelium and work with VEGFR
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late proteins on serine and threonine residues. In some cases, the to promote increased expression of VEGF. Tie-1 and Tie-2 are
kinases perform both functions (i.e., dual-function kinases). Pro- expressed on blood vessels in tumors and are important in the
tein kinases can be expressed on the cell surface, in the cytoplasm, recruitment of pericytes and smooth muscle cells to the newly
and in the nucleus. The human genome encodes more than 500 forming vascular channels. 83
kinases, of which 90 are classified as TKs. 70 Kinases in the cytoplasm act as bridges, conducting signals
TKs on the cell surface that are activated through binding of generated by RTKs to the nucleus through a series of interme-
GFs are called receptor TKs (RTKs). Of the 90 identified TKs, diates that become phosphorylated. The cytoplasmic kinases
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approximately 60 are known to be RTKs. Each RTK contains an may be directly on the inside of the cell membrane or free in the
extracellular domain that binds the GF, a transmembrane domain, cytoplasm. With respect to tumor cell biology, two particular
and a cytoplasmic kinase domain that positively and negatively cytoplasmic pathways are often dysregulated in cancer. The first
regulates phosphorylation of the RTK (Fig. 15.5). 71–73 Most RTKs includes members of the RAS-RAF-MEK-ERK/p38/JNK fami-
are monomers on the cell surface and are dimerized through the lies (Fig. 15.6). 85,86 Most of these are serine/threonine kinases and
act of GF binding; this changes the three-dimensional structure of their activation leads to ERK phosphorylation, translocation into
the receptor, permitting ATP to bind and autophosphorylation to the nucleus, and subsequent alteration of transcription factor and
occur, generating a downstream signal through subsequent bind- nuclear kinase activity important for controlling the cell cycle.
ing of adaptor proteins and nonreceptor kinases. Dysregulation Some examples of dysregulation in human cancers include RAS
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of RTKs resulting in pathway activation/uncontrolled signaling mutations in lung cancer, colon cancer, and several hematologic
is known to contribute to several human cancers, and work is malignancies and BRAF mutations in cutaneous melanomas and
ongoing to characterize such abnormalities in canine and feline papillary thyroid carcinomas. 87–89 Interestingly, BRAF mutations
cancers. Examples of RTKs known to play prominent roles in spe- synonymous to those in human malignant melanomas are also
cific cancers include KIT, Met, EGFR, and ALK, all which can found in canine transitional cell carcinomas, with more than 80%
be activated by overexpression, mutation, and/or chromosomal of tumors testing positive. 90
translocation. 74–78 The second cytoplasmic pathway includes phosphatidyl inosi-
Although RTK signaling is critical for regulating typical cell tol-3 kinase (PI3K) and its associated downstream signal transduc-
functions, it is also an important driver of angiogenesis, a process ers AKT, nuclear factor κB (NFκB), and mTOR, among others
considered essential for continued tumor cell growth. The RTKs (Fig. 15.7). 91,92 PI3K is activated by RTKs and in turn activates
involved in angiogenesis include the vascluar endothelial growth AKT, which alters several additional proteins involved in the regu-
factor receptors (VEGFRs), platelet-derived growth factor recep- lation of cell survival, cycling, and growth. AKT phosphorylates
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tors (PDGFRs), fibroblast growth factor receptors (FGFRs), and targets that promote apoptosis (BAD, procaspase-9, and Forkhead
Tie-1 and Tie-2 (receptors for angiopoietin). 79–82 VEGFRs are transcription factors) and activates NFκB, a transcription factor
expressed on vascular endothelium and VEGFR signaling drives that has antiapoptotic activity. 91–93 AKT also phosphorylates
endothelial migration and proliferation. PDGFR-alpha and other proteins such as mTOR, p21, p27, and GSK3. This leads
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