So far, four PDGF polypeptide chains have been identified and designated A, B, C, and D. Formed from these chains are five dimeric PDGF isoforms (PDGF-AA, -AB, -BB, -CC, and -DD), which exert their cellular effects through two tyrosine kinase receptors (i.e., PDGF-a and PDGF-P). Interaction of PDGF ligands with PDGF receptors leads to receptor dimerization, autophosphorylation, and further receptor activation. The activated PDGF receptors then recruit SH2 domain-containing signaling molecules (e.g., c-Src, phospholipase PLC-y, PI3K, and Grb2/Sos complex) to activate a number of signaling pathways, including c-Src-c-myc, PLC-y-PKC-Raf1-MEK-ERK, PI3K-PDK1-AKT, and Grb2-Sos1-Ras-Raf1-MEK-ERK. Activation of these pathways ultimately induces various cellular processes including division, cell proliferation, and migration (15,16).
In certain malignancies, PDGF receptor signaling is constitutively activated by the genetic alteration of either PDGF or PDGF receptors. In dermatofibrosarcoma protuber-ans (DFSP), for example, chromosomal translocation creates a fusion gene composed of collagen 1A1 and the PDGF B chain whose expression results in persistent activation the of PDGF-BB gene (17). In patients with high-grade gliomas or gastrointestinal stro-mal tumors (GIST), amplification, activating point mutations, and small deletions in the PDGF-a receptor have been reported (18,19). Constitutive activation of the PDGF-P receptor has also been described in chronic myelomonocytic leukemia (CMML) (20).
The EGFR family contains a series of structurally and functionally related receptors: EGF receptor (EGFR, or ErbR-1/HER1), ErB-2/ne|x/HER2, ErbB-3/HER3, and ErbB-4/HER4. All EGF receptors are transmembrane glycoproteins and have tyrosine kinase activity in their intracellular regions. However, the extracellular regions of the different receptors selectively bind to specific EGF-like growth factors. As for the PDGF receptors, the binding of EGF receptors to their ligands leads to dimerization and autophos-phorylation of tyrosine residues on the receptors, and finally activation. The activated receptors then activate two important intracellular kinase pathways (Ras-Raf-MEK-ERK and PI3K-PDK1-AKT), which in turn activate related transcription factors in the nucleus, resulting in cell proliferation, differentiation, migration, and adhesion (21,22).
EGF receptors are commonly overexpressed in a number of epithelial malignancies and are often associated with an aggressive phenotype. They are overexpressed in over 50% of non-small-cell lung cancers (NSCLC), head and neck squamous cell carcinoma (HNSCC), and colon cancers, along with overexpression of one or more other EGFR family members (21,23,24).
The ras oncogene family consists of three members: K-ras, H-ras, and N-ras. An estimated 10 to 50% of acute leukemias, 50% of colon carcinomas, and 90% of pancreatic carcinomas have activating mutations in different ras oncogenes. Evidence suggests that ras gene products have GTPase activity. When bound to GTP, ras proteins are in their active state. However, when GTP converts to GDP, ras proteins return to an inactive GDP-binding state. A single amino acid substitution at ras codon 12, 13, or 61 affects the GTPase activity, resulting in the accumulation of the ras-GTP binding isoform and the constitutive activation of downstream pathways, such as Ras-Raf-MEK-ERK, PI3K-PDK1-AKT, Tiam1-Rac, and Ral GEF-Ral. Activation of these pathways leads to transformation, invasion, and metastasis (26,27).
Karyotypic abnormalities, including the translocation, duplication deletion, and loss of chromosomes, have long been recognized. Most chromosomal abnormalities do not correlate with cancer types, suggesting that these abnormalities are likely secondary events and reflecting the inherent genetic instability of cancer cells. In contrast, some types of malignancies consistently undergo certain chromosomal changes. For example, a reciprocal translocation between chromosomes 9 and 22 occurs in the leukemia cells of more than 90% of patients with chronic myelogenous leukemia (CML) (28). As a result of this translocation, the abl proto-oncogene, on the long arm of chromosome 9 is translocated to chromosome 22. The translocation breakpoints on chromosome 9 occur either upstream or downstream of abl exon 1A. The translation breakpoints on chromosome 22 occur near the middle of a region encoding the functional bcr gene. The translocation thus produces a fusion gene comprising the half of the bcr gene and all of the abl gene except for its small 5'-end. Like the viral abl oncogene, this bcr/abl fusion protein has an enhanced tyrosine kinase activity that may cause CML (29). Two strong lines of evidence support this hypothesis. First, the bcr/abl fusion protein is capable of inducing the neoplastic transformation of hematopoietic cells in culture. Second, specific tyrosine kinase inhibitors of the bcr/abl fusion protein can induce and sustain clinical remission in CML patients (30). The key pathways of bcr/abl may involve c-myc, PI3K-PDK1-AKT, and Ras-Rafl-MEK-ERK (16).
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