A plethora of genetic mutations have been described in the cancer cells of PDAC patients. The most frequent alterations (approximate frequency indicated in parenthesis) include mutations in the K-
ras oncogene (90%), the p53 (85%) and Smad4 (50%) tumor suppressor genes, and the p16 (85% mutated and 15% silenced epigenetically) cell cycle inhibitory gene [
6,
7]. Together, these alterations promote cellular proliferation, suppress apoptotic pathways, and facilitate tumor spread and metastasis. In addition, there is overexpression of multiple tyrosine kinase receptors and their ligands which enhances mitogenesis, and loss of responsiveness to the growth-inhibitory signals of members of the transforming growth factor beta (TGF-β) family [
6,
7], which contribute in a significant manner to the biological aggressiveness of PDAC.
It is well established that human pancreatic cancer cell lines overexpress the epidermal growth factor (EGF) receptor (EGFR) and produce multiple ligands that bind directly to EGFR, including transforming growth factor-alpha (TGF-α, amphiregulin, heparin-binding EGF-like growth factor (HB-EGF), betacellulin and epiregulin [
8‐
12]. These cell lines also express other growth factors such as fibroblast growth factors (FGFs) and platelet-derived growth factor (PDGF) B chain [
13‐
16]. However, expression of receptors and ligands in cell lines does not necessarily indicate parallel alterations in PDAC
in vivo. Therefore, studies using human tissues have been of vital importance in this regard. Studies using immunohistochemistry, Northern blot analysis and
in situ hybridization techniques, have demonstrated that PDAC tissue samples overexpress EGFR and six ligands that bind directly to EGFR (EGF, TGF-α, HB-EGF, betacellulin, epiregulin and amphiregulin), as well as c-erb-B2, c-erb-B3, and c-erb-B4 [
10,
11,
17‐
19]. These cancers also overexpress basic fibroblast growth factor (FGF-2), acidic FGF (FGF-1), keratinocyte growth factor (KGF), FGF-5, PDGF B chain (but not A chain), insulin-like growth factor-I (IGF-I), the EGF-like growth factor Cripto, hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), all 3 mammalian transforming growth factor beta (TGF-β) isoforms, bone morphogenetic protein-2 (BMP-2) and activin βA [
14,
15,
20‐
29]. Many, but not all of the corresponding receptors are concomitantly overexpressed. For example, there is overexpression of PDGF receptor α and β, the IGF-1 receptor, MET (the receptor that binds HGF), the 2 Ig-like form of type I FGF receptor (FGFR-1), and the type II TGF-β receptor (TβRII) but not the insulin receptor [
16,
21,
23,
26,
30‐
33]. IGF-II and insulin are not overexpressed in PDAC [
21], whereas the type I TGF-β receptor (TβRI) is under-expressed [
31‐
33]. Thus, there is selective overexpression of specific receptors and their ligands in PDAC, and this concomitant overexpression leads to the creation of aberrant paracrine and autocrine pathways that confers a distinct growth advantage to pancreatic cancer cells.
The clinical importance of the above observations is underscored by numerous observations. For example, the concomitant presence in the cancer cells of EGFR and either EGF or TGF-α is associated with disease progression and decreased survival of PDAC patients [
34]. Overexpression of c-erbB3 [
19], FGF-2 [
20] or TGF-β [
35] is associated with decreased patient survival. The aberrant cytoplasmic localization of amphiregulin [
36] is also associated with decreased patient survival. Dominant negative inhibition of either EGFR or FGFR-1 markedly attenuates pancreatic cancer cell growth [
37‐
39]. Expression of a cyclin D1 antisense construct in pancreatic cancer cells lowers cyclin D1 levels in these cells, attenuates their growth
in vitro, and blocks their tumorigenicity in vivo [
40]. EGFR blockade with an anti-EGFR antibody attenuates pancreatic tumor growth, and inhibition of EGFR tyrosine kinase activity suppresses pancreatic tumor angiogenesis [
41,
42]. Together, these findings are among many that support the hypothesis that tyrosine kinase receptors and ligands have an important role in PDAC.