The tumor microenvironment is extremely complex and depends on the interaction between the tumor cells and responding host cells. Angiogenesis, new blood vessel growth from the preexisting vasculature, is a preeminent feature of the successful growth of all solid tumors. As one of the hallmarks of cancer of the exocrine pancreas, angiogenesis is an essential event that is involved in pancreatic cancer progression and metastasis.
The proliferative index of tumors decreases as the distance from the nearest capillary blood vessel increases, and the rapid exponential growth of tumors is dependent on the vascularization of the tumor mass. Without angiogenesis, pancreatic tumors are limited in size by the distance that oxygen can diffuse, namely, 1–2 mm. Hypoxia results when the rate of new blood vessel growth is exceeded by the growth of the tumor. Hypoxia in pancreatic cancer results in changes at a transcriptional level, which alter cellular metabolism and stimulates angiogenesis [27
Angiogenesis is not necessarily linked to invasive pancreatic cancer, but it is an early event in pancreatic cancer genesis; the process of angiogenesis consists of multiple, sequential, and interdependent steps with the involvement of myriad positive and negative regulators of angiogenesis. The survival of pancreatic cancers and their metastases are dependent on the balance of endogenous angiogenic and anti-angiogenic factors such that the outcome favors increased angiogenesis.
Multiple molecules such as VEGF, angiopoietins, FGF, PDGF, and TGF-β regulate angiogenesis. Angiogenesis plays an important role in the growth, progression and metastasis of a tumor. Inhibiting the angiogenic process or targeting existing tumor vessels can be used to treat tumors either as an alternative to or in parallel with conventional chemotherapy. Many anti-angiogenic factors are under investigation, and some are already being used in clinical practice with varying results.
Vascular Endothelial Growth Factor (VEGF)
The VEGF family of growth factors, including the VEGF-A, VEGF-B, VEGF-C, VEGF-D, and VEGF-E factors as well as the placenta growth factor (PIGF), play a critical role in the process of tumor angiogenesis.
VEGF factors regulate endothelial cell proliferation, migration, and vascular permeability by binding to their receptor tyrosine kinases such as VEGFR1, R2, and R3 [28
]. However, accumulating evidence shows that VEGFR2 is the crucial and main receptor mediating the angiogenic and vascular permeability activity whereas VEGFR3 is mainly involved in the lymph angiogenic activity [29
]. In angiogenesis during pancreatic cancer, VEGFR2 activation leads to the activation of diverse intracellular signaling in endothelial cells and regulates multiple critical steps by phosphorylating different downstream substrates, which results in pancreatic cancer metabolism, growth, proliferation, and survival [30
The principle form of VEGF is the homodimeric glycoprotein VEGF-A. VEGF-A consists of five major isoforms, all of which act as anti-apoptotic agents, possess vasodilatory abilities, and promote endothelial cell migration and proliferation via binding with to their tyrosine kinase receptors, VEGFR-1 (flt-1) and VEGFR-2. The biological effect of VEGF-A is exerted through its interaction with the cell surface receptors that include VEGFR-1 and VEGFR-2, which are selectively located on vascular endothelium and are upregulated during angiogenesis. The VEGF-A–VEGFR-2 interaction also plays a critical role in pancreatic cancer angiogenesis through the coordinate signaling of endothelial cell proliferation, migration and the recruitment of endothelial cell progenitor cells.
A number of studies [31
] have shown that the increased expression of VEGF, a potent mitogen for endothelial cells at the primary site, is correlated with a poor prognosis for pancreatic cancer. Conversely, VEGFR1 contains a classical tyrosine kinase domain; however, the primary function of VEGFR1 may be as a negative regulator in vascular development [32
Recently, an anti-VEGF antibody (bevacizumab), when used in combination with chemotherapy, was shown to significantly improve the survival and response rates in patients with metastatic colorectal cancer; this finding validates the importance of VEGF pathway inhibitors as a new treatment in cancer therapy [33
Fibroblast Growth Factor (FGFs)
Fibroblast growth factors (FGFs) comprise a family of 22 members that play important roles during embryogenesis and adulthood, and FGFs regulate many cellular behaviors including proliferation, migration, survival, and differentiation.
The FGF family includes factors such as FGF-1, FGF-2, FGF-5, FGF-7, and FGF receptors are regulated in pancreatic cancer tissue samples and cell lines [34
]. These findings suggest that FGF-dependent downstream biologic events are likely to play an important role in the pathobiology of pancreatic cancer.
FGFs stimulate endothelial cell proliferation and migration and the production of collagenase and plasminogen activator. FGFs induce development of blood vessels in vivo in the chick chorioallantoic membrane and cornea, thus supporting their role in angiogenesis.
FGFs are mitogenic, promote angiogenesis and chemotaxis, and participate in the regulation of cellular differentiation and tissue repair. Acidic and basic fibroblast growth factors (aFGF or FGF1 and bFGF or FGF2, respectively) are described as inducers of angiogenesis [35