Angiogenesis in tumors leads to a chaotic, poorly organized vasculature with tortuous, irregularly shaped, and leaky vessels that are often unable to support efficient blood flow. Because of the imbalanced expression pattern of angiogenic factors, tumor vessels appear to be in a constant state of remodeling, which involves simultaneous formation and regression of vascular tubes (Bergers and Benjamin, 2003; Folkman, 2000
). Just as tumor endothelial cells differ from the normal, quiescent endothelium, tumor pericytes also differ from normal pericytes. illustrates tumor pericytes, visualized with different markers, in three tumor types derived from transgenic or orthotopic mouse tumor models: glioblastomas, pancreatic islet carcinomas, and mammary carcinomas. In general, pericytes in tumors appear to be more loosely attached to the vasculature, and their cytoplasmic processes can extend into the tumor tissue (). They seem to be less abundant in some tumor tissues in comparison to the respective normal tissue () and can change their pericyte expression profile () (Benjamin et al., 1998; Morikawa et al., 2002
). For example, pericytes in pancreatic islet tumors and glioblastomas appear to contain a higher number of α-SMA-positive pericytes than the respective normal tissue (Morikawa et al., 2002
) ( and ). In addition, tumor vessels differ among tumor types: The vasculature of mammary carcinomas is enormously enlarged and thickened, glioblastoma vessels appear thin walled and hyperdilated, and vascular tubes in islet carcinomas are more irregular but only slightly hyperdilated (). Pericyte coverage of blood vessels is also dependent on the tumor type. While islet carcinomas have reasonably dense pericyte coverage, glioblastomas and mammary carcinomas exhibit a more dramatic reduction in pericyte density when compared to the respective normal tissues ().
Fig. 3 Pericytes in tumors. Tumor sections from three mouse models of tumorigenesis were used to visualize pericytes in glioblastomas (a–d), pancreatic islet carcinomas (e–h), and mammary carcinomas. SV40 Tag/H-ras transformed astrocytes intracranially (more ...)
For all of these reasons, pericytes are thought to be rather abnormal or dysfunctional in tumors and therefore, until recently, have been neglected as important contributors to tumor angiogenesis. The exact causes of abnormal pericyte behavior are still unknown, but may include imbalanced endothelial-cell/pericyte signaling circuits and/or a limited pool of recruitable pericytes (Abramsson et al., 2002
). It is also notable that hematopoietic cells from bone marrow that expressed the pericyte marker NG2 were recently identified in close contact with blood vessels in xenograft Bl6-F1 melanoma tumor models (Rajantie et al., 2004
) and in the transgenic model of pancreatic islet carcinomas (Song et al., 2005
). This suggests that recruitment of bone-marrow-derived cells to sites of a growing vasculature is not limited to endothelial cells, but can also include pericytes.
It is surprising that normal vessels can apparently tolerate a substantial reduction in the density of pericytes, at least in mice; although a reduction in pericyte density produces functionally and structurally abnormal vessels, only pericyte reductions of >90% are lethal (Abramsson et al., 2003
). This observation suggests that even small numbers of pericytes, as observed in tumors, can still be functional and important for vessel stability and endothelial-cell survival. Recent experiments targeting pericytes in tumors support this view. Glioblastomas contain a substantial fraction of blood vessels that are not covered by pericytes (see also ). It has been demonstrated that these vessels are more dependent on VEGF as an endothelial survival factor, because they are selectively eliminated when VEGF is withdrawn from the tumors (Benjamin et al., 1999
). In contrast, glioblastomas or fibrosarcomas that overexpress PDGF-B exhibited an increased pericyte density around blood vessels (Guo et al., 2003
). Blocking PDGFR signaling in a transgenic mouse model of pancreatic islet carcinogenesis (Rip1Tag2) with the receptor tyrosine kinase inhibitor SU6668 caused regression of blood vessels, which was due to the detachment of pericytes from tumor vessels, and thereby restricted tumor growth and stabilized the cancer (Bergers et al., 2003
). Similarly, SU6668 detached and diminished pericytes in xenotransplant tumors and thereby restricted tumor growth (Reinmuth et al., 2001; Shaheen et al., 2001
). The functional significance of PDGFRβ signaling in tumor pericytes was confirmed by studies in PDGF-B retention mice. PDGF-Bret/ret
mice lack the C-terminal retention motif in PDGF-B that mediates PDGF-B binding to proteoglycans at the cell surface and in the ECM. These mice are viable but have fewer pericytes, as they lack proper recruitment and integration of pericytes within the vessel wall, particularly in the retina and kidney (Lindblom et al., 2003
). Implanted tumors in PDGF-Bret/ret
mice are hemorrhagic and contain few pericytes around the tumor blood vessels that become hyperdilated. It is notable that ectopic expression of PDGF-B in those tumor cells was able to increase pericyte density but failed to cause pericytes to attach more firmly to blood vessels, which indicates that localized PDGF-B from the endothelium is essential for proper pericyte adhesion to the vessel wall (Abramsson et al., 2003
). These data suggest that tumors use the same signal mechanisms that are used in developmental angiogenesis. These results also imply that tumor pericytes, albeit less abundant and more loosely attached than normal pericytes, still regulate vessel integrity, maintenance, and function. The fact that tumor vessels without pericytes appear more vulnerable suggests that they may be more responsive to antiendothelial drugs. Indeed, combinations of receptor tyrosine kinase inhibitors that target endothelial cells and pericytes by blocking VEGF and PDGF signaling, respectively, more efficiently diminished tumor blood vessels and tumors than any of the inhibitors individually (Bergers et al., 2003
). The same effect was achieved when PDGF inhibitors were combined with an antiangiogenic chemotherapy regimen that targeted endothelial cells (Pietras and Hanahan, 2005
). Targeting PDGFR signaling disrupted pericyte support, while the antiangiogenic chemotherapy targeted the sensitized endothelial cells, collectively destabilizing the preexisting tumor vasculature. When considered together, these data provide evidence that pericytes are potentially important and functional vascular-cell components in tumors that elicit survival mechanisms to establish and maintain tumor vessels.