Evasion of Anti-Angiogenic Therapy
Anti-angiogenic therapy has been a very promising field of study in the recent history of cancer medicine, and multiple approaches have been taken to utilize angiogenesis as a target for cancer therapy. However, as we discussed previously, most of these approaches, including angiogenesis inhibitors targeting VEGF as well as vascular disruptive agents, offer significant but limited benefits. This tumour resilience has been attributed to two distinct mechanisms: evasion of anti-angiogenic therapy and indifference to anti-angiogenic therapy (1). In the former, tumors adapt to pressures exerted by therapy, and utilize alternative methods of maintaining vascularization. In the latter, the tumors have pre-existing characteristics which render them non-responsive to therapy (1).
While this chapter has focused largely on the effetcs of VEGF, there are numerous other pro-angiogenic growth factors, providing alterative pathways to recruit blood vessels to a tumor when VEGF has been blocked by anti-VEGF therapies. Such factors include fibroblast growth factor (FGF), Ephrins, and angiopoeitin family proteins. These factors have been shown to be reponsible for many of the relapses observed following the transient response of tumors to anti-VEGF treatments such as Avastin (1).
Hypoxia induced by the regression of tumor blood vessels upon anti-VEGF therapy not only induces expression of alternative pro-angiogenic growth factors, but it also has the effect of recruiting an assortment of cells from the bone marrow to aid in resupplying the tumor with blood flow. Acting through hypoxia-inducible factor 1α, low oxygen conditions can attract a population of vascular progenitors, including both endothelial and pericyte progenitors (1). These cells are incorporated directly into new blood vessels, and as such evade anti-VEGF therapy. Alternatively, hypoxia can attract pro-angiogenic monocytes from the bone marrow, which promote angiogenesis through a variety of pro-angiogenic cytokines and proteases (1).
Another recently emerging theory behind the evasiveness of tumors to anti-VEGF therapy attributes this phenomenon to a process called perivascular invasion. In some instances, when a tumor is unable to recruit blood vessels to supply it, the tumor will adapt by aggresively migrating into normal tissues. This phenotype has been observed in glioblastoma tumors, where the glioblastoma cells co-opted normal blood vessels, and use them as a track or conduit to travel further into the brain (1). This aggresive invasion allows the tumor to situate itself around blood vessels, an attain vascular sufficiency independant of VEGF (1).
Indifference to Anti-Angiogenic Therapy
First observed in pancreatic ductal adenocarcinoma (PDAC), Characteristic Hypovascularity, a form of anti-angiogenic indifference, may be another mechanism of angiogenesis therapy resistance in some tumors. As the name suggests, this phenomenon involves tumors which are predisposed to poor vascularization (1). Somehow these tumors are not extensively necrotic, which suggests that these cells possess adaptations for survival in extremely hypoxic environments. It seems that these cells have undergone a sort of metabolic switch away from aerobic metabolism, allowing them to sustain themselves utilizing anaerobic metabolism. Presently this mechanism is not well understood, and it is not clear why these tumors, in the absence of anti angiogenic pressures, do not employ some method of recruiting vasculature. However, this peculiar predisposition does render such tumors particularly resistant to anti-angiogenic therapies, as they have no reliance on angiogenesis to thrive.
Although tumors typically recruit host vasculature into the tumor mass to supply blood, some tumors are capable of forming thier own blood vessel-like passages to allow blood flow. Vasculogenic mimicry is characterized by the presence of a network of tubular structures which are formed in the absence of epithelial cells, and are instead lined with a layer of extracellular-matrix material that has the appearance of a basement membrane (Figure 7.11.2) (2). Blood cells have been found within these structures, enforcing the theory that they act as an alternative circulatory system for tumors (2). Electron microscopy of such structures reveals no cells or nuclei on the luminal side of this basement membrane, where one would usually expect to find endothelial cells (2). As a result, these non-endothelial derived vessels are inherently resistant to anti-angiogenic therapies that typically target VEGF-expressing endothelial cells. In fact, vasculogenic mimicry in tumors is highly associated with a poor prognosis (3). This event is well characterized in melanoma cells, but has been seen in breast, lung, prostate, and ovarian cancers as well (3). Vasculogenic mimicry is incredibly plastic and tumor populations possessing this ability have gene expression profiles more closely resembling those of undifferentiated embryonic-like cells (3). Specifically, changes in endothelium-associated and signal transdction gene expression are seen; for example, VE-Cadherin, EPHA2, FAK, and PI3K levels are often altered in these tumors (3).
1. Bergers, G., & Hanahan, D. (2008). Modes of Resistance to Anti-Angiogenic Therapy. Nature Reviews Cancer 8, 592-603.
2. Ruoslahti, E. (2002). Specialization of Tumour Vasculature. Nature Reviews Cancer 2, 83-90.
3. Hendrix, M. J., Seftor, E. A., Hess, A. R., & Seftor, R. E. (2003). Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nature Reviews Cancer 3(6), 411-421.