Review
Tumour angiogenesis: Its mechanism and therapeutic implications in malignant gliomas
Introduction
Two distinct processes have been described for the formation of vasculature. Vasculogenesis refers to the formation of primitive blood vessels from mesoderm by differentiation of angioblasts during embryonic development.1 After the primary vascular plexus is formed, further expansion of the circulatory network relies on sprouting or splitting from pre-existing vessels in a process termed angiogenesis.[2], [3], [4], [5] Blood vessels formed in later stages of embryonic development or in adults as a result of tissue demands are predominantly products of angiogenesis.6 The formation of new blood vessels occurs physiologically during embryogenesis, the reproductive cycle in females and wound healing.[5], [7], [8] Angiogenesis also takes place in a variety of pathological states, including ischemic diseases, chronic inflammatory reactions, and cancer.[2], [9]
It was almost a century ago that the association between angiogenesis and cancer was initially observed.[10], [11], [12] In 1966, Folkman et al. first showed that tumour growth and metastasis required the formation of new blood vessels.13 Sufficient nutrients and waste exchange can be achieved by diffusion if tumour cells are situated within about 100 μm of blood vessels.[14], [15] However, growth of tumours beyond this limit necessitates the recruitment of a new blood supply and consequently leads to the emergence of an angiogenic phenotype.[3], [14] Exponential growth of tumours exceeding 1–2 mm3 occurs after a vascular network is established through angiogenesis.[10], [13], [16], [17], [18], [19], [20]
The hypothesis that tumours produced a diffusible angiogenic substance was proposed in 1968.[21], [22] Folkman et al. subsequently proposed in 1971 that tumour growth and metastasis were angiogenesis dependent, and hence, blocking angiogenesis could be a strategy to arrest tumour growth.23 In 1976, Gullino showed that cells in pre-malignant tissue acquired angiogenic capacity as part of the transformation to become fully malignant.24 Genetic studies subsequently confirmed that the acquisition of an angiogenic phenotype was one of the hallmarks of cancer.[3], [25], [26], [27], [28]
Angiogenesis is recognised as a key event in the progression of glioma.[29], [30], [31] Among all solid tumours, glioblastoma multiforme (GBM) has been reported to be the most angiogenic by displaying the highest degree of vascular proliferation and endothelial cell hyperplasia.32 Such intense vascularisation is partly responsible for the pathological features of GBM, including peritumoral oedema resulting from the defective blood brain barrier (BBB) in the newly formed tumour vasculature.[33], [34], [35], [36] These vessels are associated with increased risks of intratumoural haemorrhage[37], [38] and are also responsible for contrast enhancement on neuroimaging.[36], [39], [40], [41]
Unlike tumours in other locations, gliomas rarely metastasise to distant organs and their aggressive behaviour and poor prognosis are determined by their histological grade. Microvascular proliferation is a diagnostic criterion distinguishing low grade from high grade astrocytomas and is a histopathological hallmark of GBM.[42], [43], [44], [45], [46]
Although it is uncertain if microvascular proliferation is the cause or effect of malignant tumour behaviours, neovascularisation in gliomas correlates positively with their biological aggressiveness, degree of malignancy and clinical recurrence and inversely with the post-operative survival of patients.[43], [44], [45]
The angiogenic potential of GBM was first recognised in 1976 by observing new vessel formation elicited by GBM implanted into rabbit corneas.47 Moreover, glioma cells induced endothelial cell proliferation and tube formation in vitro.[48], [49] Angiogenic factors such as vascular endothelial growth factor (VEGF) have been identified in pseudopalisading tumour cells adjacent to necrotic zones and hyperplastic vessels, implicating their role in glioma angiogenesis.[50], [51], [52], [53], [54] Hypoxia inducible factor-1 (HIF-1)α is also expressed in pseudopalisading cells in conjunction with VEGF, which provides a link between hypoxia and angiogenesis in malignant glioma.[52], [54], [55], [56]
Section snippets
The mechanism of angiogenesis
Angiogenesis involves a sequence of coordinated events that is initiated by the expression of angiogenic factors such as VEGF with subsequent binding to its cognate receptors on endothelial cells (Fig. 1). VEGF increases vascular permeability, which leads to extravasation of plasma proteins and dissociation of pericyte coverage.[50], [53] Endothelial cell migration and proliferation then follow in preparation for the new vasculature.57 Local degradation of the vascular basement membrane and
Mediators of glioma angiogenesis
Vascular homeostasis is governed by a balance between pro-angiogenic and anti-angiogenic factors. More than 25 different growth factors and cytokines have been identified that are able to induce angiogenesis72 (Fig. 2). The production of angiogenic growth factors is either the result of genetic alterations or is induced by hypoxia.
Anti-angiogenic therapies in malignant gliomas
Strategies have been devised to inhibit angiogenesis in malignant gliomas: blocking growth factor production, neutralisation of circulating growth factors, inhibition of RTK activation and suppression of intracellular signalling cascades. Although no anti-angiogenic drug has been approved for the treatment of malignant gliomas, many have undergone Phase I/II clinical trials (Table 1, Fig. 3).
Conclusions
Tumour-related angiogenesis is a fertile ground for developing effective anti-cancer treatments. Anti-angiogenic agents have special roles in the treatment of central nervous system tumours because they can bypass the BBB in exerting their effects. In addition, GBM is one of the most angiogenic tumours in humans, thus rendering it an ideal target for anti-angiogenic treatment.32 Most angiogenesis inhibitors are not highly effective as a monotherapy. Fortunately, many of these agents are able to
Acknowledgements
We thank the Royal Australasian College Surgeons Surgeon Scientist Scholarship and the Friends of Royal Melbourne Hospital Neuroscience Foundation for their support.
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