**Author details**

*Current Cancer Treatment*

angiogenic tumours.

anatomical sites.

**12. Conclusion**

anti-angiogenic factors (angiopoeitin-2).

such agents with immunomodulatory agents.

vessel co-option tumours, there was increased expression of genes involved in oxidative phosphorylation in primary [146]. Surprisingly, no differences in classic hypoxia or angiogenesis related genes were found between angiogenic and non-

In a glioma rat model of breast cancer brain and lung metastasis, co-opted blood vessels were seen in early-stage tumours and these vessels were found to overexpress angiopoietin-2, a natural antagonist of angiopoietin-1 [147]. As these tumours grew to become more hypoxic, VEGF was upregulated at the hypoxic tumour periphery and stimulated angiogenesis [147]. These observations suggest that a transition from vessel co-option to angiogenesis, or vice versa, may be dependent on the relative expression of pro-angiogenic growth factors (angiopoeitin-1, VEGF) and

Cell adhesion molecules have been implicated in facilitating the process of vessel co-option. In a preclinical brain metastasis model, Carbonell et al. demonstrated that the β1 integrin subunit in breast cancer and lymphoma cells facilitates (a) tumour cell adhesion to the vascular basement membrane of existing brain vessels, (b) tumour cell invasion and (c) the process of vessel co-option [148]. When the function of the β1 integrin subunit was blocked, adhesion to vessels was attenuated

and brain metastasis colonies failed to become established and grow [148].

Furthermore, the L1 cell adhesion molecule (L1CAM) has been shown to be involved in vessel co-option in the brain [149]. The ability of cancer cells to coopt blood vessels was suppressed when L1CAM expression was depleted using shRNA. Conversely, when L1CAM was overexpressed, tumour cells demonstrated enhanced adherence to the outer surface of vessels and tumour growth alongside them. Although such mechanisms are likely to be more specific for vessel co-option in the brain, similar mechanisms may be at work during vessel co-option at other

Tumour vascularisation is modulated by the complex interplay of several endogenous factors and processes that can be up-regulated or downregulated, depending on the tumour microenvironment and the treatment pressures that are imposed on it. A multitude of studies have shown that the majority of solid tumours exhibit an overexpression of VEGF, one of the key drivers of sprouting angiogenesis. As a result, various anti-angiogenic therapies targeting VEGF or VEGFR have now been developed and are used conventionally in the clinic. Compellingly, recent pre-clinical and clinical studies using anti-angiogenic agents in combination with immunotherapies (e.g. ICI's), have demonstrated a synergistic effect in reducing tumour growth. This highlights that there is promise, not only in incorporating anti-angiogenic therapy in the management of most cancers, but also in combining

However, as is the case with many cancer treatments, drug resistance can limit the efficacy of these agents. Trials of VEGF-targeted therapies in advanced malignancies have not consistently demonstrated beneficial outcomes in terms of tumour response and survival. Importantly, only a proportion of patients benefit from anti-angiogenic therapy, control of tumour growth is generally transient, there remains significant risk for therapeutic toxicity and we are still challenged by the burden of health costs. Limited clinical outcomes with anti-angiogenic therapies are felt to be driven by either intrinsic or acquired resistance mechanisms, and several of these have now been proposed. In this chapter, we have reviewed the most commonly used antiangiogenic agents in the clinic and have highlighted the spectrum of mechanisms

**60**

Sophia Frentzas1,2\*, Caroline Lum1 and Ting-Yu Chen3

1 Department of Medical Oncology, Monash Health, Clayton, Victoria, Australia

2 Department of Oncology, Monash University, Clayton, Victoria, Australia

3 Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia

\*Address all correspondence to: sophia.frentzas@monash.edu

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
