Breast Tumour Angiogenesis
The central importance of tumour neovascularization has been emphasized by clinical trials using antiangiogenic therapy in breast cancer. This review gives a background to breast tumour neovascularization in in situ and invasive breast cancer, outlines the mechanisms by which this is achieved and discusses the influence of the microenvironment, focusing on hypoxia. The regulation of angiogenesis and the antivascular agents that are used in an antiangiogenic dosing schedule, both novel and conventional, are also summarized.
It has been 3 years since the last critical review of antiangiogenic therapy was published in Breast Cancer Research, and since then the central importance of tumour neovascularization has been emphasized by clinical trials in various tumour types, including breast cancer. Many of these trials have used bevacizumab (Avastin™; Genentech, South San Francisco, CA, USA), which was specifically designed to target vascular endothelial cell growth factor (VEGF). Bevacizumab is a recombinant VEGF antibody derived from a humanized murine monoclonal antibody that can recognize all known isoforms of VEGF-A and prevents receptor binding, thereby inhibiting angiogenesis and tumour growth. The critical contribution of this angiogenic factor in controlling many of the processes involved in angiogenesis and its importance as a paradigm for the rational design of an anticancer agent have been among the successes of antiangiogenic treatment, which was first suggested by Judah Folkman more than 35 years ago. The attractiveness of the antiangiogenic approach has always been the wide therapeutic window, since all tumours (including liquid such as leukaemias) are angiogenesis dependent, that angiogenesis is highly restricted in the adult, that endothelium of the vessels are accessible and that any treatment would be amplified through subsequent tumour infarction. Furthermore, the erstwhile problem in oncology of resistance should not be an issue because endothelial cells are non-neoplastic and should have a stable genome.
Nevertheless, although these trials have demonstrated significant improvements in response rates, findings to date have not indicated substantial benefits in terms of survival. This is likely to be due to redundancy in breast tumours with an individual tumour being able to utilise several angiogenic pathways at any one time with changes in this profile during tumour progression coupled with the use of other mechanisms to establish a blood supply. Indeed, the central tenet that tumours are angiogenesis dependent (in that for a tumour to grow, this must be preceded by a wave of angiogenesis to deliver nutrients and meet the metabolic requirements of the growing tumour) has been challenged. Thus, a number of nonangiogenic mechanisms may contribute to establishing tumour blood supply; these include co-option, vasculogenesis, vascular remodelling, intussusception and vascular mimicry.
A further important issue that has not been addressed is stratification of patients for appropriate treatment; specifically, individual patients given antiangiogenic agents have yet to be selected based on the characteristics of their tumour. It is therefore likely, as has been demonstrated for other targeted agents such as herceptin, that benefit will be restricted to those patients whose tumours rely largely on VEGF signalling for their angiogenic response. The administration of agents based on the biology of the individual tumour (so-called personalized medicine) will become increasingly important not only to generate maximum therapeutic benefit to the patient but also to realize the optimal economic advantage from the finite resources available.
The central importance of tumour neovascularization has been emphasized by clinical trials using antiangiogenic therapy in breast cancer. This review gives a background to breast tumour neovascularization in in situ and invasive breast cancer, outlines the mechanisms by which this is achieved and discusses the influence of the microenvironment, focusing on hypoxia. The regulation of angiogenesis and the antivascular agents that are used in an antiangiogenic dosing schedule, both novel and conventional, are also summarized.
It has been 3 years since the last critical review of antiangiogenic therapy was published in Breast Cancer Research, and since then the central importance of tumour neovascularization has been emphasized by clinical trials in various tumour types, including breast cancer. Many of these trials have used bevacizumab (Avastin™; Genentech, South San Francisco, CA, USA), which was specifically designed to target vascular endothelial cell growth factor (VEGF). Bevacizumab is a recombinant VEGF antibody derived from a humanized murine monoclonal antibody that can recognize all known isoforms of VEGF-A and prevents receptor binding, thereby inhibiting angiogenesis and tumour growth. The critical contribution of this angiogenic factor in controlling many of the processes involved in angiogenesis and its importance as a paradigm for the rational design of an anticancer agent have been among the successes of antiangiogenic treatment, which was first suggested by Judah Folkman more than 35 years ago. The attractiveness of the antiangiogenic approach has always been the wide therapeutic window, since all tumours (including liquid such as leukaemias) are angiogenesis dependent, that angiogenesis is highly restricted in the adult, that endothelium of the vessels are accessible and that any treatment would be amplified through subsequent tumour infarction. Furthermore, the erstwhile problem in oncology of resistance should not be an issue because endothelial cells are non-neoplastic and should have a stable genome.
Nevertheless, although these trials have demonstrated significant improvements in response rates, findings to date have not indicated substantial benefits in terms of survival. This is likely to be due to redundancy in breast tumours with an individual tumour being able to utilise several angiogenic pathways at any one time with changes in this profile during tumour progression coupled with the use of other mechanisms to establish a blood supply. Indeed, the central tenet that tumours are angiogenesis dependent (in that for a tumour to grow, this must be preceded by a wave of angiogenesis to deliver nutrients and meet the metabolic requirements of the growing tumour) has been challenged. Thus, a number of nonangiogenic mechanisms may contribute to establishing tumour blood supply; these include co-option, vasculogenesis, vascular remodelling, intussusception and vascular mimicry.
A further important issue that has not been addressed is stratification of patients for appropriate treatment; specifically, individual patients given antiangiogenic agents have yet to be selected based on the characteristics of their tumour. It is therefore likely, as has been demonstrated for other targeted agents such as herceptin, that benefit will be restricted to those patients whose tumours rely largely on VEGF signalling for their angiogenic response. The administration of agents based on the biology of the individual tumour (so-called personalized medicine) will become increasingly important not only to generate maximum therapeutic benefit to the patient but also to realize the optimal economic advantage from the finite resources available.
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