Antiangiogenic breast cancer therapy
Angiogenesis refers to the growth of new blood vessels out of pre-existing blood vessels. Angiogenesis is of course a normal part of growth and wound healing, but is also an essential step in the development of a breast cancer tumor. Some breast cancer researchers think of angiogenesis as a ‘switch‘ which takes a breast tumor out of a dormant state and into a malignant one.
So this page is kind of getting a little bit out-dated, and so because of that, I have came to the decision to create a newer version with more up-to-date information on Antiangiogenic Breast Cancer Therapy. However – don’t get me wrong, this page is still great for research and I would still recommend using it as well.
In order for breast cancer tumor cells to grow and proliferate, they need a blood supply. Antiangiogenic therapy aims at inhibiting or interrupting this needed supply of new blood vessels, thus preventing the tumor from growing.
‘Transfection‘ of tumor cells by peptides has shown to increase breast tumor growth, and ‘inhibitors‘ decrease growth: Antiangiogenic therapy?
In the experimental clinical setting, the transfection of tumor cells with angiogenic stimulatory peptides has been shown to increase tumor growth, invasiveness, and metastasis. (‘Transfection‘ is the process by which nucleic acids are deliberately introduced into cells).
Conversely, transfection of breast tumor cells with inhibitors of angiogenesis decreases growth and metastasis. This does raise the potential of an ‘antiangiogenic therapy‘ in which certain growth suppressant agents are introduced into potential malignant breast cancer cells at very early stages, inhibiting the tumor’s ability to grow.
Matrix metalloproteinase (MMP) and Hypoxia are key elements for angiogenesis in breast tissue
Hypoxia is felt to be a key signal for inducing angiogenesis. Hypoxia is a pathological condition in which either the body as a whole (generalized hypoxia) or a region of the body, such as the breast (tissue hypoxia) is deprived of adequate oxygen supply.
Hypoxia-inducible factors (HIF-1 and HIF-2) have been shown to progressively increases as a lesion progresses from normal breast tissue to usual ductal hyperplasia to ductal carcinoma-in-situ, and finally to invasive ductal carcinoma.
The expression of subunit HIF-1{alpha} tends to be higher in poorly differentiated breast tumors than in well-differentiated lesions and may therefore be associated with increased proliferation and expression of estrogen receptors and vascular endothelial growth factors (VEGF).
Carbonic anhydrase IX expression may indicate a more difficult prognosis
Additionally, the expression of carbonic anhydrase IX, which is an HIF-1{alpha}-dependent enzyme important in the regulation of pH levels, has been associated with a shorter relapse-free period following breast cancer treatment, and an overall shortened survival time in invasive breast cancer patients.
Inhibiting MMP production may slow breast tumor growth
Matrix metalloproteinases (MMP) are a famly of enzymes which degrade the basement membrane and extra-cellular matrix of cells, and is associated with a family of endogenous inhibitors, called ‘tissue inhibitors of metalloproteinases‘ (TIMPs). In healthy tissues these enzymes are held in balance, but during angiogenesis this balance is disrupted.
In the context of breast cancer growth, one then finds a subsequent increase in levels of MMPs as the tumor moves from pre-invasive, through invasive and metastatic stages of breast cancer and increased histologic tumor grade. Angiogenesis is a ‘switch‘ which turns on the overproduction of MMP. If there were a way to ‘inhibit‘ the production of MMP, this might stall breast tumor cell growth and proliferation.
Antiangiogenic breast cancer therapies must target VEGF
Vascular endothelial growth factor (VEGF) is thought to be an important signaling protein involved in the processes of vasculogenesis (neovascularity- growth of completely new blood vessels), and angiogenesis. VEGF activity tends to be restricted mainly to vascular endothelial cells, but they can influence a limited number of other cell types.
So, antiangiogenic therapies must also target VEGF receptors, and an agent called ‘Bevacizumab‘ is thought to function effectively in this capacity.
The body will react to impaired angiogenesis and find other ways to supply blood to growing breast tumors
One of the potential difficulties in using antiangiogenic agents, as that the body will react and compensate. It is reasonable to expect VEGF production will increase in response to treatment with the pure antiangiogenic agents. Various cancer studies using models have demonstrated the breast cancer tumors to use alternative methods to obtain the needed blood supply when the ‘classical‘ angiogenesis is not permitted.
(It is believed that inflammatory breast cancer relies on neovascularity rather than angiogenesis).
Antiangiogenic agents suppress breast tumor growth
So, the challenge with antiangiogenic therapy is not just to suppress tumor growth through antiangiogenic agents, but to somehow control the compensatory responses the body initiates to counter the suppression of classic angiogenesis.
For further reading, I suggest you visit this page for an overview of breast cancer treatments.
References
- Miller K, Sledge GW: Dimming the blood tide: Angiogenesis, antiangiogenic therapy and breast cancer, in Nabholtz JM (ed): Breast Cancer Management Application of Clinical and Translational Evidence to Patient Care (ed 2nd). Philadelphia, PA, Lippincott Williams & Wilkins, 2003, pp 287-308.
- Bos R, Zhong H, Hanrahan CF, et al: Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. J Natl Cancer Inst 93:309-314, 2001.
- Chia SK, Wykoff CC, Watson PH, et al: Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma. J Clin Oncol 19:3660-3668, 2001.
- Stuttfeld E, Ballmer-Hofer K (September 2009). "Structure and function of VEGF receptors ". IUBMB Life 61 (9): 915–22
Back to Breast Cancer Treatment Options or to the brand new Breast Cancer Homepage.
