Angiogenesis

Angiogenesis is one example of laboratory research translated into clinical practice. It is the growth of a new blood supply from pre-existing vasculature. The existing capillaries sprout new branches to serve and nurture the tumour. This is triggered by proteins known as tumour angiogenesis factor and involves numerous biological activities (Tortora and Grabowski, 2003).

Preclinical studies have demonstrated the major role of angiogen-esis, tumour growth and formation of metastases, which lead to the thinking that suppression of the blood supply suppresses the tumour (Pinedo and Salmon, 2000). Most cancer treatments have been targeted at killing the cell. Although treatments have been modified and refined over the past 50 years, the aim of treatment remains targeted at the same tumour cell. An understanding of angiogenesis and the notion that the tumour is angiogenesis or blood supply dependent have led to the second target in cancer treatment - the newly formed capillaries.

As mentioned above, the current thinking is that cancer treatment targets the cancer cell to cause cell death. Folkman et al. (2001) suggest that the cancer genome is clever in its make-up, continually mutating or changing at both primary (main) and distant (secondary or metastases) sites. This creates challenges for the clinical staff because eventually these changes will create a resistance to the drugs targeted at them. In stark contrast, the cells that line the new capillaries at the tumour site are stable with a virtually non-existent mutation or change rate. These cells, known as microvasculature endothelial cells, are needed for further tumour growth which makes them a very powerful player in any malignant process. These endothelial cells not only supply oxygen and nutrients to the tumour; it is now known that they also provide a gateway for anti-apoptotic factors, or anti-switch-off factors, and so protect the tumour by allowing its cells to go into mass production. Simply, what the above is saying is that we know that a tumour continually changes its make-up and that it is dependent on a blood supply. The ever-changing nature of the tumour cells may result in drug resistance. Added to this, the blood supply remains constant, supplying nutrients so that the tumour thrives.

Killing the blood supply will kill the tumour whether or not mutated and drug resistant. This is the basis of this translational research.

Cytotoxics directly target and kill tumour and normal cells

Anti-angiogenics kill blood supply

Cytotoxics directly target and kill tumour and normal cells

Figure 10.1 Targets for cell death.

Preclinical and clinical work is ongoing. Some centres use anti-angiogenesis agents alone and/or in combination with chemotherapy. The aim is to inhibit tumour growth, reduce metastases, prolong survival and improve quality of life (Pinedo and Salmon, 2000). However, is it possible to have concurrent use of cytotoxic chemotherapy and anti-angiogenic agents? If the blood supply is suppressed, how do the cytotoxic drugs reach the tumour? This is a valid concern, but one that has not yet been elucidated. Animal studies of lung cancer by Leicher, cited by Pinedo and Salmon (2000), demonstrated a synergistic effect. Combination therapy reduced not only the number of metastases but also the size of the metastases, providing evidence that anti-angiogenic therapies can improve treatment.

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