Recently, I wrote a post about how we may find the solutions to some of our most baffling problems where we least suspect them. This one develops on that somewhat, discussing how we could use our knowledge about the characteristics of cancer to our advantage.
First, a little bit about one of the most common characteristics of most cancers. When our normal cells gain a mutation that drives them towards becoming cancerous a number of genes are either switched on, such as those that express self-acting growth factors or receptors for such growth factors, or switched off, such as those that code for proteins that limit a cell’s progression through its life and growth cycle. Now we have a mass of cells that are dividing without limit, whilst also resisting death-inducing pathways.
The newly formed tumour can continue in this manner for a while, but eventually it will grow so large that the environment it is growing in can no longer sustain it; the current system of vasculature is unable to supply enough nutrients and oxygen to the growing mass of cells, while also not being able to remove their waste products.
The tumour needs to force the generation of new blood vessels – a process called angiogenesis – to continue proliferating. This is achieved by making the most of the cellular response to hypoxia (oxygen starvation) which results in angiogenesis. This process relies on the action of the Hypoxia Inducible Factor-1 (HIF-1). This transcription factor binds to the regions controlling the expression of the Vascular Endothelial Growth Factor (VEGF) gene, whose product controls the generation of new blood vessels.
Since cells do not want VEGF active all the time, HIF-1 is split into two parts: HIF-1α and HIF-1β. Both subunits are constitutively expressed by all cells, but the α subunit is rapidly degraded when the cell is not hypoxic. This degradation is achieved either by the action of prolyl hydroxylase enzymes, which cut the protein at specific proline residues, or by the action of ubiquitin ligase enzymes, which add ubiquitin to proteins targeted for degradation by the proteasome.
When a cell is hypoxic, as many of the cells in a growing tumour are, the prolyl hydroxylase enzymes are inactivated by reactive oxygen species generated by the hypoxic environment. This leads to an accumulation of HIF-1α, which is now free to bind HIF-1β and form the complete HIF-1 dimer. HIF-1 then binds to the VEGF gene, leading to expression of VEGF. VEGF stimulates the generation of new blood vessels, giving the tumour enough nutrients and oxygen to continue to grow.
The linkage of VEGF to the generation of blood vessels has generated interest regarding this growth factor. Specifically, it is hoped that this growth factor can be used to treat damaged hearts. There are generally two ways the heart’s arteries can be damaged: by myocardial infarction or by accumulation of fat or cholesterol. The former is more often than not dealt with by bypass surgery, which uses a section of artery from elsewhere in your body to divert the flow of blood away from the area of damage. The latter involves the addition of a stent into an artery to open it up and improve flood flow past a blockage.
But what if VEGF could be used to heal damaged arteries instead of these surgical procedures? In ischaemic cardiomyopathy, blood flow to the muscle cells of the heart is disrupted, leading to cell death and the replacement of the muscle cells by fibrous scar tissue. In order to prevent this occurring, new blood vessels will develop, providing alternative circulation to the affected cells. Expression of VEGF has been found to be induced by myocardial ischemia and a higher level of expression of VEGF has been associated with better collateral circulation development during ischemia.
