Hypoxic Signalling and Disease

Cancer

Cancer is the disease that occurs when cells grow and divide out of control. They invade the surrounding tissue and may spread to other areas of the body (metastasis).

A fertilised egg is a single cell that needs to grow and divide many, many times in order to form a whole organism. Division is also required to replace cells that worn-out, such as skin and blood cells. Cell division is balanced quite tightly, otherwise as adults we would grow all the time – or start shrinking! The major result of out of control cell division is the growth of tumors – either benign growths, which don’t invade or metastasize, or cancerous tumors, which can do both.

Before dividing a cell must duplicate its genome (the DNA content of a cell) so that the new ‘daughter’ cell and the original ‘parent’ cell each has its own copy of the genome. It is during the copying of the genome that most genetic changes (also called mutations) happen. Cancer basically occurs when a cell accidentally acquires mutations that stop it obeying the normal cell division control signals (or factors). In a great majority of cases this happens when a cell accidentally acquires mutations that inappropriately activate cell division promoting factors or inactivate growth inhibiting factors.

A good example is basal cell carcinoma (BCC) of the skin, which is the most common skin cancer. BCC is usually caused by the loss of a gene that blocks a cell division signal called Hedgehog. Another example is cancer of the gut; a frequent cause is the loss of a gene that blocks the cell division factor, named Wnt (pronounced as ‘wint‘). In both cases a cell division promoting signal becomes activated, due to the loss of an inhibitory factor. The causes of cancer can be quite complicated due to the interaction of many different cell division promoters and inhibitors!

The hypoxic signal below is also involved in cancer, both directly and indirectly. It can cause kidney cancer directly when inappropriately activated, but can indirectly influence all kinds of tumors.

All these signalling pathways are also present in animal models for human disease: mouse, fish and even the fruit fly. In fact, two of these cell division signals (Hedgehog and Wnt) were initially discovered in the tiny fruit fly. It was only much later that it was realised that these signals could cause cancer! So next time say “thank you fly“, before you hit it with a fly swatter….

Hypoxia

Oxygen is an essential molecule for complex organisms, allowing efficient generation of cellular energy. Cells can extract a little bit of energy from glucose without oxygen, but this is 10 times less efficient. Generation of energy under these conditions produces all kinds of nasty by-products and requires adaptation of the cell on several levels. It is therefore not surprising that cells have evolved a sensitive alarm system that becomes active when there is a shortage of oxygen. It has been named the hypoxic signalling pathway. The master regulator of this is a protein called HIF (hypoxia induced factor).

Normally, HIF is continually produced but quickly destroyed under the influence of oxygen. However, if oxygen is at a low level HIF can accumulate.

HIF orchestrates a whole suite of other genes, some of which help the cell to cope with this situation whilst others “call for help” in order to get more oxygen transported to the cell .

Hypoxia and Cancer

Unfortunately in the case of cancer, hypoxic signalling may be counterproductive!

Most tumors would grow very rapidly if they were not limited by a low oxygen supply. Once a tumor manages to attract new blood vessels, it becomes much more dangerous since it can get further oxygen and keep growing. In addition, these vessels can transport tumor cells to other sites in the body where they can form metastases.

The hypoxic signalling pathway is important in this respect since it helps the tumor cells to survive under these difficult hypoxic conditions, and it leads to production of proteins that stimulate blood vessel growth.

Hypoxia and Zebrafish

We are using the zebrafish larvae to study these processes. They can get cancer too and have a hypoxic signalling pathway very similar to ours.

Zebrafish larvae are transparent and we have fluorescent marked lines available to us that will allow us to follow blood vessel development in live fish larvae. Other fluorescent lines allow us to visualise the activity of the hypoxic signalling pathway in a living larva. We can therefore really study these processes as they are happening.

In addition, we would like to search for chemicals that activate or inactivate the low-oxygen signal. In order to do this, we will use eggs from our line of fish that turns fluorescent when the hypoxic signal is switched on. Such chemicals might well be the basis for future therapeutic drugs in humans.