Scientists study potential of FLT-1 blockers for cancer

The research aims to boost current leukaemia research, which has stalled in recent years. Soaring cases, especially in children have exacerbated the problem, which threatens to spiral out of control.

It is known that leukaemia development, like it happens with solid tumours, depends on the development of extra blood vessels (a process known as vascularisation), which serve to supply the fast multiplying cancerous cells with nutrients and help rapid cancer expansion and often metastasis formation.

Interestingly, it has also been found that molecules involved in vascularisation seem to be capable of act directly on the cancerous cells. One such example is VEGF (Vascular Endothelial Growth Factor) that appears to affect division, survival and migration of cancer cells and consequently cancer growth and dissemination.

FLT-1 or "Vascular endothelial growth factor receptor," which binds to VEGF, is another molecule involved in vascularisation that has been suggested to have a role in the division and migration of cancer cells.

Rita Fragoso, Teresa Pereira, Sérgio Dias and fellow research colleagues in Portugal and the United States believe that FLT-1 blockers appear as a promising new treatment against leukaemia.

If they are used in combination with chemotherapy they will be able to shape treatment strategy as result of the cells being more readily available to the injected drugs when stopped within the BM.

The research involved using cells from patients with acute lymphoblastic leukaemia (ALL), the most common childhood leukaemia, and one in which the abnormally proliferating cells are immature blood cells called lymphoblasts.

Cells from noticeably different from ALL patients, which produced distinct amounts of FLT-1, were injected into mice with no blood cells and followed in order to understand how different quantities of this molecule could affect cell fate and disease progression.

What the researchers found was that FLT-1 levels influenced both migration and cell survival, and therefore also disease outcome.

In fact, cells expressing high quantities of FLT-1 were found in the "exit area" of the BM (from where blood cells migrate into the periphery), in the peripheral circulation and also in other organs, such as the spleen and liver.

Cells with low or no FLT-1, on the other hand, stayed within the BM where part of them die.

As consequence, animals injected with these last cells presented a slower spread of leukaemia and a higher survival rate than animals injected with cells producing high quantities of FLT-1.

Further experiments showed that the different patterns of migration were associated with a gradient of VEGF (which binds FLT-1) found throughout the BM.

What these results showed for the first time was that the localisation of different subsets of leukaemia cells within the BM was dependent on their FLT-1 production, and that different localisations affected cell survival and leukaemia expansion and consequently also the survival of animals/patients suffering from the disease.

This work has helped to understand better the biology of leukaemia cells within the BM, how they behave and why, and also the importance of what happens within this organ in disease severity and treatment susceptibility.

In fact, migration of ALL cells to outside of the BM not only correlates with a more severe disease but also with a worst response to treatment, since these cells will be less accessible to therapy when spread throughout the body than when restricted to a small area.

Leukaemia, or cancer of the white blood cells, affects 4 out of 100,000 people worldwide and in the United States alone more than 2,000 children and 27,000 adults are diagnosed with the disease every year.

The illness originates from an abnormal multiplication of the cancerous cells in the BM that leaves little no space for normal blood cells to grow resulting in an impaired immune system that, among other problems, is incapable of efficiently fight infection.

The research is available to view in an advance online publication of the journal Blood.​