AML: Antibodies against Fare-Dodgers

24. November 2009
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On its way from the bone marrow to other tissue, a molecule on the cell’s surface protects against macrophages. Not only hematopoietic stem cells but also cancer cells take advantage of this ticket for a free ride. If it’s seized, the chances for leukemic stem cells drop.

They are police, guard duty and garbage removers and face internal and external terror threats. They make short shrift of suspects: Circle, kill, eat. Macrophages lurk in many tissues and blood vessels waiting for microbes but also for defect and old cells not functioning good any more. Every once in a while they also mingle with cancer cells or their precursors. Irving Weissman and his team at the Stem Cell Center in Stanford/California now discovered how juvenile hematopoietic stem cells – but cancer cells just the same – protect themselves from being arrested by the ‘immune police force’.

“Free ride” for hematopoietic stem cells

Hematopoietic stem cells are looking for niches from where they are doing their reproduction work. Their way there leads through vessels where macrophages keep an eye on conspicuous passers-by in the traffic. Earlier tests already proved that a signal on the cell surface named CD47 means ”free ride“. In its latest publication in the high-ranking professional journal “Cell”, the team of researchers now showed that hematopoietic stem cells up-regulate CD47 in order to wangle protection for themselves.

With according factors like G-CSF, the researchers mobilized the bone marrow cells in mice or reconstructed an inflammation with lipopolysaccharide. On the stem cells, there were significantly more of those molecules now. Cells capable of producing CD47, like for example in according “knock-out” mice, fail in bone marrow transplantation on genetically intact relatives as well. They don’t have a chance to grow onto them. If the scientists “turn off” the macrophages police by using an antibody, the surgery turned out to be successful.

Particularly vicious thanks to CD47

Really important for future strategies in the hospital though might be the observation that cancer stem cells like those in AML in mice and men have learned that trick as well to get around the supervision. Acute myeloid leukemia is particularly well suitable for this kind of studies because a stem cell population can be isolated rather easily – as David Ritchie and Mark Smyth at Melbourne University wrote in an editorial. Especially with this type of blood cancer, healthy and neoplastic stem cells are resisting even aggressive chemotherapy-strategies exceedingly persistently.

The researchers then examined patients with myeloid leukemia and found their presumptions confirmed. The most aggressive tumors like for example those in patients with CML during blast crisis and with AML at the same time showed the highest CD47 level.

In a normal metabolism the molecule connects – depending on the cell partner – with different receptors such as integrins, thrombospondin-1 or also SIRPα on macrophages. It is also involved as a signal molecule in the migration of neutrophile granylocates, the axon extension of neurons and the stimulation of T-cells. Tests with mice with implanted human AML-cell lines also show that the connection with macrophages-SIRPα and cancer cells works as ‘unpalatable-signal’. An antibody against CD47 completely suppresses growth of the cell line.

An antibody against leukemias?

Such an antibody could be a promising candidate for the hospital because the treatment of murin AML with such a reagent stops the tumor growth and at the same time spares the normal bone marrow cells.

Actually this story is too good to be true. Especially since a further article fresh from the press in the new professional magazine Science Translational Medicine reports about additional advantages of a CD47 blockade: After a combination therapy with radiation and CD47-antisense nucleotides, melanomas or lung cancer cells grew 90% slower than with radiotherapy alone. In addition the CD47 blockade protected the surrounding tissue: “The dramatic protection showed on skin, muscles and bone marrow cells”, explains Jeff Isenberg, co-author of the publication at the Pittsburgh University. “Cells which should be dead due to the treatment, were alive and functioning if they were previously treated with agents interacting with thrombospondin-1/CD47 way of metabolism.”

It is not quite clear yet how such wonderful effects come about and whether perhaps inflammations, cardiac diseases or other types of cancer might react to a prior treatment with a CD47 blocker. That is exactly what the researchers want to try next. But there are many examples where patients did not show the same promising results like lab mice. The unsuccessful drug test made with the autoimmune regulator TGN1412 developed in Germany in 2006 resulted in dramatic consequences for the first volunteers. CD47 connects to quite a number of receptors of many different cell types. That means: Serious and far-reaching side effects cannot be excluded. Nonetheless an effective method might develop from those surprising observations helping the macrophages police force gaining better control during terror attacks by cancer cells.

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