Q J Med 2004; 97: 181-182
QJM vol. 97 no. 3 (c) Association of Physicians 2004; all rights reserved.
Biologic |
What's the target?
The aim of therapy in neoplasia varies, ranging from complete eradication of tumour in the common malignancies of childhood, to the devising of a strategy to control the disease within an acceptable lifestyle in the elderly. Profound knowledge of the biology of any tumour is invaluable in the construction of both of these therapeutic objectives. Control of a tumour that cannot be eliminated may depend on the prevention of ulceration, of painful lesions in bone or of infiltrations, but in all cases it is necessary or desirable for tumour cell mass to be reduced. So what should be the target?
It has been suggested that those cells that are critical in what might be called the developmental biology of tumours in a number of neoplasms (in leukaemia, breast cancer, and some cerebral tumours) are, in effect, acting as stem cells. Both neoplastic and conventional stem cells are self-renewing, and it is this population in a neoplasm that is responsible for the continued ‘success’ of the lesion—as normal stem cells are in the maintenance of the gut, say. In acute myeloid leukaemia (AML), the use of the immunodeficient NOD/SCID mouse in irradiation ablation and bone marrow re-population studies using blood from Man, confirms that very few cells in human AML (around 1 x 106) have the ability to re-establish the disease. Critically, these experiments showed that this number does not equate with the number of colony-forming cells—the ability to grow is not the same as the ability to keep a tumour going. In leukaemia, the cells that can support neoplasia are CD34-positive and CD38-negative, like normal human haemopoietic stem cells. However, when these cells were put back into mice, they produced the variety of AML (a very heterogeneous disease) that the original donor had. Dick and his group have suggested that the mutations that give rise to leukaemia arouse in normal stem cells alone.1,2 In 8;21 translocation AML, where the AML gene on chromosome 21 is fused to the ETO gene on 8, the translocation is found in some mature cells as well as tumour cells, suggesting that other mutations are necessary for uncontrolled growth.
A similar picture is found in breast cancer, using the same experimental model. Breast cancer stem cells are CD44-positive and CD24-negative, or express CD24 at a very low level. In cerebral tumours, a mouse model of neurofibromatosis using a mutated oncogene neurofibromatosis I and p53 produced tumours at brain stem cell sites (lateral ventricles and hippocampus). All these data are preliminary, but the reports support the notion that the aggressiveness of a tumour may depend on the size of its stem cell population.
To be honest, we really don’t have stem cells mastered yet. It is known that Bmi-I and Wnt are necessary for cell self-renewal; the Bmi-I knockout mouse cannot support persistent marrow re-population in normal irradiated mice. This gene is also necessary for leukaemic cell self-renewal. Wnt (Wingless/Integrated) is an important gene in determining cell fate decisions in normal development, where it acts by binding to a cell surface receptor. Wnt-produced glycoproteins are found in all animals, from hydra to insects, worms and vertebrates. There are nineteen genes in Man (and seventeen in the mouse). The surface receptors for Wnt proteins are members of the Frizzled transmembrane receptor family, of which there are at least ten in Man. These receptors produce their intracellular effects via the Dishevelled protein; this acts in the Wnt pathway by inhibiting the phosphorylation and subsequent destruction of ß-catenin by the protein destructive mechanisms of the cell. Thus in the absence of Wnt signalling, ß-catenin is rapidly destroyed. Stabilized (non-phosphorylated) ß-catenin is translocated into the nucleus, where it induces transcription of c-myc and Cyclin D, and thus affects cell proliferation. The APC gene, altered early in the genesis of colon carcinoma, is part of the Wnt cascade, and there are some interesting data relating to this.
Looking at colorectal cancer cells, Clevers and his colleagues have shown that Wnt up-regulates 120 genes and down-regulates 115. Looking at the sites of normal stem cells in the gut, they found a similar pattern, but towards the surface of the epithelium where differentiated cells are found (and Wnt signals are presumably absent), they found that the 120 genes up-regulated in cancer were down-regulated, and many of the down-regulated genes were turned up. Presumably the other genetic changes in colon cancer have prevented the stem-cell-like expression from being turned off. In skin cancer, ß-catenin over-activation by mutation causes pilomatrixoma.
Now all this is problematic. It seems possible to me that it is only the stem cell that is around in the colon long enough to acquire the 7/8 genetic changes necessary to produce tumour–like behaviour, say, but this argument is less convincing for other neoplasms. Even so, it is sensible to target the critical cell population in any tumour, and the emphasis on attacking dividing cells is perhaps misdirected; most stem cells are quiescent. Dick has also suggested that the enthusiasts for the use of stem cell therapy in a number of diseases should be more cautious; it is often the case that stem cells are proposed for use in a manner that suggests that the population obtained should be made to divide to a provide a particular mass. If so, would this provide too much opportunity for mutation? This seems unlikely to me. In cells known to have one genetic change (the 8;21 translocation in AML, for example) stem cells differentiate normally in culture, having been studied for 15 years in some cases of AML in remission.
Targeted therapy is easy to propose, but difficult to accomplish. However, with cell sorting procedures and immunotherapy, with targeted direction of chemotherapeutic agents and with (perhaps) transcriptional regulators for the Wnt cascade, there is plenty to explore.
References
1. Bonnet D, Dick JE. Human myeloid leukemia is organised as a heirachy that originates from a primitive hematopoietic cell. Nat Med 1997; 3:730–7.[CrossRef][Web of Science][Medline]
2. Bonnet D, Bhatia M, Wang JC, Kapp U, Dick JE. Cytokine treatment or accessory cells are required to initiate engraftment of purified primitive human hematopoietic cells transplanted at limiting doses into NOD/SCID mice. Bone Marrow Transplant 1999; 23:203–9.[CrossRef][Web of Science][Medline]
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