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The virtues of self-restraint
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The root cause of both cancer and stem cells is multicellularity. In the distant past, when all living things had only one cell, that cell’s reproduction was at a premium. In the body of an animal, however, most cells have taken a vow of self-denial. Reproduction is delegated to the sex cells. The rest, called somatic cells, are merely supporting actors, specialised for the tasks needed to give the sex cells a chance to get into the next generation. For this to happen required the evolution of genes that were able to curb several billion years’ worth of instinct to proliferate without killing that instinct entirely. Only then could somatic cells do their job, and be present in appropriate numbers. 2 e' a1 c! z) p. G* V
The standard model of tumour formation was based on the fact that somatic cells slowly accumulate mutations. Sometimes these disable the anti-proliferation genes. If enough of the brakes come off in a somatic cell, so the theory went, it will recover its ancestral vigour and start growing into a tumour. Cancer, then, is an inevitable cost of being multicellular.3 ~8 y7 c6 T+ }0 S& P6 [# p
The discovery of stem cells changed this picture subtly, but importantly. Blood stem cells were found a long time ago, but only recently has it become apparent that all tissues have stem cells. The instincts of stem cells lie halfway between those of sex cells and ordinary body cells. They never stop reproducing, but they cannot look forward to making the generational leap. When the body dies, so do they. However, they are few in number, and because at cell division only one daughter continues to be a stem cell, that number does not grow.
t9 B; v5 \+ } L7 I0 MThis division of labour may even be another type of anti-cancer mechanism. It allows stringent locks to be put on somatic cells (which, for example, strictly limit the number of times they can divide), yet it permits tissue to be renewed. Without stem cells, such tissue-renewal would be the province of any and every somatic cell—a recipe, as the traditional model observes, for tumorous disaster. The obverse of this, however, is that if a stem cell does mutate into something bad, it is likely to be very bad indeed. That, in essence, is the stem-cell hypothesis of cancer.
( g- R5 }( f; B4 W. Z7 r* W One obvious prediction of this hypothesis is that tumours will have at least two sorts of cell in them: a dominant population of daughter cells and a minority one of stem cells. The first person to show that to be true was John Dick, a molecular biologist at the University of Toronto. In 1997 he isolated what looked like stem cells from a blood cancer called acute myeloid leukaemia (AML). Blood cancers are easier to deal with in this context than solid tumours because their cells do not have to be separated from one another before they are examined. One characteristic of AML cells is that they have two sorts of a protein, called CD34 and CD38, on their surfaces. Dr Dick thus used two sets of special antibodies for his experiment. One sort stuck only to the CD34 molecule, the other only to CD38. Each sort was also attached to a fluorescent tag.
9 g7 H) e! o' R" ?/ D By mixing the AML cells from his patients with the two antibodies and running them through a machine that sorted them according to how they fluoresced, he showed that most were positive for both proteins. However, a small fraction (as low as 0.2%) were positive only for CD34. These, he suspected, were the stem cells.* V/ v$ ^- q# c4 i- e, t- h
He was able to confirm this by injecting the minority cells into mice. The resulting tumours had the same mix of cells as those from human patients. However, when he injected mice with samples from the majority cells, with both sorts of the protein, no tumours resulted. The CD34-only cells thus acted as cancer stem cells.2 E8 T* T3 _* t. \* I( M, z
Moreover, this phenomenon was not confined to leukaemia. In 2003 a group of researchers at the University of Michigan in Ann Arbor, led by Max Wicha and Michael Clarke, used a similar trick on breast-cancer cells. In this case the surface proteins were known as CD24 and CD44, and the minority were those positive only for CD44. As with AML, these minority cells produced cancers in mice, whereas the majority cells did not.
0 K( d! U! f, s Since these two pieces of work, the list of cancer stem cells has multiplied. It now includes tumours of the breast, brain, prostate, colon, pancreas, ovary, lung, bladder, head and neck, as well as melanoma, sarcoma, AML, chronic myelogenous leukaemia, Hodgkin’s lymphoma and myeloma. * U' P; m( Y" [* e; |* T' C$ o
That is quite a list. The question is, what can be done with it? Jeremy Rich, a neurologist at Duke University in Durham, North Carolina, has one idea. He created mice that had human glioblastoma tumours, a form of brain cancer, growing in them. Then he treated these mice with radiation (the standard therapy for such cancer in people). He found that the cancer stem cells were more likely to survive this treatment than the other cells in the tumour. That turned out to be because, although all the tumour cells suffered equal amounts of DNA damage from the radiation, the stem cells were better able to repair this damage. When he treated the mice simultaneously with radiation and with a drug that interferes with DNA repair, however, the stem cells no longer had an advantage. They were killed by the radiation along with the other cells.
. }7 q' q7 \9 B3 N1 Z! f% ` If that result applies to people as well as rodents, it opens up a whole avenue of possibility. In fact, Dr Rich is now in negotiations with several companies, with a view to testing the idea in humans. That “if” is a real one, though. A mouse is not a human being.
8 V2 E3 I0 C- S* k) V& k Indeed, the stem-cell hypothesis is often criticised for its reliance on animal models of disease. Some researchers worry that the experiments used to identify putative cancer stem cells are too far removed from reality—human tumour cells do not naturally need to survive in mice—and thus may not reflect human cancer biology at all. 9 C1 P6 R3 d h, l' n7 r" z. a% |, C
Proponents of the hypothesis are alive to that concern, but they think that the same pattern has been seen so often in so many different cancers that it is unlikely to be completely wrong. The practical test, though, will be whether the hypothesis and ideas that emanate from it, such as Dr Rich’s combination therapy, actually help patients survive. |
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