What if proliferation is the norm for cells – and a very different theory of cancers’ cause is waiting in the wings?

THE pursuit of knowledge is always an uncharted adventure: it is mostly conducted in the twilight between what is known and what is not. As a consequence, there is no sure method to search for big ideas. Louis Pasteur said that chance helps the prepared mind, while in the early 20th century, Niels Bohr is widely quoted as having said: “…how wonderful that we have met with a paradox. Now we have some hope of making progress”.

But these days and for the forseeable future, merely identifying a paradox guarantees nothing in the field of experimental biology. A great deal of effort goes into seeking funds and making oneself heard amid the deafening noise of the worldwide research enterprise. The vagaries of long-term funding, intellectual steadfastness and a lot of luck are all as crucial as stumbling on the right paradox.

Our meandering road to a new theory of carcinogenesis started over 40 years ago when Carlos Sonnenschein was asked to answer the “straightforward” question of how ovarian oestrogens “stimulated” the proliferation of their target cells in the uterus, vagina, mammary gland, pituitary gland and other organs. The obvious first step was for him to establish a cell line that was sensitive to oestrogens - the first time this had been done.

This milestone motivated Ana M. Soto to join the lab because this cell line promised to become an effective tool for studying how oestrogen regulated gene expression, a popular subject at the time. However, the paradoxical behaviour of the cell line puzzled us: in animals, these cells proliferated only when the animals had been treated with oestrogen, but when tested in a cell culture dish, they proliferated equally well with or without oestrogens.

According to the prevailing theories of the 1960s, cells from a multicellular organism placed in a cell culture dish should have been in a state of quiescence, that is, not proliferating, when in the presence of an optimal concentration of nutrients. They would have proliferated only when a signal - a growth factor - induced them to do so.

However, microbiologists also knew that unicellular organisms such as bacteria, amoebas and yeast did not need any signal: if nutrients were available, they would readily proliferate. Thus, the default state of these organisms was proliferation, an idea that made sense evolutionarily. How else, after all, could organisms have propagated?

Given that the cell cycle components of unicellular and multicellular eukaryotes are essentially similar, was there evidence for the textbook interpretation of the default state in these cells? After exhaustively searching the literature, we found neither data nor theories to explain a radical change in their default state with the advent of multicellular organisms. This prompted us to search for the agent that could explain the conflicting results of oestrogen in vivo and in vitro.

We found this in blood serum, which inhibited the proliferation of cells targeted by oestrogen. Thus oestrogens merely neutralised the inhibitory effect of serum. In the cell culture dish, serum was not present, so the oestrogens had no effect.

Several years after our findings were published, others concluded that the default state of embryonic stem cells is proliferation, and that reproductive quiescence in lymphocytes is induced, not inherent. Briefly, multicellular organisms developed ways of regulating the proliferation of their cells: they are always poised to proliferate, but are constrained from so doing by the influence of other cells and by the physical constraints of the tissue in which they reside.

After reading evolutionary biologist Leo Buss’s influential 1987 book The Evolution of Individuality, we proposed that motility was the default state in unicellular and multicellular organisms. Cells in animals move, streaming from the location of their birth to that of their death, while some cell types, such as those present in blood, move more freely.

With over two decades of research experience, we embarked on the exhilarating adventure of writing a book on the control of cell proliferation and cancer. At that time, along with everyone else, we thought that cancer was a problem of cell proliferation, and we reasoned that our understanding of the control of cell proliferation would unravel the mechanism of carcinogenesis.

However, at the end of the 19th century, there had been another view that interpreted cancer as a tissue-based disease akin to embryonic development gone awry. It was only in 1914 that the German biologist Theodor Boveri proposed that cancer was a cell-based disease.

This cell-centred view, now known as the somatic mutation theory (SMT), became more dominant as the molecular biology revolution gained momentum, fostering the gene-centred notion that everything in biology must be explainable at the molecular level.

The historical perspective made us reinterpret various experiments that could not be explained when seen from the cell-based point of view. Among these are some that show cancer cells returning to normal when placed in the healthy tissue of the organ the cells came from (say, liver cancer cells into normal liver, or embryonic carcinoma cells into the blastocyst). Another example is research showing how normal cells become abnormal when transplanted into the wrong place, say, embryonic cells into a testicle.

We interpreted these experiments to mean that an organ’s normal architecture is maintained by tissue interactions - similar to those that determine basic shape, or morphogenesis, in the embryo. To reflect this change of perspective from a cell-centred view to a tissue-centred one, we entitled our book The Society of Cells. We put forward and developed what we call the tissue organisation field theory (TOFT) of carcinogenesis, and designed experiments to test it.

One of these experiments involved exposing only the support tissue, or stroma, of rat mammary glands to a carcinogen. This was sufficient to induce cancer in the unexposed normal epithelial cells once the two tissues were recombined.

Conversely, placing epithelial cells isolated from a rat mammary cancer into a normal mammary stroma resulted in the formation of normal epithelial tissues. These experiments pointed to the reversibility of the cancer and suggested that the study of tissue interactions could lead not only to a better understanding of cancer, but also to its reversal.

Our theory fits better than the SMT with the fact that the vast majority of phenomena observed during embryonic development are seldom explained by research that focuses solely at the cell level. Both normal development and carcinogenesis take place at the tissue level of biological organisation.

The cell-centred view, on the other hand, is increasingly unable to fit emerging, conflicting data with its key premises; these difficulties are dealt with by ad hoc additions, or labelled as “mysterious steps”. As for directly validating the main theory of carcinogenesis - thereby finally vindicating the idea that the cell designated as the “founder” cell of a cancer is in fact its true originator - the difficulties are now technically insurmountable.

So we are left with an unfinished story. But while the impact of discoveries is unpredictable and depends on a raft of imponderables, simply identifying the paradox may still be considered the best predictor of scientific and technological breakthroughs.

BANKING that benefits everyone?

The UK Stem Cell Bank in South Mimms is about to receive a deposit fromPeter Braude’s team at King’s College London: human embryonic stem cells (hESCs) that are safe to use in medical applications. Best of all, researchers will be able to withdraw the cells for free.

The two new cell lines differ from all other known sources of hESCs because they have never been exposed to animal products, and so carry no risks of passing on animal diseases to patients.

“These are going in the bank for public benefit,” says Braude. His team has spent 10 years developing the “clinical grade” stem cells. “They’re in the public domain for national and international use.” Industry may have to pay for the cells, though.

“Something should go back into the public pocket,” Braude says.