Society of Cells : Cancer and Control of Cell Proliferation

For more than 30 years, the majority of researchers have assumed quiescence to be the default state of all cells and so have provided cells in culture with "growth factors" to allow them to proliferate. During this time, many putative growth factors have been identified and ever more complect mechanisms through which they could interact and stimulate cells have been proposed. However, quiescence as the default state does not make evolutionary sense and many sets of data do not support this hypothesis. In "The Society of Cells", an alternative explanation for these results is proposed by applying the premise that the default state must be proliferation, with division and multiplication being "built in" properties of life.

The authors begin by reviewing the concepts and theories that guide research ont he control of cell proliferation and cancer, and asking the question "what is the nature of the default state of all cells - quiescence or proliferation?" Later chapters concern cancer, where cell proliferate at above normal rates and the usual tissue organization is lost.

Despite decades of work and financial support to explore the somatic mutation theory, we appear no nearer to explainin what causes cancer. This requires researchers to take stock and consider new hypotheses and alternative approaches to the study of cell proliferation, and cancer in particular. "The Society of Cells" is intended to encourage such a re-evaluation.

The Society of Cells is a deceptively simple presentation of a profound hypothesis. This little book of only 154 pages should not be dismissed because of its seeming simplicity or because most of its points have not yet been proved; some of the points have indeed been demonstrated, and the argument is heuristically appealing. The viewpoint of the authors needs to be considered carefully by all biologists.

In part 1 of their book, Sonnenschein and Soto argue persuasively that healthy, well-nourished cells, unless constrained by inhibitory factors or signals, will undergo mitosis. According to their view, cells do not remain quiescent of their own accord. The argument originated in the observation that free-living cells will divide if they are given the opportunity. With the rise of multicellularity, this inherent predilection had to be controlled; hence, the default state of a cell is to divide. The failure of a cell to divide is evidence of an applied external constraint necessary for an ordered multicellularity.

Under this formulation, apparent growth factors do not, in actuality, stimulate cell division; rather, they block or inactivate one or more of the inhibitors that are postulated -- and in some cases demonstrated -- to be restricting the default tendency to divide. Data supporting this idea have been presented most convincingly in relation to the sex hormones and the supposed trophic activity of such hormones on target organs of the endocrine system. The authors even go so far as to suggest -- without evidence but consistently with their proposition -- that immune lymphoid cells are probably not stimulated by antigen but, rather, that antigen acts to neutralize an inhibitor of the proliferation of specific lymphoid cells. Thus, the hypothesis applies to all cells, with no exceptions.

Many, perhaps most, readers of this book will not accept easily the proposition that a predilection to divide is the default condition and that the failure to divide is necessarily evidence of external inhibitors. Would it not be expected that in multicellular animals, evolution would eventually provide intracellular controls over inappropriate division? Perhaps, but the hypothesis put forth by the authors is appealing and, in the opinion of an increasing number of investigators, could be correct.

Part 2 of the book applies the conclusions of part 1 to an examination of the nature of cancer. An almost universally held dogma is that somatic mutation is the cause of this malady of cellular proliferation. However, if cellular proliferation is the default state of all cells, a state that is constrained in multicellular animals by factors or conditions in the cellular environment, it follows that cancer is the result of a failure of these constraints rather than of mutations of oncogenes or tumor-suppressor genes. Put another way, cancer results from a breakdown of tissue organization that disrupts the normal inhibitions of proliferation that are inherent in the tissue architecture of a multicellular society of cells.

It is often thought naively that because cancer represents a heritable alteration at the cellular level, and because genes are the units of inheritance, cancer must be caused by untoward somatic mutations. Indeed, somatic mutations are often plentiful in cancer cells. However, the differences between liver cells and muscle cells are inherited at the cellular level, even though both have the same genome; different cell types are distinguished by the pattern of gene expression rather than by genomic differences. Thus, it is entirely possible that cancer is caused by differences in gene expression rather than by somatic mutations. This possibility has been put forth by others but is not even entertained by most investigators. Perhaps this book, with its clear exposition, will correct this situation.

Most questions and objections that readers may have are dealt with at length by the authors; they give plausible, if not always absolutely convincing, answers to any and all challenges. The book is written in a clear and logical manner that makes its arguments accessible to both the layperson and the professional. I hope it will be read with an open mind -- especially by those who are certain that cancer is caused by somatic mutations.

Reviewed by R.T. Prehn, M.D.
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