Cell biologists have recently come to understand that asymmetry of division is an important regulatory phenomenon in the fate of a cell. In adult organisms asymmetric divisions regulate the stem cell reservoir and are a source of the drift that contributes to aging. This book describes the phenomenon in different organisms and addresses its implications for the development of the organism, cell differentiation, human aging and the biology of cancers.

The problem of the long-term proliferation of cells is a seminal one. It has always been a hot subject in biology, a source of far-reaching hypotheses, even more so now when explanations for the mechanisms of cell prolifera tive mortality or immortality seem within our reach. A question which is still debated is whether an infinite division potential can be a normal trait or is always the result of modifications leading to abnormal cell growth and escape from homeostasis. In general, investigators have been advocates of one of the two extremes, universal limited or unlim ited normal proliferative potential. Since the long-term proliferative potential of cells concerns regulation of development, regeneration of tissues, and homeostatic control of cell growth, in brief survival of living organisms, and since the regulation of these processes is so different along the evolutionary scale, it is not surpris ing that there does not seem to be any universal trait. The question of whether cells are endowed with finite or infinite prolifera tive phenotypes has to be seen using the perspective of comparative biology."

In this book, tumour growth is perceived as a deviation from the normal development of the human organism. The molecular, cellular, and tissue determinants of different tumours are discussed showing that each is a different disease, often corresponding to a particular developmental stage. The natural history of several cancers illustrates how clinical incidence can be just the visible part of the iceberg, while the first changes at the tissue level sometimes occur several years before tumour growth becomes manifest. Several mechanisms are proposed to explain the distribution of cancers during the human life span and the decline of the incidence of cancers during human senescence.

This volume gives the reader a comprehensive overview of the fundamental and biological aspects of aging. First, the field is described from a historical perspective. Then, the author analyzes the three fundamental mechanisms of survival: energy utilization, molecular and cellular redundancy, and the organization of information. The genetics of aging is reviewed rejecting some simple-minded interpretations. A bridge is established between the molecular, cellular, and tissue modifications that have been reported in the literature, and the clinical manifestations of the aging syndrome. Special relevance is given to the problem of the supposed association between cancers and aging, giving a new interpretation of that relationship.

The survival of the human species has improved significantly in modern times. During the last century, the mean survival of human populations in developed countries has increased more than during the preceding 5000 years. This improvement in survival was accompanied by an increase in the number of active years. In other words, the increase in mean life span was accompanied by an increase in health span. This is now accentuated by progress in medicine reducing the impact of physiologic events such as menopause and of patho logical processes such as atherosclerosis. Up to now, research on aging, whether theoretical or experimental, has not contributed to improvement in human survival. Actually, there is a striking contrast between these significant modifications in survival and the present knowledge of the mechanisms of human aging. Revealed by this state of affairs are the profound disagreements between gerontologists in regard to the way oflooking at the aging process. The definition of aging itself is difficult to begin with because of the variability of how it occurs in different organisms."

The containment of cell growth is at the core of the homeostatic regulation of metazoans, and considerable progress has been made in the understanding of how this is achieved. Most knowledge comes from the isolation of molecu les with positive and negative regulatory effects on cell proliferation, and most emphasis so far has been on these molecules. Some of these molecules are already available for therapeutic purposes, and others look promising in this respect. This volume gives examples of such approaches. The understanding of the control of cell growth is also fundamental to grasp phylogenic and ontogenic development. Why organisms have developed increasingly sophisticated mechanisms that control their size and that of their organs, how different cells originate, some destined for renewal and repair, others for specialized functions in a postmitotic state or evolving through division, others like the germinal cells waiting for the signal to start another organism. There is one mechanism of growth containment, however, about which we know very little. It concerns the structural characteristics of the cell, i.e. the relationship between structure and function. How structure can change the response to identical signals. The positive and negative growth regulators may be conserved, but the structure and organization of the genetic material and of other cell components differ widely and are responsible to a great extent for the differences in cell proliferative behaviour."

The genetic information contained in a cell needs the appropriate environment to express itself, not only the intracellular environment but also the extracel- lular one. The latter is provided to a great extent by the molecules which constitute the extracellular matrix. On the one hand, the matrix creates inter alia the right pH and osmotic envi- ronment and allows the diffusion of messengers targeting the cell membrane; on the other hand, it has a mechanical effect whose relevance began to be understood 28 years ago. Basically, the messages that reach the cell and are then transported to the genome depend on molecular conformational flexibility. Molecular structures usually prevail because they represent states of minimum potential energy cre- ating energy barriers which are activated through conformational changes. From the periphery to the nucleus the information flows through the activa- tion of energy barriers. The tools used to switch from low-energy to high- energy molecular configurations are: the binding of ligands to their receptors, gradients of electrochemical potential created by ion pumps, Ca2+ mobiliza- tion, and phosphorylation and dephosphorylation. Variation in molecular con- figuration through molecular binding is in itself sufficient to trigger ion pumps and activate kinases and phosphatases. This is one aspect of the mechanical role of the extracellular matrix dealt with herein: the induction of molecular and supramolecular conformational modifications through interactions with the cell membrane, which promote the transduction and centripetal progression of signals.

The problem of the long-term proliferation of cells is a seminal one. It has always been a hot subject in biology, a source of far-reaching hypotheses, even more so now when explanations for the mechanisms of cell prolifera tive mortality or immortality seem within our reach. A question which is still debated is whether an infinite division potential can be a normal trait or is always the result of modifications leading to abnormal cell growth and escape from homeostasis. In general, investigators have been advocates of one of the two extremes, universal limited or unlim ited normal proliferative potential. Since the long-term proliferative potential of cells concerns regulation of development, regeneration of tissues, and homeostatic control of cell growth, in brief survival of living organisms, and since the regulation of these processes is so different along the evolutionary scale, it is not surpris ing that there does not seem to be any universal trait. The question of whether cells are endowed with finite or infinite prolifera tive phenotypes has to be seen using the perspective of comparative biology."

Cell biologists have recently come to understand that asymmetry of division is an important regulatory phenomenon in the fate of a cell. In adult organisms asymmetric divisions regulate the stem cell reservoir and are a source of the drift that contributes to aging. This book describes the phenomenon in different organisms and addresses its implications for the development of the organism, cell differentiation, human aging and the biology of cancers.