Biology of Cancer by Weinberg

The science described in this book is the opus of a large, highly interactive research community stretching across the globe. Its members have moved forward our understanding of cancer immeasurably over the past generation. The colleagues listed below have helped the author in countless ways, large and small, by providing sound advice, referring me to critical scientific literature, analyzing complex and occasionally contentious scientific issues, and reviewing individual chapters and providing much-appreciated critiques. Their scientific expertise and their insights into pedagogical clarity have proven to be invaluable. Their help extends and complements the help of an equally large roster of colleagues who helped with the preparation of the first edition. These individuals are representatives of a community, whose members are, virtually without exception, ready and pleased to provide a helping hand to those who request it. I am most grateful to them. Not listed below are the many colleagues who generously provided high quality versions of their published images; they are acknowledged through the literature citations in the figure legends. I would like to thank the following for their suggestions in preparing this edition, as well as those who helped with the first edition. (Those who helped on this second edition are listed immediately, while those who helped with the first edition follow.) Compared with other areas of biological research, the science of molecular oncology is a recent arrival; its beginning can be traced with some precision to a milestone discovery in 1975. In that year, the laboratory of Harold Varmus and J. Michael Bishop in San Francisco, California demonstrated that normal cell genomes carry a gene—they called it a proto-oncogene—that has the potential, following alteration, to incite cancer. Before that time, we knew essentially nothing about the molecular mechanisms underlying cancer formation; since that time an abundance of information has accumulated that now reveals in outline and fine detail how normal cells become transformed into tumor cells, and how these neoplastic cells collaborate to form life-threatening tumors. The scientific literature on cancer pathogenesis has grown explosively and today encompasses millions of research publications. So much information would seem to be a pure blessing. After all, knowing more is always better than knowing less. In truth, it represents an embarrassment of riches. By now, we seem to know too much, making it difficult to conceptualize cancer research as a single coherent body of science rather than a patchwork quilt of discoveries that bear only a vague relationship with one another. This book is written in a far more positive frame of mind, which holds that this patchwork quilt is indeed a manifestation of a body of science that has some simple, underlying principles that unify these diverse discoveries. Cancer research is indeed a field with conceptual integrity, much like other areas of biomedical research and even sciences like physics and chemistry, and the bewildering diversity of the cancer research literature can indeed be understood through these underlying principles. Prior to the pioneering findings of 1975, we knew almost nothing about the molecular and cellular mechanisms that create tumors. There were some intriguing clues lying around: We knew that carcinogenic agents often, but not always, operate as mutagens; this suggested that mutant genes are involved in some fashion in programming the abnormal proliferation of cancer cells. We knew that the development of cancer is often a long, protracted process. And we knew that individual cancer cells extracted from tumors behave very differently than their counterparts in normal tissues. Now, almost four decades later, we understand how mutant genes govern the diverse traits of cancer cells and how the traits of these individual cells determine the behavior of tumors. Many of these advances can be traced to the stunning improvements in experimental tools. The techniques of genetic analysis, which were quite primitive at the beginning of this period, have advanced to the stage where we can sequence entire tumor cell genomes in several days. (This is in sharp contrast to the state of affairs in 1975, when the sequencing of oligonucleotides represented a formidable task!) Given the critical role of genotype in determining phenotype, we now understand, as least in outline, why cancer cells behave the way that they do. On the one hand, the molecular differences among individual cancers suggest hundreds of distinct types of human cancer. On the other, molecular and biochemical analyses reveal that this bewildering diversity really manifests a small number of underlying common biochemical traits and molecular processes. viii Amusingly, much of this unification was preordained by decisions made 600 million years ago. Once the laws and mechanisms of organismic development were established, they governed all that followed, including the behavior of both normal and neoplastic cells. Modern cancer researchers continue to benefit from this rigid adherence to the fundamental, evolutionarily conserved rules of life. As is evident repeatedly throughout this book, much of what we understand about cancer cells, and thus about the disease of cancer, has been learned by studying the cells of worms and fruit flies and frogs. These laws and principles are invoked repeatedly to explain the complex behaviors of human tumors. By providing context and perspective, they can be used to help us understand all types of human cancer. While these basic principles are now in clear view, critical details continue to elude us. This explains why modern cancer research is still in active ferment, and why new, fascinating discoveries are being reported every month. While they create new perspectives, they do not threaten the solidity of the enduring truths, which this book attempts to lay out. These principles were already apparent seven years ago when the first edition of this book appeared and, reassuringly, their credibility has not been undermined by all that has followed. In part, this book has been written as a recruiting pamphlet, as new generations of researchers are needed to move cancer research forward. They are so important because the lessons about cancer’s origins, laid out extensively in this book, have not yet been successfully applied to make major inroads into the prevention and cure of this disease. This represents the major frustration of contemporary cancer research: the lessons of disease causation have rarely been followed, as day follows night, by the development of definitive cures. And yes, there are still major questions that remain murky and poorly resolved. We still do not understand how cancer cells create the metastases that are responsible for 90% of cancer-associated mortality. We understand rather little of the role of the immune system in preventing cancer development. And while we know much about the individual signaling molecules operating inside individual human cells, we lack a clear understanding of how the complex signaling circuitry formed by these molecules makes the life-and-death decisions that determine the fate of individual cells within our body. Those decisions ultimately determine whether or not one of our cells begins the journey down the long road leading to cancerous proliferation and, finally, to a life-threatening tumor. Contemporary cancer research has enriched numerous other areas of modern biomedical research. Consequently, much of what you will learn from this book will be useful in understanding many aspects of immunology, neurobiology, developmental biology, and a dozen other biomedical research fields. Enjoy the ride! Robert A. Weinberg Cambridge, Massachusetts March 2013