The Biology of Cancer (Second Edition)
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.
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
Chapter 1: The Biology and Genetics of Cells and Organisms 1
Chapter 2: The Nature of Cancer 31
Chapter 3: Tumor Viruses 71
Chapter 4: Cellular Oncogenes 103
Chapter 5: Growth Factors, Receptors, and Cancer 131
Chapter 6: Cytoplasmic Signaling Circuitry Programs Many of the Traits of
Chapter 7: Tumor Suppressor Genes 231
Chapter 8: pRb and Control of the Cell Cycle Clock 275
Chapter 9: p53 and Apoptosis: Master Guardian and Executioner 331
Chapter 10: Eternal Life: Cell Immortalization and Tumorigenesis 391
Chapter 11: Multi-Step Tumorigenesis 439
Chapter 12: Maintenance of Genomic Integrity and the Development of Cancer 511
Chapter 13: Dialogue Replaces Monologue: Heterotypic Interactions and the
Biology of Angiogenesis 577
Chapter 14: Moving Out: Invasion and Metastasis 641
Chapter 15: Crowd Control: Tumor Immunology and Immunotherapy 723
Chapter 16: The Rational Treatment of Cancer 797
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