Cancer is the second leading cause of death in the United States; only cardiovascular diseases exact a higher toll. Even more agonizing than the associated mortality is the emotional and physical suffering inflicted by neoplasms. Patients and the public often ask, “When will there be a cure for cancer?” The answer to this simple question is difficult, because cancer is not one disease but rather many disorders that share a profound growth dysregulation. Some cancers, such as Hodgkin lymphoma, are highly curable, whereas others, such as cancer of the pancreas, are virtually always fatal. The only hope for controlling cancer lies in learning more about its pathogenesis, and great strides have been made in understanding the molecular basis of cancer. This chapter deals with the basic biology of neoplasia—the nature of benign and malignant neoplasms and the molecular basis of neoplastic transformation. The host response to tumors and the clinical features of neoplasia also are discussed.
Before we discuss the features of cancer cells and the mechanisms of carcinogenesis, it is useful to summarize the fundamental and shared characteristics of cancers: • Cancer is a genetic disorder caused by DNA mutations. Most pathogenic mutations are either induced by exposure to mutagens or occur spontaneously as part of aging. In addition, cancers frequently show epigenetic changes, such as focal increases in DNA methylation and alterations in histone modifications, which may themselves stem from acquired mutations in genes that regulate such modifications. These genetic and epigenetic changes alter the expression or function of key genes that regulate fundamental cellular processes, such as growth, survival, and senescence.
Genetic alterations in cancer cells are heritable, being passed to daughter cells upon cell division. As a result, cells harboring these alterations are subject to Darwinian selection (survival of the fittest, arguably the most important scientific concept in biology). Cells bearing mutations that provide a growth or survival advantage outcompete their neighbors and thus come to dominate the population. At the time of tumor initiation, these selective advantages are conferred on a single cell, and as a result all tumors are clonal (i.e., the progeny of one cell). However, even beyond the point of initiation, Darwinian selection continues to shape the evolution of cancers by favoring the emergence of genetically distinct subclones with more aggressive characteristics, an important concept referred to as progression and discussed in more detail later in this chapter.
Mutations and epigenetic alterations impart to cancer cells a set of properties that are referred to collectively http://ebooksmedicine.net as cancer hallmarks. These properties produce the cellular phenotypes that dictate the natural history of cancers as well as their response to various therapies. The molecular underpinnings of each hallmark of cancer are discussed in later sections.
Basic research has elucidated many of the cellular and molecular abnormalities that give rise to cancer and govern its pernicious behavior. These insights are in turn leading to a revolution in the diagnosis and treatment of cancer, an emerging triumph of biomedical science.
Neoplasia literally means “new growth.” Neoplastic cells are said to be transformed because they continue to replicate, apparently oblivious to the regulatory influences that control normal cells. Neoplasms therefore enjoy a degree of autonomy and tend to increase in size regardless of their local environment. Their autonomy is by no means complete, however. All neoplasms depend on the host for their nutrition and blood supply. Neoplasms derived from hormone responsive tissues often also require endocrine support, and such dependencies sometimes can be exploited therapeutically.
In common medical usage, a neoplasm often is referred to as a tumor, and the study of tumors is called oncology (from oncos, “tumor,” and logos, “study of”). Among tumors, the division of neoplasms into benign and malignant categories is based on a judgment of a tumor’s potential clinical behavior.