Cancer Cell Biology

Chapter 77 | Harrison's 22e

KEY CLINICAL POINTS

• See source text for full details

RAW CONTENT

[PAGE 528] 528 PART Oncology and Hematology obstacle. For example, when a tumor-suppressor gene is inactivated, those derived from hematopoietic tissue are leukemias, lymphomas, some downstream component of the pathway is likely to be activated, and plasma cell dyscrasias (including multiple myeloma). thereby presenting a realistic target. Alternatively, the mutational inac- Cancers arise as a consequence of genetic alterations, the vast tivation of a DNA repair pathway might create a unique dependence majority of which begin in a single cell and therefore are monoclonal on the repair pathways that remain intact. An example of this is pro- in origin. However, because a wide variety of genetic and epigenetic vided by PARP-1 inhibitors, which have been successfully used to treat changes can occur in different cells within malignant tumors over patients whose tumors have inactivating mutations of genes involved in time, as well as varied responses with their microenvironments and the DNA repair processes, such as BRCA1. Patterns of global gene expres- biology of the patient, most cancers are characterized by plasticity and sion can be used to help unravel such pathways and are already being marked heterogeneity in the populations of cells and their composite used to predict drug sensitivities and provide prognostic information behavior. In addition, extrinsic factors in the cancer environment (e.g., in addition to that provided by DNA sequence analysis. Evaluation of the stroma, infiltrating cells, various cell-to-cell interactions, spatial proteomic and metabolomic patterns may also prove useful for this orientation, secreted factors, and availability of oxygen and nutrients) purpose. vary in different areas within the tumor or different metastases, com- pounding this heterogeneity. This heterogeneity significantly compli- THE FUTURE cates the treatment of most cancers because it is likely that there are A revolution in cancer genetics has occurred in the past 30 years. Most subsets of cells that will be resistant to therapy for a variety of reasons types of cancer are now understood at the DNA sequence level, and and will therefore survive and proliferate even if the majority of cells this accomplishment has led to an increasingly refined understanding are killed. of tumorigenesis. Cancer gene mutations have proven to be reliable A few cancers appear to, at least initially, be primarily driven by an biomarkers for cancer detection and monitoring as well as for inform- alteration in a dominant gene that produces uncontrolled cell prolif- ing therapeutics through precision medicine approaches. Gene-based eration. Examples include chronic myeloid leukemia (abl), about half tests are already standard of care for patients with certain tumor types, of melanomas (braf), Burkitt’s lymphoma (c-myc), and subsets of lung such as colorectal and lung cancers, and the utility of these tests will adenocarcinomas (egfr, alk, ros1, met, ret, braf, and ntrk). Genes that undoubtedly be expanded in the coming years as new therapies and can promote cell growth when altered are often called oncogenes. They ways of predicting responses to therapies are developed. While effec- were first identified as critical elements of viruses that cause animal tive treatment of advanced cancers remains difficult, the early promise tumors; it was subsequently found that the viral genes had normal shown by immune-based therapies notwithstanding, it is expected that counterparts with important functions in the cell and had been cap- breakthroughs in these areas will continue to emerge and be applicable tured and mutated by viruses as they passed from host to host. to an ever-increasing number of cancers. Moreover, with the hoped-for However, most human cancers are characterized by a multiple-step advances in diagnostics, particularly in the earlier detection of cancers, process involving many genetic abnormalities, each of which contrib- the new and old therapies for cancer can be expected to have a much utes to the loss of control of cell proliferation and differentiation and greater impact on reducing cancer deaths. the acquisition of capabilities, such as tissue invasion, the ability to metastasize, angiogenesis (development of new blood vessels required Acknowledgments for tumor growth), and alteration of the extracellular environment. The authors gratefully acknowledge the past contributions of Pat J. These properties are not found in the normal adult cell from which Morin, Jeff Trent, and Francis Collins to earlier versions of this chapter. the tumor is derived. Indeed, normal cells have a large number of safeguards against DNA damage (including multiple DNA repair and FURTHER READING extensive DNA damage response mechanisms), uncontrolled prolif- Bunz F: Principles of Cancer Genetics, 3rd ed. Dordrecht, Springer, eration, and invasion. Many cancers go through recognizable steps of 2022. progressively more abnormal phenotypes: hyperplasia, to adenoma, to Le DT et al: PD-1 Blockade in tumors with mismatch-repair deficiency. dysplasia, to carcinoma in situ, to invasive cancer with the ability to N Engl J Med 372:2509, 2015. metastasize (Table 77-1). For most cancers, these changes occur over a Vogelstein B, Kinzler KW: The path to cancer—three strikes and prolonged period of time, usually many years. you’re out. N Engl J Med 373:1895, 2015. In most organs, only primitive undifferentiated cells are capable of Vogelstein B et al: Cancer genome landscapes. Science 339:1546, proliferating and cells lose the capacity to proliferate as they differenti- 2013. ate and acquire functional capabilities. The expansion of the primitive cells (stem cells) is linked to some functional need in the host, such as normal turnover of tissues or regeneration after acute injury, through receptors that receive signals from cells and other factors in the local tissue microenvironment or through hormonal and other influences delivered by the vascular supply. In the absence of such signals, the cells are at rest or quiescent (out of the cell cycle but capable of being activated to reenter the cell cycle). The signals that induce quiescence in primitive cells as well as those that keep the cells at rest are com- plex, including the process for quiescent entry, maintenance, and exit. 77 Cancer Cell Biology Although much has been learned, including the importance of notch signaling, the STING pathway, other quiescent factors, and transcrip- Jeffrey W. Clark, Dan L. Longo tional, posttranscriptional, and epigenetic regulation in quiescent entry and maintenance, overall control of the process within the body remains incompletely understood. These signals must be, at least in CANCER CELL BIOLOGY part, environmental, based on the observations that a regenerating liver Cancers are characterized by unregulated cell division, avoidance of stops growing when it has replaced the portion that has been surgically cell death, tissue invasion, and the ability to spread to other areas of the removed after partial hepatectomy and regenerating bone marrow body (metastasize). A neoplasm is benign when it grows in an unregu- stops growing when the peripheral blood counts return to normal. lated fashion without tissue invasion or metastasizing. The presence Cancer cells clearly have lost responsiveness to such controls and do of unregulated growth, tissue invasion, and the ability to metastasize not recognize when they have overgrown the niche normally occupied is characteristic of malignant neoplasms. Cancers are named based on by the organ from which they are derived. A better understanding of their tissue of origin: those derived from epithelial tissue are called car- these mechanisms of growth regulation in the context of organ homeo- cinomas, those derived from mesenchymal tissues are sarcomas, and stasis continues to evolve. [PAGE 529] Cancer Cell Biology 529 CHAPTER TABLE 77-1 Phenotypic Characteristics of Malign