Lea Harrington, Robert G. Bristow, Richard P. Hill, and Ian F. Tannock
1.1 Perspective and History
1.2 Recent Advances in Oncology References
1.3 The Future of Oncology and Cancer Treatment
References
1.1 PERSPECTIVE AND HISTORY
One of the first scientific investigations into the cause of cancer dates from 1775, when Sir Percival Pott carried out an epidemiological study and suggested that the causative agent of scrotal cancer in young chimney sweeps in the United Kingdom might be chimney soot (now known to be tar). Frequent washing and changing of clothing that trapped the soot was recommended so as to reduce exposure to the “carcinogen” (see Chap. 4). Not only did Pott’s study identify a putative carcinogenic agent but it also demonstrated that a cancer may develop years after exposure. One other dramatic example is mesothelioma, which is a rare lung cancer that develops decades after exposure to asbestos. A third epidemiological example is the identification of tobacco smoke as a major environmental cause of cancer. Doll and Hill (1950) showed that cigarette smoking is causative in lung cancer: heavy smokers older than the age of 50 years have a 1 in 2 chance of dying from a smoking-related disease such as lung cancer (see Chap. 3). On the positive side, individuals who quit smoking exhibit a gradual return to a near-normal risk of lung cancer after a 10-to 15-year smoke-free period. These and other studies underscore the possibility that, with some types of cancer, a degree of prevention may be achieved via changes in lifestyle.
Early advances in understanding of the biological properties of cancer followed the development of the microscope, which allowed Virchow, a 19th-century pathologist, to declare: “Every cell is born from another cell.” This property is true of both normal and cancer cells. Microscopic examination of tumors and normal tissues established many important properties, including the characteristics of the cell cycle; the hierarchical organization of cells within normal tissues and to a lesser extent in tumors; the requirement for angiogenesis for tumor growth; heterogeneity among tumor cell populations; and relationships between histopathological characteristics of tumors and their prognosis. Development of methods to culture cells, and establishment of colony forming assays to reflect reproductive survival allowed quantitative studies of the response of cancer cells to radiation and drugs, and allowed therapeutic response of tumors to be related to the sensitivity of individual cells within them. The establishment of inbred (syngeneic) mice allowed tumors to be transplanted between them, while subsequent development of immune-deprived mice allowed further study of some human tumors, and of cell lines derived from them, in an in vivo environment. Together with large-scale cell cultures that allowed screening of drugs in a semiautomated way, these tools were instrumental in allowing agents to be evaluated for antitumor effects and led to the development of some of the drugs used in cancer therapy.
The 1980s ushered in the modern era of molecular biology that led to the discovery of genes involved in cancer development. Notably, dysregulation of endogenous genes encoded in normal cells, called (proto)oncogenes, and/or loss of function of genes that provided checks on processes such as cell proliferation, called tumor-suppressor genes, were found to be associated with cancer induction and progression (see Chap. 7). These findings helped to explain earlier observations that viruses can cause cancer as they had evolved to carry oncogenes that mimic cellular gene function and subvert normal cellular processes to promote viral replication, such as the Rous sarcoma virus that was first discovered to be a causative factor in the development of tumors in chickens (v-src). Viruses are now known to be causative in the development of some common human cancers, including hepatitis viruses (B and C) as precursors of hepatocellular carcinoma, and human papilloma viruses (HPVs) as a causative agent for cervical and oropharyngeal cancer (see Chap. 6). The development of vaccines against HPVs (Future II Study Group, 2007) and of vaccination programs against hepatitis B virus (HBV) and hepatitis C virus (HCV) in regions where these viruses are endemic (Luo and Ruan, 2012) holds promise for marked reduction in the incidence of these cancers.
Other historically important contributions to the understanding of cancer include an appreciation that cancer is heritable. Studies of geographically or socially isolated populations, such as the Mormons in Utah, and of changes in cancer incidence in migrant families, demonstrated that both genetic predisposition and environmental factors are important in cancer causation. Analysis of cancer-prone families have assisted in the identification of genetic abnormalities that can lead directly to malignancy, such as mutation of tumor-suppressor genes, including the retinoblastoma gene (Rb) in children, the p53 gene in the Li-Fraumeni syndrome, and the BRCA1 and BRCA2 genes, which are associated with familial breast and ovarian cancer (see Chap. 7). Thus cancer has been established as a genetic disease.
1.2 RECENT ADVANCES IN ONCOLOGY
The underlying biology of cancer can perhaps be best conceptualized as a process of many small changes similar to evolution. Genetic changes that affect growth potential provide an environment permissive for further changes that are selected for (or against) by environmental conditions. Increasing knowledge of cellular signal-transduction pathways has revealed that many aspects of cellular function, including proliferation and death, are controlled by a balance of positive and negative signals received from inside and outside the cell (see Chaps. 8 and 9). Thus, a decreased or increased ability to respond to a specific signal may allow the cell to proliferate in the face of other signals that would normally prevent such proliferation. Interaction of cancer cells with their surrounding tissue (stroma) is also a key factor in cancer initiation, progression, and metastasis (see Chap. 10). For example, the development of the vascular networks in tumors (angiogenesis) is necessary for tumor growth, and the behavior of cancer cells is influenced by external signals from circulating molecules (hormones and growth factors) and from neighboring cells and the extracellular matrix (see Chap. 11). Furthermore, changes to the extracellular environment in tumors (such as poor oxygenation) can cause changes in gene expression that enhance the development of more aggressive tumor phenotypes (see Chap. 12). These investigations have led to a better understanding of how and why cancer cells can spread from the primary tumor to grow at other sites in the body; metastasis is the property of a malignant cancer, which makes it particularly difficult to treat successfully (see Chap. 10). Although cancers may originate from a single cell, they become heterogeneous in their cellular properties and cells within different regions of an established tumor may express different genes (Gerlinger et al, 2012). One aspect of heterogeneity may be retention of a limited number of cells with high proliferative potential that can regenerate the tumor after treatment, known as cancer stem cells (CSCs; see Chap. 13). Surface markers have been identified, which appear to characterize CSCs, but the stability of these markers, and of the CSC phenotype is uncertain and may be heterogeneous within and between tumors. The plasticity of cancer cells allows them to develop or select for resistance to therapeutic agents, and this property will likely pose a major challenge to treating tumors by targeting specific genetic pathways (see Chap. 19).
The past 10 years has yielded a watershed in our molecular understanding of the genetic basis of cancer (see Chap. 2). The use of genetically modified mice has enabled researchers to demonstrate that loss-of-function or gain-of-function in tumor-suppressor genes and oncogenes are important changes that occur during the development of cancers. Such animal models, for example those deficient in TP53 or harboring constitutively active cellular signaling factors (eg, the guanosine triphosphatase [GTPase] Ras), have provided key model systems in which to dissect the progression from normal cell growth to malignant transformation and metastasis. These studies have yielded a working model in which cancer acquisition and progression is believed to result from a series of successive mutations that destabilize the genome and permit unregulated cell growth, which, in turn, elicit further alterations in the surrounding tissue that permit growth and invasion (see Chap. 5). These genetic alterations may arise directly or indirectly from inherited gene mutations, chemical- or radiation-induced DNA damage and genetic instability, incorporation of certain viruses into the cell, or random errors during DNA synthesis (see Chaps. 3 and 15). The behavior of cancer cells is also determined by epigenetic modifications that influence the expression of genes, and which contribute to more transient changes in properties of cancer cells, including those that convey resistance to therapy (see Chap. 2).
Cancer treatment has evolved to employ a combination of traditional approaches, such as surgery, chemotherapy, and radiotherapy, increasingly in conjunction with each other and with drugs that target specific biological networks (see Chaps. 15–20). Some successful targeted biological therapies already in clinical use include the treatment of chronic myelogenous leukemia with a specific, competitive inhibitor (imatinib) of the binding site of the Bcr-Abl protein kinase, the protein that is aberrantly expressed as a result of the Philadelphia chromosome translocation. Another example is trastuzumab, a monoclonal antibody that recognizes the HER2/neu receptor expressed on the tumor cells of some patients with aggressive breast cancer; treatment with this agent has been shown to improve quality and duration of survival. A third example is vemurafenib, which improves survival by inhibiting the BRAF kinase in the approximately 50% of human melanomas that have a BRAF mutation. Although these therapies have improved outcome for patients, tumor cells can become resistant to them; for example, resistance to imatinib develops as a result of outgrowth of tumor cells bearing a drug-resistant mutation within Bcr-Abl, and resistance of metastatic disease to other targeted agents develops invariably after a few months of therapy. Thus, as with more traditional approaches, a combinatorial approach to cancer treatment is most likely to be successful, although combinations of targeted therapies have in some instances proven to be more toxic.
Traditional methods have also undergone substantial refinement and improvement. New methods for delivery of radiotherapy, such as image-guided and intensity-modulated radiotherapy and stereotactic body radiotherapy, have allowed higher doses to be delivered to the tumor with increased precision and at the same time, lower doses to normal tissue. These techniques have improved local control of primary tumors, such as those in the prostate and brain, and new combinations of radiation with surgery and chemotherapy are also improving patient survival. One instrument, called the Cyber-knife, is an example of stereotactic precision radiotherapy, which is already in use in cancer centers around the world, and is able to deliver a highly focused beam of irradiation (in 3 dimensions) to tumors in the brain. Development of these techniques has paralleled that of enhanced methods of imaging tumors in the body with high resolution including CT, MRI, and positron emission tomography (PET) (see Chap. 14).
1.3 THE FUTURE OF ONCOLOGY AND CANCER TREATMENT
The recent ability to sequence the DNA and RNA of cancer and normal tissue genomes has provided insights into the molecular signals that are associated with various types of cancers. Molecular profiling of key oncogenic factors has allowed many types of cancers to be subdivided into subcategories and is being validated for use in defining better treatments for subpopulations of patients to optimize survival (see Chaps. 2 and 22). For example, a breast tumor is now defined not just by “stage” (size of the primary tumor, and whether it has spread to lymph nodes) and grade (the extent to which it differs from normal breast tissue), but whether the tumor is estrogen-responsive (eg, estrogen receptor or ER-positive or ER-negative) and whether it expresses HER-2 (see Chap. 20). These data enable the clinician to recommend treatment with agents that inhibit stimulation of growth by estrogens (tamoxifen or aromatase inhibitors) and by agents such as trastuzumab (which targets the HER-2 receptor). More recently, larger scale genomic profiling with Oncotype DX or the “Amsterdam” 70-gene signature are aimed at defining patients whose outcome can be significantly improved by adjuvant chemotherapy, or those where it adds only toxicity and hormonal therapy should be instead used alone.
Another area where the last decade of research has shown considerable progress is immunotherapy (see Chap. 21). Research is leading to an understanding of how to promote an immune response against cancers as well as developing a detailed understanding of how the tumor microenvironment exerts a negative influence. Reagents have been developed that are directed against many molecules that have the potential to modulate immune responses and clinical trials have begun to demonstrate an impact in promoting patient survival. Novel immunotherapeutic approaches are starting to take their place in the cancer treatment armamentarium.
There is intense research in large cancer centers into “personalized medicine,” where the goal is to provide treatment of an individual’s cancer that will be tailored to the genetic profile of his or her cancer. The cost for sequencing an entire genome costs approximately $800 in 2012, and many genomes from tumor samples have been analyzed; however, the cancer genome is far more complex than many anticipated and still requires high costs for complex bioinformatic analysis in order to understand the results of such sequencing. For example, a recent study of the genomes of 100 breast cancer patients found that the genetic profiles of their cancers were extremely diverse and did not fit neatly into histopathological classifications (Stephens et al, 2012). Furthermore, the tumor microenvironment (eg, hypoxia) may further alter gene expression and tumor biology such that both microenvironmental and genetic heterogeneity may have to be addressed in providing a “true” state of an individual’s cancer genome (see Chaps. 10 and 12). Also, several studies have confirmed that genetic sequencing of single cells or from small regions of primary cancers shows substantial heterogeneity. This implies that there is ongoing mutation of cancer cells after tumor induction, and that multiple targeted agents would be necessary to eradicate all of the cells within a tumor. Anecdotal instances have been reported in which an individual’s tumor has been sequenced and the information used to obtain access to an early stage clinical drug. Although such patients may have a transient response, the inability to achieve a substantial extension in life span or quality of life may reflect the limitations of the early stage drug itself, or that we have much to learn about simplistically choosing a single therapy based on a cancer genotype.
A positive aspect arising from the sequencing of cancer genomes is the realization that each cancer may have an Achilles heel. In single-celled organisms, such as the budding yeast Saccharomyces cerevisiae, the concept of synthetic lethality is well established. This phenomenon is based on the observation that a mutation in a gene pathway “A,” although not lethal on its own, becomes incompatible with survival when combined with another nonlethal mutation in a separate gene pathway “B.” Because cancer genomes possess many mutations that differentiate them from surrounding normal tissue, it should be possible to exploit this unique complexity of the cancer cell. As one example, researchers discovered that mutations in BRCA1 and BRCA2 predispose cancer cells to cell death upon inhibition of members of the polyadenosine diphosphate (ADP) ribosyl polymerase (PARP) gene family (Farmer et al, 2005; see Chaps. 5 and 17). Treatment with PARP inhibitors elicits cell death with exquisite specificity in BRCA-deficient tumor cells, and several highly potent PARP inhibitors are now in clinical trial for BRCA-mutated ovarian cancers.
The notion of personalized medicine also raises several social and ethical questions. Should insurance companies have access (or be able to request) a person’s genomic data? Will all people, regardless of socioeconomic status, have access to personalized medicine? Will people whose normal cells show a genetic predisposition to a particular cancer be subjected to prophylactic treatments, and is this option financially feasible? These are but a few of the many challenges that face our society in addition to the scientific challenges that remain to disentangle the tremendous complexity of cancer. In the face of this genetic complexity, it has become all the more important to pursue research into the fundamental principles of how cancer gene networks interact with one another and how they affect cell growth, signaling, and response to the environment. The goal of the chapters which follow is to provide a succinct but comprehensive summary of the basic science underlying oncology.
REFERENCES
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