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, 16, 17, 18, 19, 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).