Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
The “hallmarks of cancer” were described by Hanahan and Weinberg in 2000 and detail the features required for a tumor to progress to an invasive malignancy. The “next generation” hallmarks, published in 2011, include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming energy metabolism, and escaping immune destruction. Boss et al. framed the hallmarks with the historical context of radiation biology. Tumors need to overcome numerous natural barriers in order to survive. Understanding the molecular events underlying each of these features is key not only to cancer prevention but also to achieving cancer control. This chapter provides an overview of the fundamentals of cancer biology as well as emerging areas of understanding how this knowledge might be used to improve cancer therapy, with a focus on radiation biology.
Cancer development is a multistep process marked by accumulation of multiple genetic and molecular changes, resulting in dysregulation of a number of normal cellular and organism processes. A common initiating event in tumor formation is either a gain of function mutation or amplification of a proto-oncogene, or loss of function mutation or deletion of a tumor suppressor gene. Oncogene activation requires alteration of only one allele and often results in increased proliferation and/or prevention of cell death. Commonly affected genes include those in the myc family, ras family, and bcl-2 . Loss of tumor suppressor activity requires functional loss of both alleles. Examples of commonly altered tumor suppressors include p53 and Rb , which are both critical regulators of the DNA-damage response (DDR) and can direct cell fate following DNA-damaging chemotherapies and ionizing radiation (IR). p53 , the most common somatic tumor mutation, is considered a “gatekeeper” gene, as its function is important for maintaining the fidelity of the genome, and for inducing cell death in cases in which genome fidelity is threatened. Upstream inactivation of gatekeeper genes allows accumulation and propagation of additional genetic abnormalities, ultimately resulting in tumor formation. This concept of multistep carcinogenesis is perhaps best illustrated through the natural history of familial colon cancer. Early loss of DNA mismatch repair genes, including MSH2 or MLH1 , result in a “mutator phenotype” and persistent DNA mismatches. Additional mutations occur in the precancerous adenomas over the course of several years that allow the development of invasive cancer.
The Cancer Genome Atlas (TCGA), an expansive multiplatform effort to molecularly characterize 32 different types of cancer, has uncovered significant information not only about the genetic landscape and heterogeneity of human tumors but also the mRNA and protein expression profiles associated with different mutational backgrounds ( https://cancergenome.nih.gov/ ). In some cases, comprehensive clinical data is also available, allowing analysis of omics data in the context of therapies including radiation and disease and survival outcomes following treatment.
Alterations of proto-oncogenes through activating genetic mutations, translocation, or gene amplification can result in increased proliferation. Similarly, genetic loss of tumor suppressors that normally keep cellular proliferation in check contributes to abnormal progression through the cell cycle. Cellular proliferation is stimulated by soluble growth factors. Cancer cells overexpress growth factors or bypass the need for a ligand through activating mutations within the growth factor receptors or downstream factors. For example, BRAF mutations are common in melanoma and differentiated thyroid cancers and are thought to result in constitutive activation of the mitogen-activated protein (MAP)-kinase pathway. Mutations in the phosphoinositide 3-kinase (PI3-kinase) family of proteins are common in several cancer subtypes and result in downstream activation of Akt/protein kinase B (PKB). In cervical cancer, mutations along the PI3K/Akt pathway are associated with glucose avidity and cancer recurrence, suggesting that these growth-promoting genetic alterations can also affect tumor response to standard therapy.
Regulated cell death (RCD) is a process by which cells die in order to maintain physiological homeostasis and is governed in part by master regulator proteins, such as p53. Loss of proapoptotic factors and upregulation or increased activity of antiapoptotic factors, most commonly of the Bcl-2 family, allow tumor cells to evade these regulated cell death signals. Accumulated DNA damage in the setting of hyperproliferation is one known trigger of RCD in normal cells, but this process is dysregulated in many tumor cells, allowing propagation of cells with increasingly abnormal genomes. Tumor cell evasion of this response occurs through the loss of tumor suppressor p53, through either genetic mutation, or epigenetic silencing, which functions as a critical sensor of DNA damage. Dysregulation of autophagy in cancer is also common; however, this process can permit tumor cell survival or promote cell death.
With rapid proliferation and generally increased metabolic turnover, developing tumors can quickly outpace their blood supply. In order to avoid nutrient and oxygen deprivation and to allow elimination of toxic metabolic byproducts, tumors induce an “angiogenic switch,” inducing formation of neovasculature from quiescent mature blood vessels. A balance between proangiogenic factors such as vascular endothelial growth factor-A (VEGF-A) and members of the fibroblast growth factor (FGF) family and antiangiogenic factors, including thrombospondin-1 (TSP-1) and endostatin, is tipped in favor of angiogenesis in many expanding cancers and characteristic tumor neovasculature results. These new vessels are recognizably abnormal, with premature capillaries, convoluted vessel branching, and vessel leakiness. Several therapeutic strategies take advantage of the differences between tumor vasculature and normal blood vessels, including a monoclonal antibody against the receptor for VEGF, VEGFR, called bevacizumab, which is approved by the US Food and Drug Administration for a number of cancer indications. It has become increasingly clear, however, that simple inhibition of VEGF signaling is not sufficient to destroy a tumor's blood supply, and the concept of the angiogenic switch and the factors that regulate it is likely to be tumor type and individual specific.
Telomeres are an array of 6-nucleic acid sequence repeats (TTAGGG in humans) bound by the shelterin complex that prevent chromosomal ends from being recognized as damaged DNA. The shortening of telomeres with each cell division constitutes the main mechanism of somatic cellular aging. With respect to cancer development, terminal telomere shortening has two main and opposing consequences: (1) the tumor-suppressor effect of activation of the ATM/ATR kinase cascade and resultant halting of proliferation; and (2) the telomeric crisis, marked by extensive genome instability and cancer progression. This interplay is complex and incompletely understood but may partially explain the increased risk of cancer development associated with aging. Telomerase reverse transcriptase (TERT) can reverse the process of telomere shortening by adding GGTTAG repeats to the chromosomal 3′ DNA terminus. TERT is genetically silenced in most somatic cells during development, resulting in programmed telomere shortening and either senescence or apoptosis following activation of the DDR by the unprotected ends of chromosomes.
Available evidence suggests that, in some cancer cells, activation of the telomeric crisis results in reactivation of TERT, extending the proliferative capacity of cells with extensive mutations and chromosomal instability and malignant progression. Using markers of previous telomeric crisis as a determinant, TERT reactivation is thought to contribute to the development of chronic lymphocytic leukemia (CLL), breast cancer, colorectal adenomas, and other solid tumors. Mutations in the TERT promoter are the most commonly recognized mechanism of TERT activation in cancers. However, in many cases, the mechanism of activation is unclear. Despite reactivation of TERT in up to 90% of human cancers, there is evidence that telomeric dysfunction persists, and the resultant combination of perpetuated chromosomal instability and unrestrained proliferation supports the malignant phenotype.
The multistep process of invasion and metastasis is a series of required steps, known as the invasion-metastasis cascade. Cancer cells first locally invade the basement membrane, intravasate into nearby blood and lymphatic vessels, and transit through the lymphatic and circulation systems. Tumor cell survival in the circulation requires prosurvival signals from the extracellular matrix (ECM), hemodynamic sheer forces, and attacks by the immune system. Subsequent extravasation of these cells from the blood or lymphatic vessels into the tissues of distant organs involves adhesion to endothelial cells, disruption of and invasion through the endothelial barrier. This can occur with single cells in larger vessels or small groups of cells that have proliferated in end capillaries. Once in the tissue parenchyma, these cells must proliferate to form small micrometastases.
Disrupted cell polarity, loss of basement membrane integrity, and cell motility all contribute to this process. Decreased expression of cell surface adhesion molecules, such as E-cadherin, that mediate cell-to-cell and cell-to-ECM connections is found in many cancer types and is mediated by many of the same transcription factors that direct embryogenesis and wound healing, including Snail, Slug, Twist, and Zeb1/2. Transforming growth factor-β (TGFβ), a strong antiproliferative signal in normal cells, instead appears to participate in this process, termed the epithelial-to-mesenchymal transition (EMT) when present in transformed epithelial cells. In addition to loss of adherence to adjacent cells and the ECM, cells with activation of EMT take on a mesenchymal-like morphology; secrete enzymes, including matrix metalloproteases that break down the basement membrane; and display increased motility. While the relationship between tumor cells and the surrounding microenvironment is heterotypic, tumor-associated fibroblasts can promote this process of invasion.
Once in the metastatic niche, tumor cells adapt a number of mechanisms to make the often uninviting environment more welcoming. In one elegant study, Valiente and colleagues demonstrated that plasmin acts as a natural defense mechanism against establishment of brain metastases. They further demonstrated that lung tumor cell metastasis to the brain through the hematological vasculature, in turn, secretes plasminogen-activating inhibitor serpins, including neuroserpin and serpinB2, to counteract this effect and allow colonization of the brain. Similar instances of opposing forces offers some explanation of the predilection of certain tumor cell types for colonization of specific distant sites.
Most cancers have adapted the preference for glucose metabolism by glycolysis, even in the presence of oxygen, in at least a subset of tumor cells. First recognized in the early half of the 1900s by Otto Warburg, this process of aerobic glycolysis, or the “Warburg phenomenon,” is a cancer phenotype characterized by greater uptake and metabolism of glucose in cancer cells, resulting in lactic acidosis even in the presence of oxygen. Tumor cells compensate for the 18-fold lower yield of ATP derived from aerobic glycolysis mainly by increased surface expression of the GLUT1 glucose transporter. Fluorodeoxyglucose positron emission tomography (FDG-PET) scanning exploits the significant increase in glucose uptake, as 18 F-deoxyglucose is phosphorylated upon uptake into cells and accumulates in cancer cells, allowing detection by PET imaging.
The “metabolic switch” to a significantly less efficient glycolysis pathway may be a byproduct of oncogene activation in some cancers. Ras oncogene activation and hypoxia increase activity of HIF-1α and HIF-1β transcription factors, leading to enhancement of the glycolytic pathway. Nevertheless, with evidence of aerobic glycolysis in cancers even without these direct links, a physiological advantage seems certain. In the last several years, it has become increasingly clear that metabolic reprogramming in tumors is a dynamic and overall advantageous trait of main cancers. A revisited hypothesis that byproducts generated through glycolysis such as pyruvate can be redirected to enhance amino acids and other critical cellular components is increasingly supported by emerging evidence. In a comprehensive review, Pavlova and Thompson propose six metabolic hallmarks of cancer, stating that not all cancers display all six hallmarks, but most display many of these. Many features of altered metabolism in human cancers are a result of either mutation or altered expression of one or more of the various enzymes involved in cellular energy metabolism. An example of this is IDH1, which is mutated in many low-grade gliomas and overexpressed in glioblastoma. By altering lipid metabolism and redox stress, IDH1 promotes tumor cell growth and therapeutic resistance in vitro and in vivo and can be targeted molecularly with antitumor effect. In keeping with the recognized importance of the tumor microenvironment and host contributions, one of these hallmarks is metabolic interactions with the microenvironment. Although the mechanism is not yet understood, obesity, an increasing comorbidity among cancer patients particularly in the developed world, is thought to affect not only cancer risk but also response to primary therapies, including IR. The intimate relationship between energy utilization and redox balance could account for response to therapy.
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here