Evolution and cancer

Evolution is the process by which living organisms change through time, and natural selection is the process which leads some organisms to thrive and others to die out. Evolutionary medicine tries to explain why traits leading to susceptibility to disease get maintained or even positively selected. Cancer, being a genetic disease, can be analysed as an example of evolution by natural selection. The observation that humans in developed societies have much higher rates of cancer can be analysed and explained by an evolutionary approach. At a cellular level, tumours are made up by a population of cells continuously growing and mutating while interacting with the microenvironment of the body. Thus, the mechanism of changes in individual tumours is the process of natural selection. Evolutionary biology is now increasingly used to better understand tumour growth and therefore to improve treatments.

Cancer biology through immunohistology

Immunohistology is the microscopic study of cells and tissues using specific antibodies that bind to individual molecules expressed by the cellular and non-cellular components of the tissues. This branch of science is an essential link in the analysis and interpretation of data from high throughput genomic and proteomic technologies. Its use, both in the research and in the clinical arenas, has led to an increased understanding of cancer biology. This knowledge has also resulted in improvements in diagnosis, the provision of prognostic and predictive information, and highlighted the use of appropriate treatments. Furthermore, immunohistochemistry is a critical component in the search for personalized treatments. The ongoing advances in the availability of specific validated antibodies, continued improvements in staining and image analysis, and the integration of different technologies will ensure that immunohistochemistry becomes an even more essential tool in the study of cancer biology.

Cancer-associated stroma

Tumorigenesis is a dynamic process. Research on cancer development and metastases focuses on the tumour ‘host’ interface, and in particular on the role of the stromal tissue. For a few decades now, it has been well established that the tumour-associated stroma affects cancer growth and progression. Fibroblasts of the stroma orchestrate the recruitment of immune cells to promote cancer growth. Moreover, the tumour stroma of each tumour is different in terms of quantity and of cellular composition. The tumour stroma has gained interest in the clinic with regard to patient prognosis and its potential to influence therapy response. Where cancer drug development traditionally focused on targeting the tumour cells, emphasis has now shifted towards the tumour microenvironment for the development of novel therapeutics.

Growth factors and associated signalling pathways in tumour progression and in cancer treatment

To gain increased proliferation, blood supply, invasiveness, and resistance to cytotoxic treatments, cancer cells continuously secrete polypeptide growth factors, or they utilize factors produced by the associated normal tissue and the immunological microenvironment. The growth factors relay biochemical messages by binding with receptor tyrosine kinases (RTKs) located at the cell surface. In response to activation and receptor auto-phosphorylation, RTKs mobilize diverse signalling pathways, which culminate in cytoplasmic and nuclear alterations, including activation of gene expression programmes. This chapter describes several well-characterized growth factors, highlights the cognate receptors and downstream signalling pathways, and exemplifies involvement of specific growth factors in maintenance of the hallmarks of cancer. An account of clinically approved drugs able to intercept growth factor signalling closes this chapter.

Proteomics and metabolomics applications in cancer biology

Methodologies for proteomics and metabolomics are providing an unprecedented wealth of insights into cancer molecular biology. Although different techniques for proteomics and metabolomics exist, molecular snapshots in cancer metabolism and alterations in the proteome are mainly possible due to advancements in state-of-the-art mass spectrometry technologies. In this chapter, we describe examples of how proteo-metabolomic approaches are contributing to our understanding of the molecular biology of cancer progression, signalling, survival mechanisms, angiogenesis, and metastasis. We also provide an overview of the translational information (including biomarkers) and clinically relevant insights that proteomics and metabolomics strategies may be able to deliver, despite limitations and technical challenges that still exist. A better understanding of cancer progression and an improvement of clinical outcomes will benefit from precision medicine initiatives, in which appropriate application of proteo-metabolomic methods are key for their success.

Molecular profiling in cancer research and personalized medicine

Recent efforts by worldwide consortia such as The Cancer Genome Atlas and the International Cancer Genome Consortium have greatly accelerated our knowledge of human cancer biology. Nowadays, complete sets of human tumours that have been characterized at the genomic, epigenomic, transcriptomic, or proteomic level are available to the research community. The generation of these data was made possible thanks to the application of high-throughput molecular profiling techniques such as microarrays and next-generation sequencing. The primary conclusion from current profiling experiments is that human cancer is a complex disease characterized by extreme molecular heterogeneity, both between and within the classical, tissue-defined cancer types. This molecular variety necessitates a paradigm shift in patient management, away from generalized therapy schemes and towards more personalized treatments. This chapter provides an overview of how molecular cancer profiling can assist in facilitating this transition. First, the state-of-the-art of molecular breast cancer profiling is reviewed to provide a general background. Then, the most pertinent high-throughput molecular profiling techniques along with various data mining techniques (i.e. unsupervised clustering, statistical learning) are discussed. Finally, the challenges and perspectives with respect to molecular cancer profiling, also from the perspective of personalized medicine, are summarized.

Cancer stem cells

The concept of cancer stem cells (CSCs) emerged from our understanding of the way in which normal tissues are generated from multipotent stem cells. Regenerative tissues exhibit a cellular hierarchy of differentiation, which is maintained by stem cells. Evidence from experimental models has indicated that a similar hierarchy is seen in at least some cancers, where CSCs give rise to disordered and dysfunctional tissues, leading to disease. The CSC model proposes that tumours can be divided into at least two distinct populations. The stem cells are a specialized population of cancer cells with the unique property of long-term self-renewal that maintain the growth of the cancerous clone. These stem cells give rise to the second population of cells, which form the bulk of the tumour, and lack indefinite self-renewal. Recently, our understanding of CSCs has been refined through combining genetic, epigenetic, and functional models of tumorigenesis. Malignant transformation occurs as the result of sequential acquisition of genetic mutations. Capacity for self-renewal is essential for a clone to survive and progress to become cancerous. If an oncogenic mutation occurs in a cell that is incapable of self-renewal, the clone will become exhausted through differentiation. CSCs may survive anticancer chemotherapy and increasing evidence indicates their role in mediating treatment resistance and relapse. Therefore, strategies to eradicate cancers must effectively target the stem cells that maintain their growth. CSC-directed therapeutic strategies are currently being explored in experimental studies and clinical trials but reducing toxicity to normal tissue stem cells represents a significant challenge.

Cancer metabolism

Abnormalities in cancer metabolism have been noted since Warburg first described the phenomenon of glycolysis in normoxic conditions. This chapter reviews the major pathways in metabolism known to be modified in cancer, including glycolysis and the Krebs cycle, the pentose shunt, and new data implicating the role of different metabolic adaptations, including oncometabolism. It highlights the genetic changes that effect metabolism including many of the commonly occurring oncogenes but also rare mutations that specifically target metabolism. Nutrient and oxygen limitation and proliferation create the microenvironmental selective stress for modifications in hypoxic metabolism, but also affect other cell types such as endothelial cells and macrophages. This range of changes provides many new therapeutic approaches. It also describes the potential value of targeting these adaptations and approaches to monitoring in vivo effects in patients to monitor therapeutic activity.

Telomerase and immortalization

The lifetime of a cell is set by the terminal ends of our chromosomes, ageing timers called telomeres. Most dividing cells, not exceptional for cancers, require telomeres to protect chromosomes. However, telomere erosion occurs at every cell cycle, thus imposing a proliferative capacity, eventually triggering a growth arrest. Cancer cells must overcome this proliferative limit in order to continue dividing. In the vast majority of cases, the growth and progression of cancers correlates with the upregulation of telomerase, an enzyme that replenishes telomeres. Telomerase is not active in normal, differentiated cells and its reactivation in cancer renders cells immortal and promotes their continued growth and development. Curiously, in cancer telomerase maintains short telomeres, retaining chromosome instability. Here, we briefly take you through history of cellular mortality with the connection to telomeres and telomerase and review their function in the normal cell to address their role during the transformation to malignancy.

Radiation as a carcinogen

The data from animals, cell lines, and humans have led to the consensus of induction of carcinogenesis by ionizing radiation, especially at low-level doses, and that there is a dose–response relationship between radiation and cancer incidence. However, additional factors, including radiation type, dose rate, specific tissues, and animal species, also provide a contribution. The development of molecular biology research has helped explain the mechanism of radiation carcinogenesis, including pathway activation and chromosome alterations. Bystander effects and abscopal effects are additionally characteristics of radiation carcinogenesis. This chapter takes a look at how radiation, from both environment and industry, has contributed to cancer incidence over the past century.