Original post by Liam Little in February 2023. Updated by Ashleigh Davey in September 2023.
Cancer is a disease of the genome. Environmental factors can certainly influence the growth and spread of cancer, but the changes that first lead to this devastating disease originate inside the cell. Once believed to be a single disease, we now know that cancer is in fact a group of related diseases characterised by cells dividing uncontrollably and spreading into surrounding tissues.
Oncogenesis
The transformation of healthy cells into cancerous cells (otherwise known as oncogenesis) is a complex, multi-step process. This process begins with deleterious changes within a cell’s genome, which can have environmental, chemical or even viral origins. The development of next generation sequencing technologies in recent years has shed light on these cancer-causing genetic changes, which are largely split into three groups – mutations, gene amplifications and chromosomal rearrangements.
By altering the expression or structure of critical genes, these changes promote the excessive growth of cancer cells, eventually allowing them to spread and infiltrate other tissues.
Driver mutations
Point mutations within genes are some of the most studied genetic abnormalities in oncological research. Defined as simple base pair changes (including insertions, deletions and substitutions), point mutations in essential genes are a major contributor to oncogenesis. For example, it is estimated that 15-20% of human tumours may contain point mutations in the Ras family of oncogenes (a group of GTPase switches which control cell proliferation).
Several hundred critical genes have now been identified which, when mutated, play a direct role in cancer development. Termed “driver genes”, most are typically associated with regulation of cell growth, with mutations in cell cycle regulators and tumour suppressor genes being frequently observed. It is estimated that 1 – 10 driver mutations are required for oncogenesis, although this number has been shown to vary depending on cancer type.
In contrast, somatic mutations caused by the increased genetic instability of cancer cells, or mutations present in cells before oncogenesis, are known as “passenger mutations”. These do not play a direct role in tumour formation or cancer development.
What causes driver mutations?
Genome changes are a natural consequence of DNA replication errors during cellular division. However, external factors (such as exposure to carcinogens or certain bacterial and viral species) can also cause DNA damage, which over time may result in the accumulation of driver mutations.
Additionally, some mutations present within reproductive cells can be inherited. Although germline mutations are less commonly linked to cancer development, several cancers are known to have a significant familial component. Notable examples are breast and ovarian cancers, where certain pathogenic mutations in the BRCA1 and BRCA2 genes may substantially increase the risk of a woman developing cancer by 70 – 80 years of age.
The hallmarks of cancer
Driver mutations typically affect the protein sequence arising from a gene – often with functional consequences. Defects in essential proteins result in cancer cells developing several key features that assist in their survival and immune system evasion. Collectively known as the “Hallmarks of Cancer”, these qualities were first documented in 2000 and have subsequently been expanded upon as next generation sequencing revolutionised our understanding of cancer genomics (see Figure 1).
Figure 1: The 14 hallmarks of cancer. Sourced from Hanahan D, 2022.
Several of these malignant traits involve critical genomic modifications that allow cancerous cells to remain in the cell cycle pathway. Due to the error-prone nature of DNA replication, the cell cycle contains essential checkpoints which evaluate the genomic integrity of the cell and prevent genetic errors from being copied into the next generation of cells. Should a defective cell be recognised, the checkpoints can trigger a variety of signalling pathways which prevent progression through the cell cycle.
Normally, excessive DNA damage triggers repair pathways or an induced cell death mechanism – apoptosis – to either fix or destroy abnormal cells. Cancerous cells employ a variety of methods to avoid this fate. This includes developing mutations which enable sustained proliferative signalling, replicative immortality, and resistance to cell death mechanisms.
Tumour Development
Following the initial genetic changes that trigger oncogenesis, the subsequent uncontrolled growth of cancerous cells results in the development of a tumour in the primary site. Defined as any mass formed from the abnormal proliferation of cells, tumours may be either benign or malignant, depending upon their ability of invade surrounding tissue or spread to secondary sites within the body. Notably, only malignant tumours are considered cancerous.
The development of tumours is a long, complex process which can take many years after the initial driver mutations occur. It is estimated that human tumours are only detectable once they number 10 – 100 billion cells, with researchers discovering that this process can take 10 years in breast and bowel cancers.
Understanding the age of a tumour by analysing the number of mutations within its genome (occasionally referred to as cancer’s “molecular clock”) is now considered a key step in cancer evolution research and early diagnosis.
Tumour classification
Tumours are abnormal masses of tissue formed by the unregulated proliferation of cells. They can be found as two distinct types: benign (not cancer) and malignant (cancer). Malignant tumours are capable of invading surrounding tissues and spreading to distal parts of the body to grow – otherwise known as metastasis.
Tumours are classified depending on the cell type from which they arise. The five main categories are carcinoma, sarcoma, leukaemia, lymphoma and myeloma (classified together), and central nervous system cancers.
Approximately 90% of human cancers fall under the carcinoma category, consisting of malignancies that arise in epithelial cells. Tumours can also be further classified depending on their tissue or organ of origin, for example erythroid leukaemias arise from precursors of erythrocytes.
The tumour microenvironment
In addition to the advantageous mutations that allow cancer cells to multiply, tumours also rely on the environment surrounding them for their continued survival. The tumour microenvironment (TME) is composed a diverse range of cell types – including tumour cells, immune cells, and endothelial cells – which are held together by components of the extracellular matrix. Tumour cells communicate with the TME using signalling molecules (such as cytokines and growth factors) to manipulate the activity of non-tumour cells in their favour.
The TME is now known to be a critical factor in tumour progression and cancer pathogenesis. At the early tumour initiation stage, cancer cells are detected by the innate immune system, which infiltrate the primary tumour site. However, as tumour growth progresses, cancer cells modulate the activity of surrounding immune cells (such as macrophages and fibroblasts) to evade immune detection and promote tumour progression.
Once the tumour is fully established, the TME also plays a role in the invasion and spread of cancerous cells into the bloodstream and secondary tissues. Advances in single cell sequencing and spatial transcriptomics have dramatically contributed to our understanding of TME composition, opening up doors to new therapeutic targets that may drastically alter the way we detect and treat cancer.
Tumour progression and metastasis
Normal cells will migrate through the body until they contact another cell, get stuck, and create a uniform array of cells. On the other hand, tumour cells exhibit a reduced expression of cell surface adhesion molecules, meaning that when they contact other cells, they don’t get stuck. Instead, tumour cells continue to migrate over and around other cells, and (in culture) will grow in a disorderly and often multi-layered pattern. This lack of adhesion molecules plays an important role in the proliferation, invasion, and metastasis of cancer.
Malignant cells are capable of secreting proteases to digest the extracellular matrix of surrounding cells, allowing a tumour to take their place. They can also secrete growth factors to promote angiogenesis and stimulate the proliferation of endothelial cells into the walls of capillaries in the surrounding tissues. This in turn aids new capillary growth into the tumour and enables it to enter the bloodstream, spread, and metastasise.
The spread of cancerous cells to a secondary site within the body (metastasis) is the primary cause of death for over 90% of cancer patients. Despite the importance of metastasis on patient prognosis, there are still many unanswered questions as to what drives cancer cell migration and how it can be prevented.
