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
Oncogenesis encompasses a wide range of biological changes that result in a normal cell becoming cancerous. This process is often the result of a gene mutation, either in the form of an oncogene (a mutated gene that, instead of regulating normal cell division, drives tumour growth) or a mutated tumour suppressor gene (a gene that usually inhibits cell proliferation and tumour development).
Germline vs somatic mutations
Mutations come in many shapes and sizes, but the two main types are germline and somatic mutations. Germline mutations occur in sperm or egg cells and can therefore be inherited. Somatic mutations occur after conception and are the result of damage to genes in a single body cell. Though these mutations cannot be passed on to offspring, they are much more common than those found in the germline and are a major focus of research in cancer genomics, prevention, and treatment.
Many cancers are the result of the accumulation of thousands of such mutations in a single cell. Some somatic mutations are known as “driver mutations,” instructing cells to function as autonomous clones that can drive tumour growth. All other somatic mutations are known as “passenger mutations” and are acquired either before the first driver mutation arises, or after the transformation of a normal cell to a cancerous cell. They therefore do not contribute to cancer development but are carried along for the ride and will be present in all cells of the final cancer.
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.
Tumour progression and metastasis
The first step in the formation of a tumour is a genetic alteration that leads to abnormal proliferation. This propensity to proliferate leads to growth of clonally derived tumour cells, eventually forming a tumour. Further mutations occur within the growing population of tumour cells, conferring selective advantages.
Clonal selection – where the descendent of a cell bearing an advantageous mutation becomes dominant in the tumour population – can continue throughout tumour development, leading to an evolving and rapidly growing cancer with increased malignancy.
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.
Another unique feature of cancer cells is their ability to evade apoptosis. While normal cells will undergo programmed cell death at even the faintest whiff of DNA damage, tumours (or parts of tumour populations) can survive even the immense stress of chemotherapy or irradiation, creating a significant problem in terms of treatment resistance.
The tumour microenvironment
The tumour microenvironment (TME) consists of the extracellular matrix, surrounding blood vessels, immune cells, fibroblasts, and signalling molecules. Tumour cells can influence the TME by secreting extracellular paracrine signals into their environment, inducing peripheral immune tolerance and supporting angiogenesis.
In the initial stages of tumour development, cancerous cells in the TME are poor stimulators and are not strong targets for the immune system. This gives these cells time to become resistant to the body’s innate immune response, and eventually actively impair the adaptive immune response. In late-stage solid tumours, the TME has become highly heterogeneous, but the continued growth of the tumour triggers a cascade of changes to the TME that may further drive tumour growth and metastasis.
