9.5: Cancer cells evolve
( \newcommand{\kernel}{\mathrm{null}\,}\)
Cancer is not a static disease. Cells become cancerous by acquiring mutations that inactivate tumor suppressors and activate protooncogenes -- but then cancer cells continue to acquire mutations that change the phenotype of the cells. Those cells whose phenotype improves their fitness persist and give rise to daughter cells -- that is, cancer cells evolve. Not only is this important in the ongoing development of cancer, it also has important implications for cancer therapy.
Natural selection in cancer
There are three necessary and sufficient conditions for natural selection, all of which are met in a neoplasm:
- There must be variation in the population. Neoplasms are mosaics of different mutant cells with both genetic and epigenetic changes that distinguish them from normal cells.
- The variable traits must be heritable. When a cancer cell divides, both daughter cells inherit the genetic and epigenetic abnormalities of the parent cell, and may also acquire new genetic and epigenetic abnormalities in the process of cellular reproduction.
- That variation must affect survival or reproduction (fitness). While many of the genetic and epigenetic abnormalities in neoplasms are probably neutral evolution, many have been shown to increase the proliferation of the mutant cells, or decrease their rate of death (apoptosis).
Cells in neoplasms compete for resources, such as oxygen and glucose, as well as space. Thus, a cell that acquires a mutation that increases its fitness will generate more daughter cells than competitor cells that lack that mutation. In this way, a population of mutant cells, called a clone, can expand in the neoplasm. Clonal expansion is the signature of natural selection in cancer.
Tumor heterogeneity
One of the conditions for natural selection is variation in the population. In cancer, there is variation in the phenotypic and mophological profiles of the cells in a tumor -- differences in size and shape, gene expression, metabolism, motility, proliferation, and metastatic potential. This phenomenon occurs both between tumours (inter-tumour heterogeneity) and within tumours (intra-tumour heterogeneity). How does this heterogeneity arise? Multiple types of heterogeneity have been observed between tumour cells, stemming from both genetic and non-genetic variability.
Genetic heterogeneity
Genetic heterogeneity is a common feature of tumour genomes, and can arise from multiple sources. Some cancers are initiated when exogenous factors introduce mutations, such as ultraviolet radiation (skin cancers) and tobacco (lung cancer). A more common source is genomic instability, which often arises when key regulatory pathways are disrupted in the cells. Some examples include impaired DNA repair mechanisms which can lead to increased replication errors, and defects in the mitosis machinery that allow for large-scale gain or loss of entire chromosomes. Furthermore, it is possible for genetic variability to be further increased by some cancer therapies (e.g. treatment with temozolomide and other chemotherapy drugs).
Other heterogeneity
Tumour cells can also show heterogeneity between their expression profiles. This is often caused by underlying epigenetic changes. Variation in expression signatures have been detected in different regions of tumour samples within an individual. Researchers have shown that convergent mutations affecting H3K36 methyltransferase SETD2 and histone H3K4 demethylase KDM5C arose in spatially separated tumour sections. Similarly, MTOR, a gene encoding a cell regulatory kinase, has shown to be constitutively active, thereby increasing S6 phosphorylation. This active phosphorylation may serve as a biomarker in clear-cell carcinoma.
Tumour microenvironment
Heterogeneity between tumour cells can be further increased due to heterogeneity in the tumour microenvironment. Regional differences in the tumour (e.g. availability of oxygen) impose different selective pressures on tumour cells, leading to a wider spectrum of dominant subclones in different spatial regions of the tumour. The influence of microenvironment on clonal dominance is also a likely reason for the heterogeneity between primary and metastatic tumours seen in many patients, as well as the inter-tumour heterogeneity observed between patients with the same tumour type.
Implications: Treatment resistance
Heterogeneic tumours may exhibit different sensitivities to cytotoxic drugs among different clonal populations. This is attributed to clonal interactions that may inhibit or alter therapeutic efficacy, posing a challenge for successful therapies in heterogeneic tumours (and their heterogeneic metastases).
Drug administration in heterogeneic tumours will seldom kill all tumour cells. The initial heterogeneic tumour population may bottleneck, such that few drug resistant cells (if any) will survive. This allows resistant tumour populations to replicate and grow a new tumour through the branching evolution mechanism (see above). The resulting repopulated tumour is heterogeneic and resistant to the initial drug therapy used. The repopulated tumour may also return in a more aggressive manner.
The administration of cytotoxic drugs often results in initial tumour shrinkage. This represents the destruction of initial non-resistant subclonal populations within a heterogeneic tumour, leaving only resistant clones. These resistant clones now contain a selective advantage and can replicate to repopulate the tumour. Replication will likely occur through branching evolution, contributing to tumour heterogeneity. The repopulated tumour may appear to be more aggressive. This is attributed to the drug-resistant selective advantage of the tumour cells.
Sources:
