TUMOUR HETEROGENEITY

Tumour heterogeneity describes the observation:

that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation, and metastatic potential. This phenomenon occurs both between tumours (inter-tumour heterogeneity) and within tumours (intra-tumour heterogeneity). A minimal level of intra-tumour heterogeneity is a simple consequence of the imperfection of DNA replication: whenever a cell (normal or cancerous) divides, a few mutations are acquired —leading to a diverse population of cancer cells. The heterogeneity of cancer cells introduces significant challenges in designing effective treatment strategies. However, research into understanding and characterizing heterogeneity can allow for a better understanding of the causes and progression of disease. In turn, this has the potential to guide the creation of more refined treatment strategies that incorporate knowledge of heterogeneity to yield higher efficacy.

Tumour heterogeneity has been observed in leukaemias, breast, prostate, colon, brain, esophagus, head and neck, bladder and gynaecological carcinomas, lip sarcoma, and multiple myeloma.
There are two models used to explain the heterogeneity of tumour cells. These are the cancer stem cell model and the clonally evolution model. The models are not mutually exclusive, and it is believed that they both contribute to heterogeneity in varying amounts across different tumour types.

The cancer stem cell model asserts that within a population of tumour cells, there is only a small subset of cells that are tumourigenic (able to form tumours). These cells are termed cancer stem cells (CSCs), and are marked by the ability to both self-renew and differentiate into non-tumourigenic progeny. The CSC model posits that the heterogeneity observed between tumour cells is the result of differences in the stem cells from which they originated. Stem cell variability is often caused by epigenetic changes, but can also result from clonally evolution of the CSC population where advantageous genetic mutations can accumulate in CSCs and their progeny (see below).
Evidence of the cancer stem cell model has been demonstrated in multiple tumour types including leukaemias, glioblastoma, breast cancer, and prostate cancer.

However, the existence of CSCs is still under debate. One reason for this is that markers for CSCs have been difficult to reproduce across multiple tumours. Further, methods for determining tumourigenic potential utilize xenograft models. These methods suffer from inherent limitations such as the need to control immune response in the transplant animal, and the significant difference in environmental conditions from the primary tumour site to the xenograft site (e.g. absence of required exogenous molecules or cofactors). This has caused some doubt about the accuracy of CSC results and the conclusions about which cells have tumourigenic potential.


The clonally evolution model was first proposed in 1976 by Peter Newell. In this model, tumours arise from a single mutated cell, accumulating additional mutations as it progresses. These changes give rise to additional subpopulations, and each of these subpopulations has the ability to divide and mutate further. This heterogeneity may give rise to sub clones that possess an evolutionary advantage over the others within the tumour environment, and these sub clones may become dominant in the tumour over time. When proposed, this model allowed for the understanding of tumour growth, treatment failure, and tumour aggression that occurs during the natural process of tumour formation.
Evolution of the initial tumour cell may occur by two methods:
Linear expansion

Sequentially ordered mutations accumulate in driver genes, tumour suppressor genes, and DNA repair enzymes, resulting in clonally expansion of tumour cells. Linear expansion is less likely to reflect the endpoint of a malignant tumour because the accumulation of mutations is stochastic in heterogenic tumours.
Branched expansion
Expansion into multiple subclonal populations occurs through a splitting mechanism. This method is more associated with tumour heterogeneity than linear expansion. The acquisition of mutations is random as a result of increased genomic instability with each successive generation. The long-term mutational accumulation may provide a selective advantage during certain stages of tumour progression. The Tumour microenvironment may also contribute to tumour expansion, as it is capable of altering the selective pressures that the tumour cells are exposed to.
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).

Mutational tumour heterogeneity refers to variations in mutation frequency in different genes and samples and can be explored by Musing. The aetiology of mutational processes can considerably vary between tumour samples from the same or different cancer types and can be manifested in different context-dependent mutational profiles. It can be explored by COSMIC mutational signatures or Mutagen.

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 his tone H3K4 demethylase KDM5C arose in spatially separated tumour sections. Similarly, MTOR, a gene encoding a cell regulatory kinas, has shown to be constitutively active, thereby increasing S6 phosphorylation. This active phosphorylation may serve as a biomarker in clear-cell carcinoma.


Mechanochemical heterogeneity is a hallmark of living eukaryotic cells. It has an impact on epigenetic gene regulation. The heterogeneous dynamic mechanochemical processes regulate interrelationships within the group of cellular surfaces through adhesion. Tumour development and spreading is accompanied by change in heterogeneous chaotic dynamics of mechanochemical interaction process in the group cells, including cells within tumour, and is hierarchical for the host of cancer patients. It is suggested that the heterogeneity of hypoxia in solid tumours is due to the mechanochemical reactions with oxygen nanobubbles. The biological phenomena of mechanochemical heterogeneity maybe used for differential gastric cancer diagnostics against patients with inflammation of gastric mucosa and for increasing ant metastatic activity of dendrite cells based on vaccines when mechanically heterogenized micro particles of tumour cells are used for their loading.