TUMOUR HETEROGENEITY AND RESISTANCE TO CANCER THERAPIES
REVIEW ARTICLE
The process of conversion from a non-malignant to a malignant cell is now understood to occur largely
through the sequential acquisition of alterations that lead to enhanced cellular proliferation, evasion of
growth suppression and cell death signals, induction of angiogenesis, and, ultimately, activation of
programmes leading to tissue invasion and metastasis.
Even after malignant transformation, a cancer remains dynamic and continues to evolve.
The ongoing evolution might ultimately generate a molecularly heterogenous bulk tumour consisting
of cancer cells harbouring distinct molecular signatures with differential levels of sensitivity to
anticancer therapies.
This heterogeneity can result from genetic, transcriptomic, epigenetic, and/or phenotypic changes.
Tumour Heterogeneity
Can be divided into intertumoral and intratumoural heterogeneity.
Inertumoural Heterogeneity refers to heterogeneity between patients harbouring tumours of the
same histological type. Has king been recognized and is believed to result from patient -specific
factors including germline genetic variations, differences in
somatic mutation profile, and environmental factors.
Intratumoural Heterogeneity the heterogeneity among
the tumour cells of a single patient. It can manifest as spatial
heterogeneity, which describes the uneven distribution of
genetically diverse tumour subpopulations across different
disease sites or within a single disease site or tumour, and as
temporal heterogeneity, a term applied to the dynamic
variations in the genetic diversity of an individual tumour
over time.
Example for Genotype-Guided Approaches
- Non-small-cell lung cancer (NSCLC), have fuelled a shift in the treatment paradigm towards the use of
personalized, or genotype-guided approaches.
- This strategy is most successful for the treatment of cancers that are dependent on key genetic
alterations, which are often referred to as ‘oncogenic drivers’, as such vulnerabilities can be
therapeutically exploited using molecularly targeted agents.
Key Points:
* Genomic instability fosters genetic diversity by providing the raw material for the generation of
tumour heterogeneity.
* Tumours with high levels of intratumorual heterogeneity might predispose patients to inferior clinical
outcomes.
* Under therapeutic selective pressure, resistance to treatment can emerge as a result of the expansion of
pre-existing subclonal populations or from the evolution of drug-tolerant cells.
* Serial characterization of genetic variants in plasma samples has the potential provide information on
spatial and temporal heterogeneity on a scale that can’t easily be achieved through analyses of tumour
biopsy samples alone.
* Multiregional sampling, research autopsies, and single-cell sequencing are all emerging informative
platforms that have the potential to enable decoding of complex clonal relationship at a high level of
resolution.
* Combinatorial approaches that pair therapies targeting the predominant drug-sensitive population of
clones in addition to the various subsets of drug-resistant and drug-tolerant cells seem likely to induce
the most-durable responses.
, Causes of Intratumoural Heterogeneity
1. Genomic Instability
- Might result from exposure to exogenous mutagens (UV radiation or tobacco smoke) and
aberrations in endogenous processes (DNA replication and/or repair errors, or oxidative stress).
- Studies involving large-scale genome sequencing have enabled the identification of characteristic
genetic signatures associated with some of these mutagenic processes.
- Although not contributing to baseline genomic instability, exposure to chemotherapy might also
increase the mutational spectrum of a tumour and create genomic instability.
- Cancers often co-opt endogenous homeostatic processes in order to increase the overall mutational
burden.
- APOBEC mutagenesis (presence of C>T and C>G mutations at TpC sites) can lead to mutations in
genes involved in treatment resistance; therefore, successful inhibition of these enzymes might
reduce genetic instability and thus improve patient outcomes.
- In some tumours, including brain tumours, genomic instability results from chromosome-level
changes that lead to gain or losses of whole-genome segments, rather than point mutations. This
process, termed chromosomal instability, arises from segregation errors that occur during cell
division, which might promote genetic diversity by upsetting the balance between activation of
oncogenes and tumour suppressors.
2. Clonal Evolution/Selection Hypothesis
- In addition to a larger role in creating copy-number imbalances, dynamic chromosomal instability can
lead to the non-uniform loss of chromosomal segments harbouring specific genetic alterations and can
indirectly contribute to mutational heterogeneity across different tumour regions.
- Increased levels of genomic instability promote the emergence of more-competitive subclones.
- Excessive levels of genomic instability can, adverse effects on cancer cell survival and fitness.
- Genomic instability might co-operate with other factors to promote the development of tumour
heterogeneity and tumour progression (Clonal Evolution and/or Selection Framework model):
* This model based on the hypothesis that tumour initiation occurs in stochastic
manner, beginning with an induced change in a previous non-malignant cell that
congers a selective growth advantage and leads to neoplastic proliferation.
* Linear evolution describes evolution owing to the successive acquisition of
mutations that confer a growth and/or survival advantage mutations
outcompeting ancestral clones.
* Branched evolution enables a greater level of opportunity to create a more
heterogenous tumour.
SPATIAL HETEROGENEITY
The molecular makeup of cancer cells that predominate at different sites can be distinct, owing to the
variable influences of micro-environment-related factors and site-specific stressors.
Owing to selective pressures that lead to further genetic evolution heterogeneity might exist even
among the cells present within the parent tumour.
The uneven distribution of genetically diverse tumour subpopulations across different sites, and
sometimes within a tumour in a single anatomical location, is termed special heterogeneity.
Heterogeneity at a Single Disease Site
Primary tumours can contain multiple geographically separated, molecularly distinct cellular
subpopulations.
REVIEW ARTICLE
The process of conversion from a non-malignant to a malignant cell is now understood to occur largely
through the sequential acquisition of alterations that lead to enhanced cellular proliferation, evasion of
growth suppression and cell death signals, induction of angiogenesis, and, ultimately, activation of
programmes leading to tissue invasion and metastasis.
Even after malignant transformation, a cancer remains dynamic and continues to evolve.
The ongoing evolution might ultimately generate a molecularly heterogenous bulk tumour consisting
of cancer cells harbouring distinct molecular signatures with differential levels of sensitivity to
anticancer therapies.
This heterogeneity can result from genetic, transcriptomic, epigenetic, and/or phenotypic changes.
Tumour Heterogeneity
Can be divided into intertumoral and intratumoural heterogeneity.
Inertumoural Heterogeneity refers to heterogeneity between patients harbouring tumours of the
same histological type. Has king been recognized and is believed to result from patient -specific
factors including germline genetic variations, differences in
somatic mutation profile, and environmental factors.
Intratumoural Heterogeneity the heterogeneity among
the tumour cells of a single patient. It can manifest as spatial
heterogeneity, which describes the uneven distribution of
genetically diverse tumour subpopulations across different
disease sites or within a single disease site or tumour, and as
temporal heterogeneity, a term applied to the dynamic
variations in the genetic diversity of an individual tumour
over time.
Example for Genotype-Guided Approaches
- Non-small-cell lung cancer (NSCLC), have fuelled a shift in the treatment paradigm towards the use of
personalized, or genotype-guided approaches.
- This strategy is most successful for the treatment of cancers that are dependent on key genetic
alterations, which are often referred to as ‘oncogenic drivers’, as such vulnerabilities can be
therapeutically exploited using molecularly targeted agents.
Key Points:
* Genomic instability fosters genetic diversity by providing the raw material for the generation of
tumour heterogeneity.
* Tumours with high levels of intratumorual heterogeneity might predispose patients to inferior clinical
outcomes.
* Under therapeutic selective pressure, resistance to treatment can emerge as a result of the expansion of
pre-existing subclonal populations or from the evolution of drug-tolerant cells.
* Serial characterization of genetic variants in plasma samples has the potential provide information on
spatial and temporal heterogeneity on a scale that can’t easily be achieved through analyses of tumour
biopsy samples alone.
* Multiregional sampling, research autopsies, and single-cell sequencing are all emerging informative
platforms that have the potential to enable decoding of complex clonal relationship at a high level of
resolution.
* Combinatorial approaches that pair therapies targeting the predominant drug-sensitive population of
clones in addition to the various subsets of drug-resistant and drug-tolerant cells seem likely to induce
the most-durable responses.
, Causes of Intratumoural Heterogeneity
1. Genomic Instability
- Might result from exposure to exogenous mutagens (UV radiation or tobacco smoke) and
aberrations in endogenous processes (DNA replication and/or repair errors, or oxidative stress).
- Studies involving large-scale genome sequencing have enabled the identification of characteristic
genetic signatures associated with some of these mutagenic processes.
- Although not contributing to baseline genomic instability, exposure to chemotherapy might also
increase the mutational spectrum of a tumour and create genomic instability.
- Cancers often co-opt endogenous homeostatic processes in order to increase the overall mutational
burden.
- APOBEC mutagenesis (presence of C>T and C>G mutations at TpC sites) can lead to mutations in
genes involved in treatment resistance; therefore, successful inhibition of these enzymes might
reduce genetic instability and thus improve patient outcomes.
- In some tumours, including brain tumours, genomic instability results from chromosome-level
changes that lead to gain or losses of whole-genome segments, rather than point mutations. This
process, termed chromosomal instability, arises from segregation errors that occur during cell
division, which might promote genetic diversity by upsetting the balance between activation of
oncogenes and tumour suppressors.
2. Clonal Evolution/Selection Hypothesis
- In addition to a larger role in creating copy-number imbalances, dynamic chromosomal instability can
lead to the non-uniform loss of chromosomal segments harbouring specific genetic alterations and can
indirectly contribute to mutational heterogeneity across different tumour regions.
- Increased levels of genomic instability promote the emergence of more-competitive subclones.
- Excessive levels of genomic instability can, adverse effects on cancer cell survival and fitness.
- Genomic instability might co-operate with other factors to promote the development of tumour
heterogeneity and tumour progression (Clonal Evolution and/or Selection Framework model):
* This model based on the hypothesis that tumour initiation occurs in stochastic
manner, beginning with an induced change in a previous non-malignant cell that
congers a selective growth advantage and leads to neoplastic proliferation.
* Linear evolution describes evolution owing to the successive acquisition of
mutations that confer a growth and/or survival advantage mutations
outcompeting ancestral clones.
* Branched evolution enables a greater level of opportunity to create a more
heterogenous tumour.
SPATIAL HETEROGENEITY
The molecular makeup of cancer cells that predominate at different sites can be distinct, owing to the
variable influences of micro-environment-related factors and site-specific stressors.
Owing to selective pressures that lead to further genetic evolution heterogeneity might exist even
among the cells present within the parent tumour.
The uneven distribution of genetically diverse tumour subpopulations across different sites, and
sometimes within a tumour in a single anatomical location, is termed special heterogeneity.
Heterogeneity at a Single Disease Site
Primary tumours can contain multiple geographically separated, molecularly distinct cellular
subpopulations.
