SIGNAL TRANSDUCTION IN CANCER
REVIEW ARTICLE
The development of cancer involves successive genetic and
epigenetic alterations that allow cells to escape homeostatic
controls that ordinarily suppress inappropriate proliferation
and inhibit the survival of aberrantly proliferating cells outside
their normal niches.
In solid tumours, alterations typically promote progression
from a relatively benign group of proliferating cells
(hyperplasia) to a mass of cells with abnormal morphology,
cytological appearance, and cellular organisation.
After tumour expands, the tumour core loses access to oxygen
and nutrients, often leading to the growth of new blood vessels
(angiogenesis), which restores access to nutrients and oxygen.
Subsequently. Tumour cells can develop the ability to invade
the tissue beyond their normal boundaries. Enter the circulation and seed new tumors at other locations
(metastasis), the defining feature of malignancy.
Tumour cells use signalling pathways to proliferate, survive and invade other tissues.
Mutations as the Cause of Cancer
Some mutations are gain-of-function mutations, producing so called oncogenes that drive tumor
formation.
Others inactivate tumour suppressor genes that normally ensure that cells do not proliferate
inappropriately or survive outside their normal niche.
Tumours can possess tens to hundreds or even thousands of mutations, but many of these are merely
so-called “passengers”.
Driver mutations cause progression of cancer. These may be point mutations, deletions, inversions, or
amplifications.
Changes in the methylation state of promoters of genes that impact cancer can also play an important
role in oncogenesis.
Epigenetic silencing is more common than mutational silencing for some genes. For example cyclin
dependent kinase (CDK) inhibitor (CKI) p16 and the mismatch repair (MMR) enzyme MLH1.
Silencing of MMR enzymes can lead to additional genetic changes because it affects proteins that
prevent errors by repairing DNA.
Mutations in the metabolic enzymes isocitrate dehydrogenase (IDH) 1 and IDH2 may promote cancer
by generating an “oncometabolite” not present in normal cells that inhibits certain chromatin-
modifying enzymes.
A few human cancers are tiggered by viruses that encode genes that promote tumorigenesis through
activation of oncogene pathways or inactivation of tumor suppressors.
Cancer-Causing Mutations Affect Signalling Pathways
o Oncogenic mutations can cause the affected genes to be overexpressed (e.g. gene amplification) or
produce mutated proteins whose activity is dysregulated (e.g. point mutations, truncations, and
fusions).
o Proteins involved in signalling pathways are commonly activated in man y physiological responses:
- Growth factor receptor tyrosine kinases
- Small GTPases
- Serine/Threonine kinases
- Cytoplasmic tyrosine kinases
- Lipid kinases
- Nuclear receptors
o Components of developmental signalling pathway include: Wnt
, o Downstream nuclear targets of signalling pathways:
- Transcription factors (e.g. Myc )
- Chromatin remodelers
- Cell cycle effectors (e.g. cyclins)
o Deletions and other mutations can inactivate negative regulators that normally function as tumour
suppressors. Indeed, one of the most commonly mutated genes in cancer is the tumour suppressor p53,
the so-called “guardian of the genome”. It is a critical hub that controls cell proliferation and stress
signals such as apoptosis and DNA damage responses.
o Many tumour suppressors function as negative regulators of cytoplasmic signalling (for example lipid
phosphatase PTEN is a negative regulator of the PI3K-Akt pathway.
o Hyperactivated oncogene pathways can also induce a state of irreversible cell cycle arrest termed
senescence. This is believed to represent a fail-safe mechanism to inhibit proliferation caused by
aberrant activation of oncoproteins in normal cells and is accompanied by changes in cellular
structure, chromatin organization, DNA damage, cytokine secretion, and gene expression.
The PI3K-Akt and Ras-ERK Pathways as Examples of Oncogenic Signalling
Ordinarily these pathways are transiently activated in response to growth factor or cytokine signalling
and ligand occupancy of integrin adhesion receptors, but genetic alterations can lead to constitutive
signalling even in the absence of growth factors.
The PI3K-Akt pathway can be activated through amplification or activating mutations affecting
several PI3K-Akt-pathway proteins, the type I PI3K isoform, Akt, and the adaptor protein PIK3R1- or
through deletion or inactivating mutations in the phosphatases that hydrolyse PI3K products.
Further downstream, mutations in the tumor suppressors TSC1 and TSC2
hyperactivate signalling by mTORC1, an important target of PI3K-Akt
signalling.
The Ras-ERK pathway is activated by mutations in Ras or its downstream
target Raf, that cause constitutive activation of these proteins or by
inactivation of GTPase-activating proteins, such as NF1,DAB2IP, that
stimulate the hydrolysis of GTP bound to Ras, which lead to its
inactivation.
Myc: it is a transcription factor which is an important downstream target
of Ras-ERK signalling and many other pathways. Myc can not only bind
to promoter regions of genes but also enhance transcriptional elongation
of polymerase II. It serves as a universal amplifier of expressed genes
rather than merely binding to promoter and initiating transcription de
novo.
Inappropriate synthesis of growth factors by cells expressing the
appropriate receptor can generate an autocrine loop driving signalling. this
can also be achieved through cleavage and release of anchored soluble
growth factors by surface ADAM proteases, which are activated
downstream from oncogenic signalling pathways.
Alternatively, the growth factor may be synthesized by a neighbouring
cell (paracrine stimulation).
Cell Proliferation
Limited availability of growth factors or nutrients, contact inhibition, and other feedback mechanisms
ensure that the pathways that regulate proliferation are normally tightly controlled.
Signalling targets that represent critical components of cell cycle control mechanisms can also undergo
genetic alterations in cancer; for example, the genes encoding cyclin D, cyclin E, and CDK4 are
amplified in certain cancers and the G1 restriction point inhibitor pRB and p16 can be deleted or
mutated as well.
REVIEW ARTICLE
The development of cancer involves successive genetic and
epigenetic alterations that allow cells to escape homeostatic
controls that ordinarily suppress inappropriate proliferation
and inhibit the survival of aberrantly proliferating cells outside
their normal niches.
In solid tumours, alterations typically promote progression
from a relatively benign group of proliferating cells
(hyperplasia) to a mass of cells with abnormal morphology,
cytological appearance, and cellular organisation.
After tumour expands, the tumour core loses access to oxygen
and nutrients, often leading to the growth of new blood vessels
(angiogenesis), which restores access to nutrients and oxygen.
Subsequently. Tumour cells can develop the ability to invade
the tissue beyond their normal boundaries. Enter the circulation and seed new tumors at other locations
(metastasis), the defining feature of malignancy.
Tumour cells use signalling pathways to proliferate, survive and invade other tissues.
Mutations as the Cause of Cancer
Some mutations are gain-of-function mutations, producing so called oncogenes that drive tumor
formation.
Others inactivate tumour suppressor genes that normally ensure that cells do not proliferate
inappropriately or survive outside their normal niche.
Tumours can possess tens to hundreds or even thousands of mutations, but many of these are merely
so-called “passengers”.
Driver mutations cause progression of cancer. These may be point mutations, deletions, inversions, or
amplifications.
Changes in the methylation state of promoters of genes that impact cancer can also play an important
role in oncogenesis.
Epigenetic silencing is more common than mutational silencing for some genes. For example cyclin
dependent kinase (CDK) inhibitor (CKI) p16 and the mismatch repair (MMR) enzyme MLH1.
Silencing of MMR enzymes can lead to additional genetic changes because it affects proteins that
prevent errors by repairing DNA.
Mutations in the metabolic enzymes isocitrate dehydrogenase (IDH) 1 and IDH2 may promote cancer
by generating an “oncometabolite” not present in normal cells that inhibits certain chromatin-
modifying enzymes.
A few human cancers are tiggered by viruses that encode genes that promote tumorigenesis through
activation of oncogene pathways or inactivation of tumor suppressors.
Cancer-Causing Mutations Affect Signalling Pathways
o Oncogenic mutations can cause the affected genes to be overexpressed (e.g. gene amplification) or
produce mutated proteins whose activity is dysregulated (e.g. point mutations, truncations, and
fusions).
o Proteins involved in signalling pathways are commonly activated in man y physiological responses:
- Growth factor receptor tyrosine kinases
- Small GTPases
- Serine/Threonine kinases
- Cytoplasmic tyrosine kinases
- Lipid kinases
- Nuclear receptors
o Components of developmental signalling pathway include: Wnt
, o Downstream nuclear targets of signalling pathways:
- Transcription factors (e.g. Myc )
- Chromatin remodelers
- Cell cycle effectors (e.g. cyclins)
o Deletions and other mutations can inactivate negative regulators that normally function as tumour
suppressors. Indeed, one of the most commonly mutated genes in cancer is the tumour suppressor p53,
the so-called “guardian of the genome”. It is a critical hub that controls cell proliferation and stress
signals such as apoptosis and DNA damage responses.
o Many tumour suppressors function as negative regulators of cytoplasmic signalling (for example lipid
phosphatase PTEN is a negative regulator of the PI3K-Akt pathway.
o Hyperactivated oncogene pathways can also induce a state of irreversible cell cycle arrest termed
senescence. This is believed to represent a fail-safe mechanism to inhibit proliferation caused by
aberrant activation of oncoproteins in normal cells and is accompanied by changes in cellular
structure, chromatin organization, DNA damage, cytokine secretion, and gene expression.
The PI3K-Akt and Ras-ERK Pathways as Examples of Oncogenic Signalling
Ordinarily these pathways are transiently activated in response to growth factor or cytokine signalling
and ligand occupancy of integrin adhesion receptors, but genetic alterations can lead to constitutive
signalling even in the absence of growth factors.
The PI3K-Akt pathway can be activated through amplification or activating mutations affecting
several PI3K-Akt-pathway proteins, the type I PI3K isoform, Akt, and the adaptor protein PIK3R1- or
through deletion or inactivating mutations in the phosphatases that hydrolyse PI3K products.
Further downstream, mutations in the tumor suppressors TSC1 and TSC2
hyperactivate signalling by mTORC1, an important target of PI3K-Akt
signalling.
The Ras-ERK pathway is activated by mutations in Ras or its downstream
target Raf, that cause constitutive activation of these proteins or by
inactivation of GTPase-activating proteins, such as NF1,DAB2IP, that
stimulate the hydrolysis of GTP bound to Ras, which lead to its
inactivation.
Myc: it is a transcription factor which is an important downstream target
of Ras-ERK signalling and many other pathways. Myc can not only bind
to promoter regions of genes but also enhance transcriptional elongation
of polymerase II. It serves as a universal amplifier of expressed genes
rather than merely binding to promoter and initiating transcription de
novo.
Inappropriate synthesis of growth factors by cells expressing the
appropriate receptor can generate an autocrine loop driving signalling. this
can also be achieved through cleavage and release of anchored soluble
growth factors by surface ADAM proteases, which are activated
downstream from oncogenic signalling pathways.
Alternatively, the growth factor may be synthesized by a neighbouring
cell (paracrine stimulation).
Cell Proliferation
Limited availability of growth factors or nutrients, contact inhibition, and other feedback mechanisms
ensure that the pathways that regulate proliferation are normally tightly controlled.
Signalling targets that represent critical components of cell cycle control mechanisms can also undergo
genetic alterations in cancer; for example, the genes encoding cyclin D, cyclin E, and CDK4 are
amplified in certain cancers and the G1 restriction point inhibitor pRB and p16 can be deleted or
mutated as well.
