Cancer mechanisms Flashcards
Overview of the abnormal properties that cancer cells often show
Independence of growth-stimulating signals
Resistance to grwoth-inhibitory signals
Differentiation block
Resistance to apoptosis
Immortality
Genetic instability
Metabolic changes
Metastasis
Angiogenesis
Evasion of immune response
Outline of cancer-relevant pathways that relay signals
Signals (growth factors) from outside the cell encourage or inhibit proliferation and survival (blocking apoptosis). Many growth factors that encourage proliferation (notably the EGF family) signal via tyrosine kinase receptors. Other growth factors are Wnts, and the TGF-β family generally inhibit proliferation in epithelial cells
(see image)
How do the cancer signalling pathways map onto Vogelstein’s model of cancer progession
(see image) Many of the cancer mutations relate to the control of proliferation. eg The Vogelstein model of colorectal cancer induces pro-proliferation pathways (the Wnt pathway), and two pathways downstream of receptor tyrosine kinase signalling (KRAS-BRAF-MAP kinase pathway and the P13kinase-Akt pathway), and a growth inhibitory pathway (TGF-β signalling)
Note that not all important cancer-causing pathways are included in the Vogelstein model. eg the pRb pathway that regulates the G1/S checkpoint isn’t listed, but it is sometimes mutated in colon cancers
The Wnt signalling pathway
This is of particular interest because almost all colorectal cancers have a mutation in it, either in APC, β-catenin, or other components such as Tcf transcription factor (TCF4). APC inactivation is the most frequent. β-catenin, acting with Tcf transcription factors in the nucelus, drives cell proliferation and/or clonal expansion. In unstimulated situations (when Wnt is inactive), APC forms part of a complex that promotes β-catenin degradation (hence stops proliferation). Wnt signalling prevents β-catenin degradation by redirecting the destruction complex. Pro-proliferative mutations are those that inactivate APC or that activate β-catenin. Activation is achieved by preventing β-catenin degradation, typically ny point mutations of the motif on β-catenin that is recognised by the cellular protein degradation machinery.
Receptor tyrosine kinases and downstream pathways
The RTKs autophosphotylate and then recruit signalling pathways to the phosphorylated residues. The ERBB/EGF-receptor family includes ERBB/EGF-receptor and ERBB2/HER2, well known as the target of the antibody drug Herceptin in breast cancer. Two downstream pathways for ERBB family signalling are i) the MAP kinase pathway which signals through RAS and RAF family members to the MAP kinases, ii) the PIP3 pathway where PI-3-kinase adds phosphate groups to the 3 position of PIP2 to make PIP3. The enzyme PTEN reverses this reaction. PIP3 activates AKT kinases, which inhibit apoptosis. As in the pRb pathway, almost all components of these pathways are at least occasionally mutated in cancers. Most are activated (so are oncogenes), the exception being PTEN, which is a tumour suppressor gene and is quite often deleted. Note that Vogelstein’s model includes KRAS and BRAF as alternatives and PI3KCA and PTEN as alternatives
The TGF-β pathway
This pathway is generally growth-inhibitory for epithelial calls. TGF-β-family peptide growth factors signal via a transmembrane receptor to the SMAD family, which carry signals to the nucleus. Mutations id TGFβRII, SMAD4 or SMAD2 are quite common in colon cancer. All are tumour suppressor genes.
Differentiation block
a) define
b) example in colon cancers
a) tissues generally differentiate in stages from self-renewing stem cells via more differentiated types to fully differentiated types which normally have lost the ability, or have limited ability, to proliferate. Cancers can arise in stem cells or in more differentiated cells, and may or may not be blocked in their ability to differentiate
b) An example of a mutation that results in a differentiation block in cancer is the first mutation listen in the Vogelstein’s model: inactivation of APC or activation of β-catenin. Mutating APC in the stem cell compartment of the cokin in an animal model blocks differentiation. The stem cell compartment expands and the proliferating cells are no longer able to migrate up the villi.
Differentiation block in leukaemias
Leukaemias can arise in stem cells and they can either have differentiation blocked, giving acute leukaemias where stem cells appear in blood. Or they can retain differentiation as in chronic myeloid leukaemia, where cancer cells in th blood are differentiated. The leukaemias with blocked differentiation are more aggressive than the differentiating ones. Leukaemias can also arise in fully differentiated lymphocytes, as in chronic B-lymphocytic leukaemia and also myeloma which arises in plasma cells. A lymphocytic precursor with blocked differentiation may become an acture lymphocytic leukaemia.
Apoptosis in cancer
Apoptosis limits proliferation and removes damaged or stressed cells. Anti-apoptotic mutations include the inactivation of BAX or p53. BAX is a major mediator of apoptosis, upregulated by p53. Bax protein antagonises a related protein, Bcl2, and mediates permeabilisation of the mitochondrial membrane and activation of caspases. The PIP3 pathway also acts to reduce apoptosis. The Vogelstein model suggests that mutations in BAX and p53 may be alternatives in colon cancer
Telomeres, senescence and immortality
Human somatic cells in culture would only divide a fixed numer of times (50-100 divisions) before entering cycle arrest, a response known as senescence. Tumour cells escaped this limit to grow indefinitely and are considered ‘immortal’. The division potential of a cell is limited by the length of its telomeres. Telomeres are the repeat structures at the ends of chromosomes, and in most somatic cells they are shortened at each division (by about 100bp). The length of telomeres is restored in the germ line by the enzyme telomerase. Most human cancer cells have re-established expression of telomerase. In about 10-20% of cancers, this is by point mutation of the promoter. In other cases a rearrangement of DNA brings the telomerase gene under the control of a promoter from another gene
a) Stress responses
b) Importance of p53
a) Various adverse signals can produce a stress response, which typically results in cycle arrest and a characteristic set of biochemical changes. The senescence caused by shortening of telomeres as cells replicate is actually only one example of a stress response. other signals that give rather similar responses include DNA damage and strong activation of some oncogenes. eg expressing mutant RAS in otherwise normal cells, which is called ‘oncogene-induced senescence’ because the cells resembled ‘senescent’ cells. Mutation of p53 (with or without mutation of RB1) alleviates these stress responses. Several viruses (including HPVs associated with cervical cancer) have proteins to overcome senescence by binding and inactivating pRb and p53.
b) p53 seems to be an integrating hub for stress signals. It receives a variety of stress signals, including signals announcing DNA damage, inappropriate oncogene activation and telomere shortening, and can signal for the cell to arrest the cell cycle or to initiate apoptosis. It is mutated in around 1/3 to 1/2 of all human neoplasms. p53 levels can be increased in minutes. The protein is constantly being translated and degraded, so blocking degradation rapidly raises its level
Angiogenesis and cancer
In order for a tumour to grow beyond a certain size, it needs to develop a blood supply, by sprouting new branches from the adjacent capillary network. This is called angiogenesis. Folkman postulated that tumour growth might be limited by the need for angiogenesis, and a tumour had to produce angiogenic factors. It is speculated whether tumours produce angiogenic factors as the result of a specific mutation, or whether these factors are a normal homeostatic mechanisms, responding to anoxia in the tumour tissue (as normal processes like wound healing induce angiogenesis).
Metastases - how they form
Tumour cells migrate (invade) through connective tissue, with cells slipping through pre-existing spaces between cells along collagen fibres etc. Cells eventually get into lymphatics or veins.
Metastases are often found in tissues that such cells might obviously reach. Carcinomas often spread down lymphatics, sp often colonise the draining lymph nodes (eg in breast cancer the axillary lymph nodes) so lymph nodes adjacent to tumours are often investigated as a rough indicator of whether the tumour has spread. If cells reach the circulation, they can circulate freely to distant sites
Experimental study of metastasis
Labelled malignant cells can be injected into the circulation (eg by using melanoma - would give black tumours, or using fluorescently labelled cells).
Cells injected into capillary beds and be found in lymphatic drainage.
Cells injected at different sites (eg left ventricle and tail vein) give much the same eventual distribution of metastatic colonies
a) what determines the site of metastasis
b) basic process of metastasis
c) which is the critical step
d) Efficiency of metastasis
a) It is in part dependent on some intrinsic property of the tumour. This was shown by selecting variants of a mouse melanoma line that preferentially colonised respectively the brain or the lung independently of where they were injected. This was done by repeated iv injection of cells and recovering colonies from the chosen organ
b) Comprises of escape of cells into vessels, survival in the circulation, escape out of the vessels into tissue, then survival and growth
c) Survival and growth in the distant site
d) Metastasis is very inefficient. Many cells may be released from a tumour with only a few metastatic colonies forming. It was suggested that only a few cells in the tumour were capable of metastasis, but this was proven wrong, as there is equal rate of metastasis in a primary tumour of many different cells as there is with a primary tumour of specific cells known to have metastasised.
