Cancer Flashcards
Cancer - definition
A large group of diseases that can start in almost any organ or tissue of the body when abnormal cells grow uncontrollably, go beyond their usual boundaries to invade adjoining parts of the body and/or spread to other organs.
hallmarks of cancer
- sustaining proliferative signalling
- Evading growth suppressors
- resisting cell death
- enabling replicative immortality
- inducing angiogenesis
- activation invasion and metastasis
- deregulating cellular metabolism
- avoiding immune destruction
- genome instability and mutations (abberation)
- tumour promoting inflammation (abberation)
sustaining proliferative signalling
cancer cells need to obtain mutated proto-oncogenes –> oncogenes, these keep the cell in a proliferative state
- can be a deletion/point mutation in promotor –> hyper active protein produced in normal amounts
- gene can be amplified/multiplied (aneuploidy)
- chromosomal rearrangement (proto-oncogene is placed next to strong promotor, or a fusion gene occurs - BCR/ABL)
- These are dominant mutations (require one hit)
examples: • BCR/ABL (Philadelphia chromosome) • RAS (a GTPase) • Cyclin D • Her2/neu
evading growth surpressors (and resisting cell death)
Cancer needs mutations in TSGs - these normally stop cell cycle when there is DNA damage or they are involved in DNA repair or apoptosis
- recessive mutation –> 2 hits (both alleles)
• p53 (40% of cancers)
• Rb
• p16/Ink4 locus
• BCL2/BAX (pro-apoptotic)
• BRCA1/2 (DNA damage repair)
- certain viruses can deactivate TSGs (Rb and p53) and cause cancer (HPV vaccine for females)
enabling replicative immortality
Cancer cells do not obey the Hayflick limit: normally when the number of telomere repeats erodes below a certain threshold, a tripwire is triggered, causing cell-cycle arrest or apoptosis mediated by p53
- Circumventing these p53-induced antiproliferative responses (by mutational inactivation of the p53 gene) allows cancer cells with eroding telomeres to ignore the short-telomere checkpoint and continue proliferating, but only transiently.
• Sooner or later, the continuing erosion of telomeric DNA leads to loss of the protective nucleoprotein caps protecting the chromosomal DNA ends, which allows end-to-end fusions of chromosomes that leads to cell death instead of cell division.
- The cancer cells in many fully developed tumours circumvent this by activating a system for telomere maintenance and extension –> telomerase expression
inducing angiogenesis
Normally when the nearest capillary is more than 200 μ away the diffusion limit is reached these cells start to express hypoxia-inducible transcription factors (HIF), which regulate hundreds of genes, including ones that directly or indirectly induce angiogenesis and other stress-adaptive capabilities
• Since tumours are ever growing there are always cells at this limit and thus angiogenesis does not stop –> resulting in leaky dilated vessels in tumours
activating invasion and metastasis
Invasive growth programs enable cancer cells to invade into adjacent tissue as well as into blood and lymphatic vessels (intravasation); these vessels serve thereafter as pipelines for dissemination to nearby and distant anatomical sites.
• Epithelial–mesenchymal transition can be induced by HIFs which initiate the transcription of genes needed for this transition and thus for invasion and metastasis
- The tissue-draining lymphatic vasculature can transport cancer cells to lymph nodes, where metastatic growths—lymph node metastases—can form; such cell colonies may serve, in turn, as staging areas for further dissemination by entering the bloodstream.
- Cells entering the bloodstream by direct intravasation within a tumour or indirectly via lymph nodes may soon become lodged in the microvessels of distant organs and extravasate across the vessel walls into the nearby tissue parenchyma.
• The resulting seeded micrometastases may die or lay dormant in such ectopic tissue locations or, with extremely low efficiency, generate macroscopic metastases—the process of “colonization.”
deregulating cellular energetics and metabolism
- Cancer cells have enhanced uptake of glucose, which is metabolized via glycolysis, even in the presence of oxygen levels that normally should favour oxidative phosphorylation.
• This may be counterintuitive, as glycolysis is far less efficient at producing ATP.
• However “aerobic glycolysis” produces, in addition to ATP, many of the building blocks for the cellular macromolecules that are required for cell growth and division - Glutamine and lactate are also emerging as key blood-borne sources of energy for tumours
- Oncogenes such as KRAS and cMYC, as well as the loss of function of TSGs such as p53, can serve to reprogram the energy metabolism of cancer cells
avoiding immune destruction
Immune self-tolerance: the vast majority of antigens expressed are likely shared with those expressed by their cells-of-origin in normal tissues and thus are ignored, reflecting the tolerance of the immune system for self-antigens
- Still cancer cells express some antigens like embryonic antigens, and novel antigens produced by mutation of the genome; such antigens can indeed elicit antitumor immune responses
- The ability to signal the immune system (IIC - Treg) to slow down immune reactions or stop them completely has been recognized as a common development in cancer
Genome instability and mutations
Genome instability and the consequent mutation of hallmark enabling genes is the primary modality of acquiring hallmark capabilities.
Tumour-promoting inflammation
- Most tumours are infiltrated by a variety of cell types of the immune system: the so-called infiltrating immune cells, or IIC
- While the inflammation caused by IIC might reasonably be considered a failed attempt to eradicate a tumour, recent evidence now clearly makes a far more insidious point: IIC help convey in paracrine fashion multiple functional capabilities, encompassing seven of the eight hallmarks.
• They supply the tumour with proliferative and survival signals, proangiogenic factors, and facilitate local invasion and blood-borne metastasis.
• Some of these IIC (T-regulatory cells and myeloid-derived suppressor cells) can actively suppress the cytotoxic T lymphocytes that have been dispatched by the immune system to eradicate cancer cells –> avoiding immune system
clonal expansion and selection
- Cancer is caused by a single abnormal cell, this cell undergoes clonal expansion and its daughters acquire more and more mutations
- The ‘best’ cancer cells, the fastest, will have the most daughter cells and outcompete the other cells causing the tumour to gain more and more mutations and cells (selection)
• So there needs to be a first hit (e.g. translocation, point mutation etc.) to give a cell an advantage in cell growth (loss of TSG or oncogene expression)
• Then during selection additional hits are needed to turn into cancer: tumour becomes immortal, invasive and metastatic. - If not all cells are removed the clonal expansion and selection will occur again and the tumour will be even more aggressive than the one you started with
Colon cancer - steps
- A single cell becomes cancerous: first mutation often APC in colon cancer - followed by a second mutation (loss of function of a TSG or gain of function for an oncogene)
• This first mutation could be inherited like the BRCA2 gene in breast cancer - This cell proliferates fast to form a small population of initial tumour cells
- These keep proliferating all with a chance to create more mutations and chromosomal duplications
- The cells with a mutation that facilitates the fastest growth (variant tumour cell) will have the most daughter cells this way the tumour keeps dividing faster and faster
- At some point the tumour has grown to a small adenoma (benign)
- Intermediate adenoma
- Large adenoma
- Carcinoma develops, indicated by invasion of the tumour cells through the basal lamina into underlying connective tissue (malignant)
- The cancer cells then continue to proliferate and spread through the connective tissues of the colon wall.
- Eventually the cancer cells penetrate the wall of the colon and invade other abdominal organs, such as the bladder or small intestine.
- In addition, the cancer cells invade blood and lymphatic vessels, allowing them to metastasize throughout the whole body
colon cancer - facts
- It typically starts as a benign tumour, often in the form of a polyp, which over time becomes cancerous –> can take over 30 years
- Most frequent the first mutation is in the wnt pathway - APC is lost (now beta-catenin will accumulate and proliferative genes will be expressed)
- After this mutation any other TSG can be lost or oncogene obtained to from an actual tumour/polyp
Metastasizing
- Separation from the primary tumour (genes need to be acquired via mutations or fusion with a neutrophil for example)
- Invasion through surrounding tissues and basement membranes
- Entry and survival in the circulation, lymphatics or peritoneal space –> metalloproteinase (present due to inflammation) to gain access to the bloodstream
- Arrest in a distant target organ.
- Extravasation into the surrounding tissue
- Survival in the foreign microenvironment
- Proliferation and induction of angiogenesis
