Week 10: Cancer Flashcards
What is cancer?
- The uncontrolled/sustained proliferation of abnormal cells that destroy the function of normal healthy tissues in the body
- Cancerous cells have replicative immortality and tend to acquire further mutations with each division
- The sequential acquisition of mutations gives cancers their “hallmarks” which are particular properties/sequences that allow them to proliferate
What are the 2 types of malignancies?
- Solid malignancies:
- Mass of abnormal cells, generally without cysts or liquid
- The cancer cells are normally derived from epithelial cells
e. g. Breast, colon, lung and prostate cancers - Haematological malignancies:
- Non-solid abnormal cells
E.g. Cancers of the blood, bone marrow and lymphatic system
What are the differences between benign and malignant cancers?
- Benign cancers:
- Slow growing (but still hyperproliferative)
- Encapsulated by a membrane
- Non-invasive
- Still resembles cell of origin
- Have the suffix oma
E.g. polyp in colon - Malignant cancers:
- Fast growing
- Cells are variable in size and shape and poorly differentiated (do not resemble cells of origin)
- Non-encapsulated
- Invasive
- Metastasize
- Have the suffix carcinoma or sarcoma
What are carcinomas in situ?
- A form of cancer that lies between benign and malignant cancers
- Tend to evolve into malignant tumours
- They do not undergo cell invasion (like benign tumours) but have the characteristics of malignant tumours meaning they have the potential to undergo cell invasion
What are the most common types of cancer?
- Cancers that originate from surface epithelium (papilloma/carcinoma) or gland/ductal epithelium (adenoma/adenocarcinoma)
What is stroma?
- Stroma are the supportive cells around tissues such as connective tissue and fibroblasts
- Plays an important role in cancer by releasing growth factors and cytokines that allow tissues to continue to proliferate
What are the microscopic characteristics of cancer cells?
- Large number of dividing cells
- Large variable shaped nuclei (due to genetic instability creating more genes/chromosomes)
- Small cytoplasmic volume compared to nuclei (the cells do not spend enough time in G1 or G2 as the cell cycle checkpoints are typically lost)
- Variation in cell size and shape
- Loss of specialised cell structures (are undifferentiated)
- Disorganised arrangement of cells
- Poorly defined tumour boundary
What factors can cause the development of cancers?
- Environmental factors:
- Radiation (UV, ionising)
- Tobacco smoke
- Obesity
- Alcohol - Immune deficiency
- Genetic factors
- Inherited mutations in tumour suppressor genes such as BRACA1 and BRACA2 - Viruses
E.g. HPV: associated with cervical cancer, leads to the production of protein E6 which ubiquitinates p53 and targets it for degradation by the proteosome pathway
List the 6 hallmarks of cancer and give an example of what can cause them:
- Sustained proliferative signalling
e. g. overexpression of growth factors - Evading growth suppressors
e. g. via TGFB - Activating invasion and metastasis
e. g. via MMPs - Enabling replicative immortality
e. g. via telomerase - Inducing angiogenesis
e. g. via VEGF - Resisting cell death
e. g. via p53 loss
How do cancers have sustained proliferation?
- This is due to a loss of proliferative regulation:
1. Cancer cells can do this by secreting growth factors such as EGF (epidermal growth factor- the master regulator of cell proliferation) which act in an autocrine manner to increase tumour growth
2. Cancer cells can also have increased EGF receptor expression
3. Cancer cells can increase IGF secretion to stimulate growth factor production (paracrine)
4. Loss of negative regulators that inhibit proliferation such as TFGBeta e.g. by downregulating the receptor for TGFB
How do cancers evade growth suppressors?
- Overcome the activity of tumour suppressors such as p53 and Rb via gene mutations:
- p53 stalls the cell cycle and is usually increased in production when DNA is damaged) - Loss of negative regulators that inhibit proliferation
e. g. Loss of TGFB - Overcoming contact-mediated inhibition of proliferation
How do cancer cells resist cell death (apoptosis)
- Loss of p53 tumour suppressor genes
- Loss of pro-apoptotic regulators (Bax, Bad)
- Gain of anti-apoptotic regulators (BCL2)
- Overcoming signals from ligand-activated death receptors (Fas)
How do cancer cells induce angiogenesis?
- Solid tumours require waste removal and nutrients/oxygen from growth greater than 1-2mm and this is achieved by inducing angiogenesis (the formation of new blood vessels)
1. Tumours express pro-angiogenic factors such as VEGF and FGF
2. Tumours suppress antiangiogeneif factors such as thrombospondin-1
3. Angiogenic factors are upregulated by oncogene expression and also hypoxia
How do cancer cells achieve replicative immortality?
- Telomeres are a region at each end of the chromosome that protects it
- As cells divide telomeres shorten, when telomeres shorten to a critical length the cell undergoes replicative senescene (and it stops dividing)
- Cancer cells often express the enzyme telomerase, which regenerates the telomeres
How do cancer cells activate cell invasion and metastasis?
- Metastasis is a multistep process involving local invasion, intravasation into vessles, extravasation from vessels and then growth in distant tissue sites
- Cancer cells achieve this by activating EMT (epithelial to mesenchyme transition) which downregulates E-cadherin
- Cancer cells are increase expression/activation of proteins that promote cell invasion such as matrix metalloproteases (MMPs) and migration (Rac)
What are the 4 new hallmarks of cancer that have been introduced?
- Avoiding immune destruction
- Tumour-promoting inflammation
- Genoome instability and mutation
- Deregulating cellular energetics: cancer cells favour glycolysis (even with O2)
Describe the typical progression of solid cancers:
- Primary tumour forms and establishes its own vascular network via secretion of VEGF
- Cells undergo EMT and secrete MMPs which allow them to degrade endothelial blood vessel walls and enter the circulation
- The cancerous cells are transported through circulation
- The cancerous cells arrest in the microvessles of various organs e.g. lungs, brain and bone
- The cancer undergoes extravasion and forms a micrometastasis in the new tissue
- The cancer forms a macrometastasis in the new tissue that undergoes angiogenesis
What is generally mutated first in a cancer, a tumour suppressor gene or a protooncogene?
- Tumour suppressor genes are generally mutated first e.g. p53
- Induction of oncogenes and epigenetic changes generally occur later
What is an oncogene?
- A mutated version of a normal gene (proto-oncogene)
- Activation requires only 1 defective allele
- The mutations are gain of function and dominant
- Most protooncogenes are receptor tyrosine kinases
Examples:
- Ras (signal transducer)
- pancreatic, lung and colon - BRAF (signal transducer)
- melanoma - Abl (signal transducer)
- CML - HER2 (growth factor receptor)
- breast cancer
What are tumour suppressor genes?
- Normal cellular genes required for hometostasis that act as ‘breaks’ on cancer development/progression e,g. by restricting cell division, repairing DNA and inducing apoptosis
- Involves loss of function mutations to both alleles of the gene (recessive)
- Mutation of one allele is followed by the deletion of epigenetic silencing of the second (2 hit hypothesis)
Examples:
- BRACA1/2 (DNA repair genes)
- Rb
- p53
- APC (signal regulator)
- TP53 (transcription factors)
How are oncogenes altered in cancer?
- Gain of function mutations:
- Increased enzyme activity, increased protein stability or loss of regulation - Translocation of the gene to a different area of the genome:
- Under different control mechanisms
- Leads to gene fusion and expression of aberrant chimeric protein - Gene amplification
- Increased expression at the mRNA/protein level without gene amplification
How are tumour suppressor genes altered in cancer?
- Loss of function mutation:
- Loss of enzyme activity, reduced protein stability and disrupted subcellular localisation
- Most TSGs are transcription factors that lose their ability to transcribe their genes - Deletion of the gene
- Epigenetic regulation:
- CpG methylation (blocks transcription)
- Histone modification (blocks transcription)
- MicroRNAs that cause post transcriptional silencing or mRNA degradation
How does epidermal growth factor receptor function in cancers?
- EGFR is mutated in 50% of lung adenocarcinomas
- Protooncogenic EGFR:
- In the absence of a ligand, the receptor is not phosphorylated and downstream signalling proteins are not activated
- If the ligand is present, the intracellular domains dimerise and phosphorylate which activates downstream molecules that signal the cell to grow and proliferate
- Oncogenic EGFR:
- Often has a mutation in the kinase domain of the receptor tyrosine kinases
- Even without the ligand binding, phosphate groups are present on the intracellular domain leading to the recruitment of effector proteins
- Mutant EGFR is active in the absence of EGF ligand and is further activated by ligand binding
Describe how p53 tumour suppressor gene is inactivated and its effect:
- p53 loss of function mutations are the most common type of mutated tumour suppressor genes in cancers
- Its normal function is activated when the DNA repair pathway is activated and the translocation of p53 to the nucleus will cause the transcription of growth arrest genes which gives the cell time to repair DNA lesions
- p53 is regulated by the heterodimer MDM2-MDM4 which ubiquinate p53 normally but when the cell is under stress they do not and p53 expression is allowed
- When p53 has loss of function mutations it allows the cells to evade cell death and DNA repair