Cancer and its Hallmarks Flashcards
What is cancer?
A group of diseases in which cells divide and grow uncontrollably, forming a malignant tumour
What is meant by the hallmarks of cancer?
Characteristics that the cell acquires, allowing them to become malignant. Help us understand essential properties of cancer cells
How common is cancer and what factors influence this?
1/2-3 chance of developing cancer in our lifetime. Influenced by age, sex, geographic location, type of cancer, socioeconomic status, ethnicity
Describe the development of cancer
Incidence increases with age, showing that cancer is the result of an accumulation of mutations. 3-7 “events” required for normal cell to become malignant - transformation. The events are genetic alterations
How can mutations lead to the development of cancer?
A mutation in a protein which checks the DNA for damage causes it to become non functional. Damaged DNA not detected and hence not repaired before replication, leading to more mutations etc.
Describe what is meant by a carcinoma
Cancer arising from epithelial cells covering the external and internal surfaces of the body. Adenocarcinomas develop within a gland or organ, and squamous cell carcinomas develop from the epithelia in the top layer of skin/covering of certain organs. Most common cancer (80-90%)
Describe what is meant by a sarcoma
A much more rare cancer, arising from the supporting tissues, such as bone, cartilage, fat, connective tissues, and muscles
Describe what is meant by myeloma
Cancer arising in the immune system, from antibody producing plasma cells
Describe what is meant by leukaemia
Cancers of the blood, arising in immature blood cells growing in the bone marrow and accumulating in large numbers in the blood stream. Acute and chronic. Lymphocytic and myelogenous (rbc and platelets)
What is meant by the term carcinogen?
Helps in causing cancer by promoting DNA damage
How does age result in an increased incidence of cancer?
It takes time for accumulations to build up in the genome, meaning that later on in life we have a higher proportion of mutations that can lead to cancer
How can someone be genetically predisposed to cancer/
Cells need mutations to become malignant. If somebody already has an inherited mutation in their genome, it can make other mutations more likely to occur
What role does the immune system play in cancer?
Immunocompromisation increases the likelihood of certain cancers such as lymphoma and cancers caused by diseases eg. HPV
How do body weight and diet impact cancer risk?
Diet high in red meat, processed meat, sat fat, dairy associated with a higher risk of cancer. Alcohol increases risk by directly promoting DNA damage and negatively affecting absorption of important nutrients and breakdown of hormones
How can the environment increase cancer risk?
Radiation from sun can cause DNA damage
How can viruses and bacteria increase the risk of cancer?
Viruses can alter genetics by their activity. Cerival, genital, anal cancers - HPV. Primary Liver cancer - Hep B/C. Lymphomas - Epstein-Barr. T cell leuk - Human T cell leuk virus.
Bacterial infection of Helicobacter Pylori can lead to stomach lining inflammation increasing cancer risk.
Describe what is meant by Hallmark 1: Self Sufficiency in Growth Signals
Cancer cells do not need external growth signals (mediated by cell-surface receptors) in the form of GFs to grow
Describe the 3 ways that cancer cells are self sufficient in growth signals
Producing their own GFs, leading to a positive feedback loop - glioblastomas produce their own PDGF and sarcomas their own tumour GF-a.
They overexpress receptors making them hypersensitive to GFs, and grow in response to GF levels that wouldn’t usually cause growth. Epidermal GF receptor overexpressed in stomach, brain, breast cancer.
They can produce downstream responses to signals even when there is no signal. Mutant Ras is present in about 25% of tumours, activating SOS-Ras-Raf-mAPK pathway
Describe what is meant by Hallmark 2: Insensitivity to Growth Signals
Cancer cells are resistant to growth inhibitors from the ECM, environment, neighbouring cells. Growth inhibitors usually act on cell cycle clock, interrupting mitosis
How is retinoblastoma protein related to Insensitivity to antigrowth signals
Retinoblastoma protein is a protein that activates a checkpoint when there is a reason the cell shouldn’t divide (DNA damage). When RB is mutant, it won’t activate the checkpoint and the damaged cell continues to divide. RB is a tumour suppressor.
Describe what is meant by Hallmark 3: Evading apoptosis
p53 is a tumour suppressor that identifies irreparable DNA damage and signals to the cell that apoptosis should occur. Mutant p53 (and others like it) result in apoptosis not being initiated when it should be - DNA damage, oncogene overexpression, external signals
Describe what is meant by Hallmark 4: Limitless Replicative Potential
Cancer cells don’t have a Hayflick limit (60-70 doublings) due to their overexpression of telomerase allowing the lengthening of their telomeres and replicative immortality
Describe what is meant by Hallmark 5: Sustained Angiogenesis
Tumours may be able to release GFs such as Vascular Endothelial GF that activate angiogenesis, and also they may be able to downregulate endogenous inhibitors of angiogenesis
Why is angiogenesis important for cancer cells?
Angiogensis is the branching of new blood vessels from existing ones. Allows the supply of cells with adequate O2 and nutrients and waste removal. All cells must be 100uM from a vessel.
Describe what is meant by the angiogenic switch
Balance between pro- and anti-angiogenic factors tilts towards pro-angiogenesis
Describe what is meant by Hallmark 6: Tissue invasion and metastasis
Cancer cells are able to break away from the site of origin and invade surrounding tissues, spreading to distant body parts. Responsible for about 90% of cancer deaths
How do cancer cells metastasise?
Pioneer cells spawn from primary tumour masses and invade adjacent tissues. Can travel to distant sites via the circulation. Newly metastasised tumours are amalgams of cancer cells and supporting cells from host
How do cancer cells break away from their site of origin?
Downregulation of E-cadherin which is the connecting molecule between cells, forming bridges between cells and also contacting intracellular molecules. On colonisation of a new site, cells can reverse this process and reestablish contact with neighbouring cells
How can cancer cells adapt to different environments?
During this process, migrating cancer cells contact new environment with different ECM. To accomodate this, they alter their integrin subunit expression. Integrins facilitate cell adhesion but have substrate preferences, which cancer cells upregulate to facilitate invasion. Some integrins can facilitate matrix degredation by proteases and this facilitates invasion through stroma, vessels, epithelia
Describe what is meant by emerging hallmarks and what are they?
Pivotal characteristics of cancer cells. Deregulation of cellular energetics, and avoiding immune destruction
Describe what is meant by enabling characteristics and what are they?
Characteristics allowing cells to acquire hallmarks. Genome instability and Tumour-promoting inflammation
How do therapies exploit the hallmarks?
Therapy involves responses to the hallmarks either on their own or in combination. eg. telomerase inhibitors, selective anti inflammatory drugs, VEGF singalling inhibitors.
What are the 6 hallmarks of anti-cancer drug resistance?
Reduced expression/mutation of drug targets Drug pump upregulation Drug detox mechanism activity increased Redcue apoptosis susceptibility Alter proliferation level Increase DNA damage repair ability
