AETIOLOGY OF CANCER 2 Flashcards
why are cancer cells called selfish cells?
they have have a selective advantage over normal, regulated cells – a form of natural selection
why are tumours said to have a ‘life of their own’?
Increase in neoplasm size persists whilst the hosts body is wasting (cachexia)
Ultimately kill themselves by killing the host
how do cancer cells and normal cells differ?
Growth control Contact inhibition Repair/death mechanisms Metastatic ability Appearance Growth rate Maturity/differentiation Immune evasion Function Angiogenesis
how can you measure tumour growth?
amount of time it takes the cell mass to double in size, and the number of such ‘doublings’
what is carcinogenesis?
process of inducing cancer
what kind of process is carcinogenesis?
A multistep process
what does carcinogenesis involve?
A normal cell evolves progressively to a cancerous state through acquiring a succession of properties
A normal cell acquires a series of molecular changes which result in the cell having new properties
what molecular changes does a cancer cell acquire?
changes to its DNA (genetic material) and to the proteins it produces
what is a change to DNA called?
mutation
define hallmarks
small number of traits
what are hallmarks?
traits that are shared by all cancers that govern the transformation of normal cells into cancerous ones
what are the 6 original hallmarks?
- sustaining proliferative signalling
- evading growth suppressors
- activating invasion and metastasis
- enabling replication immortality
- inducing angiogenesis
- resisting cell death
what does sustaining proliferative signalling involve?
Normal cells need external signals from growth factors to divide
Cancer cells are not dependent on normal growth factor signalling
Acquired mutations `short-circuit’ growth factor pathways leading to unregulated growth
give an example of ustaining proliferative signalling
mutation in Ras oncoprotein disrupts the normal -ve feedback mechanisms that dampen a signalling pathway when a mitogenic signal is hyperactivated
what does evading growth suppressors involve?
Normal cells respond to inhibitory signals
Cancer cells do not respond to growth inhibitory signals
Acquired mutations interfere with inhibitory pathways
give an example of evading growth suppressors
p53 is a common tumour suppressor gene which is inactivated in cancer cells leading to uncontrolled growth and proliferation
what does resisting cell death involve?
Apoptosis
Normal cells are removed by apoptosis, often in response to DNA damage
Cancer cells evade apoptotic signals
give an example of resisting cell death
dysregulation of anti-apoptotic BCL-2 family members
what does enabling replicative immortality involve?
Normal cells have a finite number of cell divisions after which they become senescent
The `cellular counting device’ is the shortening of chromosomal ends (telomeres) that occur after every round of DNA replication
what do cancer cells do in enabling replicative immortality?
Cancer cells maintain the length of their telomeres
Altered regulation of telomere maintenance results in unlimited replicative potential
give an example of enabling replicative immortality
Overexpression of telomerase allows tumour cells to overcome finite replicative ability
what does inducing angiogenesis involve?
Normal cells depend on established BV to supply oxygen and nutrients
Cancer cells induce angiogenesis, the growth of new BV, needed for tumour survival and expansion
give an example of inducing angiogenesis
Tumour angiogenesis is a function of multiple signals from a number of cell types residing in the tumour microenvironment
what does activating invasion and metastasis involve?
Normal cells maintain their location in the body and generally do not migrate
Cancer cells can move to other parts of the body and start secondary tumours
how does cancer grow?
Cells of malignant tumour duplicate rapidly and invade surrounding tissue (break through basement memb)
triggers angiogenesis through production of (TAFs)
how does cancer spread?
Cells compete with normal tissue for space and nutrients and eventually kills them
Some cells detach from primary tumour, enter body cavity or blood and establish secondary tumours
what are the 4 modes of tumour spread?
Local invasion
Lymphatic spread
Vascular spread
Trans-coelomic spread
what is the difference between malignant and benign tumours?
benign tour cells grow only locally and can’t spread by invasion or metastasis
malignant cells invade neighbouring tissues, enter BV, and metastasise to different sites
what are the 4 steps in the metastatic process?
Motility and invasion from the primary site – can be as single cells or clumps
Embolism and circulation in blood or lymph system – can also get spread through fluids in a body cavity
Arrest in a distant capillary & adherence to the endothelium
Extravasation into the target organ parenchyma
what do tumours need to metastasise?
they need an external stimulus through molecular cross-talk with cells in the neoplastic environment
what is EMT?
Epithelial mesenchymal transition
what is EMT involved in?
wound repair
metastasis
what does genome instability & mutation involve?
Cancer cells generally have severechromosomal abnormalities, which worsen as the disease progresses
These genetic alterations drive tumour progression
how do cancer cells promote genome instability?
they take advantage of mutations in DNA repair pathways
what has been found to induce many types of cancer?
local chronicinflammation
what do inflammatory cytokines promote?
tumour growth, proliferation and angiogenesis
how does tumour-associated inflammation promote tumour growth?
by supplying the microenvironment with growth factors, survival factors, and factors that promote angiogenesis
how are cancer cells seen by the body?
they appear to be invisible to the body’s immune system
how do cancer cells avoid immune destruction?
by disabling components of the immune system that have been dispatched to eliminate them
recruitment of inflammatory cells that are actively immunosuppressive
how do cancer cells generate energy?
use abnormal metabolic pathways
how do cancer cells produce energy?
by a high rate of glycolysisfollowed by lactic acid fermentation in the cytosol
what is the warburg effect?
Cancer cells convert available glucose to lactate irrespective of the availability of oxygen
what does the warburg effect lead to?
they divert glucose metabolites to useful anabolic processes that accelerate cell proliferation
what is the tumour stroma?
Cells co-opted in to supporting the cancer
what does the tumour stroma contain?
vascular elements
fibroblasts
macrophages
what do vascular elements do?
provide growth factors, blood supply (oxygen, nutrients)
what do fibroblasts do?
contribute MMPs for extracellular matrix degradation during cancer cell migration
what do macrophages do?
(alternatively activated), may provide defence against immune surveillance
what are the causes of cancer?
carcinogens
viral infections
oncogenes
what are carcinogens?
chemical agent or radiation that causes cancer eg. hydrocarbons, UV
what are oncogenes?
cancer causing cells
where are oncogenes derived from?
from proto-oncogenes (normal genes)
what do porto-oncogenes do?
regulate normal growth and development
what are carcinogenic agents?
chemicals
radiation
microbiologicals
what are chemical carcinogenic agents?
Some direct acting but most require metabolic conversion (procarcinogens)
what are radiation carcinogenic agents?
Hard uv light, X-rays, ß, gamma
what are microbiologicals carcinogenic agents?
RNA viruses-leukaemia
DNA viruses- Kaposi’s sarcoma
Pathogenic species- gastric carcinoma and lymphoma
give examples of carcinogens
Percival Pott
Soot
Tobacco smoke
give examples of cancers
chronic myelogenous leukaemia cervical cancer breast cancer melanoma retinoblastoma
what are the different treatments of cancer?
Surgery, chemotherapy, radiotherapy, biological - individually or in combination
what are the side effects of radiation therapy?
hair loss, nausea and vomiting (destructive effect on hair follicles and lining of stomach and intestine)
why does radiation therapy increase susceptibility to infection?
due to slow production of WBCs in bone marrow
why is treatment of cancer difficult?
as cancer contains diverse population of abnormal cells varying in their resistance to drugs
