Week 3 - Lecture 1 - Altered Cellular Proliferation and Differentiation Flashcards
cancer definitions
is a chronic disease characterised by remission and relapse
arises from uncontrolled proliferation of cells that have the ability to spread to other parts of the body and continue to grow
derived from greek word for crab, Karkinos (carcinoma)
cancer is a malignant tumour ( they can spread to other parts of the body)
a benign tumour is not malignant and cannot spread (but is still uncontrolled proliferation of cells)
tumours are also referred to as a neoplasm - new growth
not all tumours or neoplasms are cancerous (some are benign)
Cell proliferation
process of increasing cell numbers- generation of new daughter cells
normal tissue : regulated process
- actively dividing equivalent of number of dying/shed
- injury increases cell production
humans have 2 major categories of cells
gametes and somatic cells
-gametes : meiosis
-somatic cells : mitosis
in terms of proliferation
- the 200 cell types in our body are divided into 3 large groups
- the undifferentiated stem cells that be triggered to enter cell division when needed
- progenitor or parent cells that continue to divide and reproduce (blood, skin)
- Well differentiated or rarely dividing cells (neurones, cardiac and skeletal muscle)
cell differentiation
the process whereby proliferating cells becomes progressively more specialised cells types
the endpoint is fully differentiated adult cell with
- specific structure
- specific function
- specific life expectancy
- RBC is terminally differentiated : concave, oxygen carrier, lifespan of 120 days
differentiation occur under the direction genes growth factors nutrients environmental stimulation
Stem cells
highly undifferentiated
potential to divide into progenitor cells (produce more functional cells) or stem cells (produce more of themselves)
progenitor can divide further and differentiate
single stem cell can give rise to the many cells needed
once they are terminally differentiated they have a reduced mitotic rate
normal cell
grow, divide and differentiate
aware of their neighbours and curb their growth to accommodate the m
monitor their own growth
respond to their environment
do not divide when they have damaged genetic information
die when required (too old or damage beyond repair)
carcinogenesis
the origin and development of cancerous neoplasm
neoplasms : irreversible and deviant cellular development (out of control cell proliferation)
cancer : highly invasive and destructive neoplasms (they are malignant as they can spread to other parts of the body )
-cancer cells do not reopens to our body’s normal regulation of cellular proliferation and differentiation
- can develop from almost all cell types including
- proliferating parenchymal (functional) tissue/organ
- proliferating stromal (supportive) cells
- labile cells (i.e. epithelial cells, blood cells) are highly prone to neoplasm development
- cancers in permanent (undividing) cells (neurons, mature cardiac cells) are less common
what makes a cancer cell
normal cells are not immortal. In fact, your cells are only designed to divide up to 80 times before going into a permanent cell arrest. Cancers overcome this to have infinite divisions (immortality)
when our DNA is damaged, if it cannot be repaired then it will undergo apoptosis
Some cancer cells produce and secrete certain proteins to become invisible to our immune system
normal cells require close proximity to the vascular system to survive. Neoplasms cannot grow bigger than 10mm without producing proteins that encourage the growth of new blood vessels to the tumour (angiogenesis)
normal cells are usually in contact with other similar cells to form a tissue. Cancers learn to break away from their adjacent cells, invade into the blood/lymphatic system and grow in other locations
Genetics basis of cancer
cancer arises through genetic mutations to active/inactive pathways (see previous slide for some examples of pathways)
Multiple pathways are required to be altered for a cancer to develop
genetic mutation example
acquired (after birth) : exposure to mutagens, spontaneous (somatic cancers)
inherent in the germline (before brith) : passed from parent to children (familial cancers)
- inherited predisposition : high risk of developing cancer
Exposure to mutagens, spontaneous mutation
if the mutation occurs in somatic cells, it is not passed to the offspring
if the mutation occurs in germline cells, It can be passed to future generations
cancer is a dysfunction of our genes, so what genes are normally altered in cancer
oncogenes
tumour suppressor genes
Oncogenes
cancer gene
these genes in a normal (Non-mutated) state are called proto-oncogenes and their role is to promote protein synthesis and cellular growth when required
we have observed many cancers mutate these proto-oncogenes to aberrantly increase their activity (i.e. turn them on) resulting in
- promote unregulated cell growth
- inhibition of apoptosis (programmed cell death)
activation : porto-oncogenes (normal gene) become oncogenes
Altered genes leading to cancer: oncogenes
proto-oncogenes are normal genes
have viral role in regulating cell function
cancer just exploits our current tools for cell proliferation
activated through 1 of 3 ways
- point mutations
- translocation
- gene amplification
point mutation
single nucleotide base damage/mutation
may lea to increased functional activity (if the DNA mutation results in a change in the protein) or increased gene expression (eg. the mutation Is in the gene promoter)
- spontaneous (error in DNA replication during S phase )
- exposure to environmental influences
- carcinogenic chemicals
- radiation
translocation
chromosome breaks, relocates and united with one another
produces a brand new protein (encoded partly from two different chromosomes) called a fusion protein. This new fusion protein will function like an oncogene
cells deviates from expected growth and differentiation states
occurs in blood cancers (leukaemia, lymphoma )
and some solid tumours (eg. bone and fat cancers)
gene amplification
duplication of a small piece of chromosome over and over
results in an increased expression of an oncogene
overproduction of gene products
- solid tumours - liposarcoma, breast cancer, neuroblastoma
oncogenes can come from two major sources
DNA mutations / alterations of proto-oncogenes
viral infection with oncogenic viruses
some cancers (15%) are linked to viral infection, in these instances, the virus infects the cells and produces the oncogenic proteins from they genome
Altered genes leading to cancer : tumour suppressor genes
regulate the rate at which cells divide and die
major mechanism I controlling apoptosis
- optimal number of cells is maintained
mutated tumour suppressor genes become inactivated
mutated tumour suppressor genes may result in
- unrestricted proliferation and neoplastic transformation
- inhibition of apoptosis (the last resort “self destruct” button)
tumour suppressor genes
two most common tumour suppressor genes that are altered in cancers
- p53 gene
- retinoblastoma (Rb) gene
Altered genes leading to cancer: TSG
p53 mutations are the most common mutations in cancer
inactivating p53 is imperative to a cell becoming a cancer
over 50% of all cancers inactivate p53 by DNA mutation
p53 mutations are linked to 3/4 types of colorectal cancer
p53 controls cell division and repairs damaged DNA
TSG
Rb (retinoblastoma gene)
mutation lead to rare childhood cancer of the retina
- half of the cases : germline mutations (inherited)
- half of the cases : spontaneous mutation in somatic cells
mutations (inactivation) also linked to : osteosarcoma, breast cancer, pancreatic cancer, lung cancer
Rb protein stops cells progressing into S phase of the cell cycle
Carcinogens
identification
- epidemiology studies
- experimental research
- cell and molecular pathology
carcinogen : known cancer causing agent
- interfere with molecular pathways
- initiate tumours
- promote tumours
direct : cause modification in cell’s DNA
Indirect : induce immunosuppression, chronic inflammation, inactivate tumour suppressor proteins
identification is difficult
- prolonged latent period
biomedical factors for carcinogens
genetic susceptibility
hormonal factors in females
Lifestyle factors for carcinogens
smoking alcohol consumption physical inactivity and obesity chronic infections diet
environmental factors carcinogens
sunlight
radiation
occupational exposure
pollution
carcinogens ionising radiation
potential cause (promoter)
high energy radiation cause
- DNA damage in cells
- directly kill cells
- radiation induces reactive oxygen species – leads to DNA damage and mutation
labile cells are most affected by radiation
-used as a cancer treatment : killing cells that are highly proliferated (eg. cancer cells)
all individuals are exposed to natural low dose radiation
- geological properties of the place, long distance flights
accumulative effect of low dose radiation unknown/debated
- cause - effect is difficult to establish
- – background radiation : Townsville 2x of nearby cities (uranium in castle hill)
Carcinogens : UV radiation
main source : sun
short wavelength
capable of inducing carcinogenesis
- DNA damage in cells
- directly kill cells
risk for developing neoplasm
- length of exposure
- frequency of repeated burn injuries from UV exposure
- skin tone
Carcinogens : hormones
cancer promoter
some tumour cells are responsive/dependant on hormones for growth
- breast, uterus, adrenal glands have receptors responding to hormone levels
cancer treatment
- therapeutically administered to block tumour growth
- adrenal corticosteroids (prednisone) can directly kill tumour cells, inhibit mitosis
- anti-inflammatory effect
- oestrogen and testosterone can be manipulated to starve the tumour and prohibit further growth
- Tamoxifen (a common breast cancer treatment) blocks the action of oestrogen and inhibits growth in oestrogen sensitive breast tissue
- adrenal corticosteroids (prednisone) can directly kill tumour cells, inhibit mitosis
removal of organs/tissue that secrete specific hormones
- affect tumour growth by reducing systemic hormone production
- eg. castration to treat prostate cancer
carcinogens : chemicals
asbestos exposure is assoicated with mesothelioma
many cancers of the nasopharynx (nasopharyngeal carcinomas) are linked to inhalation of industrial agents
chemical carcinogenesis influenced by
- individual susceptibility
- lifestyle factors
- environmental exposure
Carcinogens: Tobacco
Tar : 1000s of substances, several of which are carcinogenic
1/3 cancer deaths in US is linked to tobacco
- inhaling smoke is toxic to respiratory mucous
- initiate or promote other types of cancer
- laryngeal, lip, oesophageal, bladder
dose effect
- longer exposure
-heavier use
=higher risk for neoplasm
carcinogens : microbes
viral infection is linked to 15% of all human cancers
most prevalent
- HPV
- sexually transmitted
- certain strains (15 strains) lead to cervical cancer
- gardasil : HPV 16, 18 : cervical cancer (and 6, 22: genital warts)
Hepatitis viruses
- sexually transmitted, parenteral (injection, infusion > latrogenic)
Hep B, C : Hepatocellular cancer
mechanism can depend on virus
- most viruses express proteins to inactive tumours suppressor genes
- once inside our cells, the HPV produces two major proteins which directly interact with and inactivate our p53 and Rb proteins
bacteria : H.Pylori is carcinogenic
- chronic inflammation due to chronic infection support tumour growth
Carcinogens : diet
toxic, carcinogenic substances in food
- compounds produced in the cooking of fat, meat or proteins
- aflatoxin - exposure leads to liver cancer
high fat- low fibre diets
obesity
- correlates with the BMI (BMI>40)
- adipose tissue is active endocrine and metabolic tissue
- in response to endocrine and metabolic signalling, adipose tissues releases free fatty acids
- increased free fatty acids gives rise to insulin resistance and causes chronic hyperinsulinaemia
- correlates with colon, breast, pancreatic and endometrial cancers
Carcinogenesis
initiation - promotion -progression theory
-initiating event must be combined with a promoting event
-initiating event (indicator) causes mutation in a cell
-promoting event (promoter) : expansion of the mutated cell’s growth
- continuing exposure to promoter required
- common promoters
chronic inflammation
- chronic gastritis – gastric cancer
- ulcerative colitis – colorectal cancer
hormoned
chemicals in environment
Carcinogenesis progression
progression : extension of promotion phase
cancerous growth NO longer depend on promoter
Growth become autonomous
Cancerous cell functioning without regulation
- growth
-division
- death (apoptosis)
initiation or promotion in isolation : no cancer
initiation or promotion exposure : not definite
multifactorial etiology
