What is cancer
is a class of diseases characterized by altered differentiation and uncontrolled division of cells, caused by an accumulation of genetic mutations
What is the outcome of cancer?
a malignant growth that may develop to invade other tissues
What does tumour mean?
literally means ‘swelling’
but primarily used to denote abnormal growth of tissue
What does neoplasm mean?
abnormal disorganized growth in a tissue or organ usually forming a distinct mass (can be benign or malignant)
What does cancer refer to (benign or malignant growths)?
malignant growths
Neoplasms invade ___ the ______ _____.
past the basement membrane
Define benign
If left untreated or with symptomatic therapy will not be life threatening
Define malignant
a clinical course that progresses rapidly to death; typically applied to neoplasms that exhibit aggressive behaviour
What is the local effect of neoplasms?
trivial to lethal occupy space OBSTRUCTS PASSAGES compress healthy tissue ulcerate and become infected hemorrhage
Common obstructions due to benign neoplasm are ________ and ____.
pulmonary and colon
When there is a benign neoplasm what does its cells do?
preform normal function (often in excess) without responding to negative feedback; remain localized
What is the local effect of malignant neoplasms?
trivial to lethal occupy space obstruct passages compress healthy tissue ulcerate and become infected hemorrhage - same as benign but…MORE AGRESSIVE (invade and destroy local tissue)
What is metastasis?
the spread of cancer from one site to another
How does the cancer metastasize to other organs?
- blood
- lymph
- in a body cavity
What criteria is met to be in each of the 5 stages of cancer?
- size
- depth
- invades adjacent organs
- if and how many lymph nodes effected
- spread to distant organs
What does the stage indicate?
how much the cancer has spread
What is the biggest predictor of survival?
the spread of the cancer
What do malignant neoplasms tissue stop doing;and start doing?
stop differentiating, and begin reproducing rapidly
What are the characteristics of a benign tumour?
- usually encapsulated
- no tissue invasion
- no metastases
- resemble normal tissue (differentiated)
- normal nuclei
- slow growth
- no new blood vessels
- little recurrence
- rarely necrotic areas
What are the characteristics of malignant tumours?
- ill defined borders
- tissue invasion
- metastases
- anaplastic (undifferentiated)
- pleomorphic
- nuclear irregularities
- fast growth
- angiogenesis
- recurrence if removed
- necrotic areas common
What does -oma indicate?
benign
What does -carcinoma indicate?
malignant epithelial cells
What does -sarcoma indicate?
malignant mesenchymal cells
Benign stratified squamous epithelium
squamous papilloma
squamous papilloma
benign stratified squamous epithelium
malignant stratified squamous epithelium
squamous cell carcinoma
Define carcinoma in situ.
Atypical squamous cells that have not advanced through basement membrane; Initially identified (incorrectly) as benign
benign glandular epithelium
adenoma
adenoma
benign glandular epithelium (gland or duct)
malignant glandular epithelium (gland or duct)
adenocarcinoma
adenocarcinoma
malignant glandular epithelium (glad or duct)
benign fibrous connective tissue
fibroma
malignant fibrous connective tissue
fibrosarcoma
fibrosarcoma
malignant fibrous connective tissue
Fibroma
Benign fibrous connective tissue
‘fibr-‘ is indicative of..
collagenous
‘lip-‘ indicative of…
adipose tissue
benign adipose tissue
lipoma
malignant adipose tissue
liposarcoma
lipoma
benign adipose tissue
‘chondro-‘ is indicative of…
cartilage
chondroma
benign cartilage
benign cartilage
chondroma
malignant cartilage
chondrosarcoma
chondrosarcoma
malignant cartilage
What is ‘osteo-‘ indicative of?
bone
Which 2 types of benign tumours are grossly similar?
chondromas and osteomas; confirm through histology
osteoma
benign bone
benign bone
osteoma
malignant bone
osteosarcoma
osteosarcoma
malignant bone
What is “-myo-“ indicative of?
muscle
benign muscle
myoma
malignant muscle
myocarcinoma
What is ‘neuro-‘ indicative of?
neurons
benign nerve fibres
neuroma
neuroma
benign nerve fibres
malignant neuron
neuroblastoma
neuroblastoma
malignant neuron
benign myelin sheath
neurofibroma or NEURILEMMOMA
neurilemmoma
benign myelin sheath
malignant myelin sheaths
neurilemmal sarcoma
or neurofibrosarcoma
benign meninges
meningioma
meningioma
benign meninge
malignant meninges
meningeal sarcoma
malignant bone marrow
leukemia
leukemia
malignant bone marrow
melanoma
malignant melanocytes
lymphoma
malignant lymphnodes
Is hematoma a neoplasm?
NO
malignant melanocytes
melanoma
malignant lymphocytes
lymphoma
What are the characteristics of ‘precancerous’ alterations to cells (dysplasia)?
- increased size and density
- REDUCED COLLAGEN
- IRREGULAR SHAPED NUCLEUS
- cytoplasmic immaturity
- irregular cell size
What are the shared characteristics of cancer cells?
- Local increase in cell number
- Loss of arrangement of cells
- Variation in cell size and shape (pleomorphism)
- Increased mitosis
What indicates abnormal mitosis
(various-shaped cells packed together without organization, many undergoing mitosis)
dark black DNA
Define transformation.
(aka carcinogenesis)
process by which a normal cell becomes a cancer cell
What are the 9 diverse behaviours of cancer cells?
- ANAPLASIA (no differentiation
- genetically unstable (due to quick mutations)
- grow independent of external growth factors
- AUTONOMOUS (no longer communicates with neighbouring cells
- loss of contact inhibition and anchorage dependence
- Tissue invasion and metastasis
- Limitless replication
- avoidance of apoptosis
- promote ANGIOGENESIS
Define angiogenesis.
blood vessel formation
What is the histological grade?
an evaluation of the aggressiveness of the tumour; marks the level of differentiation and number of mitoses (grade 1-4)
Define anaplasia.
loss of differentiation; marked cellular and nuclear pleomorphism, heavily stained nuclei, and tumour giant cells
Medium grade histological grade
cells begin to look less typical and change shape
High grade histological grade
very aggressive, normal cells die off as the compete with cancer cells for nutrients; surrounding ducts and glands are lost
Cancer cells become genetically unstable because of…
“proof-reading” genome gets deactivated, which allows mutations to accumulate more quickly
How does the cell cycle control gene contribute to cancer?
cancer cells develop a mutation of the ‘cell cycle control genes’ real easing cells from normal growth constrains
Cancer cells divide without _____ or they ____ their own
growth factor
produce
Define autonomous in regards to cancer.
lost much of their contact with surrounding cells (cell to cell communication is lost)
Why do cancer cells become autonomous?
cadherins are cell membrane molecules that bind adjacent cells
What does the loss of density-dependent inhibition do to cancer cells?
removes the limits to proliferation
When normal epithelial cells detach from neighbouring cells what happens?
undergo apoptosis
What contributes the cancers limitless replication?
telomerase
With normal cell divisions what happens?
there is non coding DNA is found at the end of each chromosome; each time a cell divides the chromosomal telomere shortens, leading to apoptosis after 50 divisions
What does telomerase do?
adds DNA back (normally at the ends of stem cells); a mutation in telomerase gene may produce this enzyme in cancer cells
How do cancer cells avoid apoptosis?
There are many genes responsible for apoptosis so any one having a mutation may prevent self-destruct signals
What is angiogenesis?
development of new blood vessels
What causes angiogenesis in cancer
mutation in angiogenic factor may allow cancers to continually produce signals for new blood vessel growth
What are the 2 most potent angiogenic factors?
FGF- fibroblast growth factor
VEGF- vascular endothelial growth factor
What does a mutation of angiogenic factors do to the rate of cancer growth?
this would allow cancer to grow faster and spread throughout the body
When do tumours become clinically relevant?
when they develop a blood supply
When are new vessels needed by a tumour?
when they consist of 100-300 cells (~2mm)
Where are we more likely to get cancer?
where cells divide rapidly; epithelial (90%)
Which cancer most commonly causes death?
lung
The most common cancers are dependant on what?
hormones
What is carcinogenesis?
literally means ‘creation of cancer’; multistage process involving genetic damage (mutation) that affect cell cycle
All cells with a ____ have access to the same ____
nucleus
genes
If ____ ____ are blocked then cells will keep _____
signalling pathways
dividing
What regulates the development, growth, differentiation and death of cells?
cell cycle control gene
What does the cell cycle control gene do?
has growth factors that turn the cells division and proliferation on or off
When would a cell be turned on?
when there is damage it needs to repair/replace
When is a cell turned off?
when repair is complete
What is responsible for turning cells on and off?
cell cycle control genes
What 2 main mechanisms are involved with transformation to cancer cells?
- Proto-oncogene activation
2. Tumor suppressor gene inactivation
What do proto-oncogenes activation cause?
stimulates inappropriate growth /activity (dominant mutation - needs only one copy of gene mutated)
What do tumor suppressor genes inactivation cause?
prevents the arrest of the cell cycle (recessive mutation - both copies must be mutated)
What are mutated pro to-oncogenes called?
oncogenes
What are proto-oncogenes responsible for?
produce growth factor that control cell size, differentiation and proliferation; typically activate cells to divide
What is ras protein?
- found on the inner surface of the plasma membrane of proto-oncogenes
- ras signals the nucleus when growth receptors are stimulated
- ras can be mutated to always convey the message to divide
What percentage of cancer have the ras gene mutation?
30 %
Define oncogene.
cancer causing gene
Ras gets converted to an ______ that tells cells to continually ____
oncogene
divide
What do tumour suppressor genes do?
suppress growth
When tumour suppressor genes are inactivated or deleted the…
tumour forms
What are 3 examples of tumour suppressor genes?
p53
retinoblastoma (Rb)
BRCA1
What is p53 involved in?
involved in producing DNA repair, growth inhibition and APOPTOSIS
How does p53 hep with DNA repair?
- helps with normal growth control (which maintains integrity)
- blocks DNA production until DNA can repair
How is p53 activated?
- by DNA damage
What is p53’s role in growth inhibition?
- encodes for protein that suppress growth
What is p53’s role in apoptosis?
induces apoptosis when DNA damage is irreversible
What is the prevalence of p53 gene mutations?
50% of cancers contain it
What happens when p53 gene is mutated?
- loss of DNA repair, growth suppression and apoptotic factors
- DNA replication and cell division without correction of DNA mutations causing genetic instability and increasing risk of cancer formation
What does DNA replication and cell division without correction of DNA mutations cause?
causing genetic instability and increasing risk of cancer formation
Can cancer develop with one mutation?
no, needs multiple.
What are some mutations that affect cancer development?
- oncogenes (self sufficient growth signals)
- tumour suppressor (insensitivity to antigrowth signals)
What are the hallmarks of cancer?
- self sufficient growth signals
- insensitivity to antigrowth signals
- evades apoptosis
- limitless replication potential
- sustained angiogenesis
- tumour invasions and metastasis
- prevent DNA repair
What is tumour heterogeneity?
tumours having different kinds of cells
Human cancers arise ______
sponatneously
frequency of mutations can be increased by exposure to _____
carcinogens or mutagens
Cancer incidences ___ with age.
increases
What cells are oncogenes inherited from?
geminal cells
What cells are oncogenes NOT inherited from?
somatic cells
What is BRCA1/2 known for?
mutation in breast cancer
____ and ____ effect your changes of getting cancer.
genes and environment
What accounts for varying cancer rates in different countries?
environmental factors
Gene environment interactions include…
- tobacco
- diet
- alcohol
- sexual/reproductive behaviour
- air pollution
- occupational hazards
- UV/ionizing radiation
- hormones
Can viruses cause cancer?
yes, accounts for 15% of cases
What kind of virus would cause cancer?
one that integrates into host genome, and carry oncogenes (more provirus)
What are some examples of viruses that cause cancer?
- human heroes virus (HHV)
- Hepatitis B or C (80% of cases with liver cancer)
- HPV (nearly 100% of cases of cervical cancer)
What is relevant in 80% of liver cancer?
hepatitis B or C
What kinds of cancers can result from human herpes virus (HHV)?
- kaposi’s sarcoma (connective tissue)
- burkitt lymphoma (bcells)
What kind of bacteria causes cancer?
- helicobacter plori
- infects 50% of the worlds population
- infects stomach- leads to gastric lymphomas and carcinomas
How does bacteria cause cancer?
- Formation of carcinogens
- Alter secretion of cytokines and growth factors
- Disrupts gastric epithelial cell cycles
- Generation of free radicals
- Decrease protective gastric secretions
How do cancer cells get from one spot to another?
- local spread by direct invasion (which is the first step in metastasis)
- malignant cells break through their basement membrane and surround connective tissue
What are the mechanisms required for metastasis to occur?
- Cellular multiplication
- Mechanical pressure
- Release of lytic enzymes
- Decrease cell-to-cell adhesion
- Increase motility of tumor cells
- Cellular multiplication:
Invasion depends on the rate of _____ _____.
tumour growth
How do you calculate tumour growth?
amount of cells replicating - the amount of cells dying= tumour growth
What is the mechanism of pressure for metastasis?
- builds up and forces sheets or fingers of tumor cells along paths of least resistance
- pressure can result in local tissue necrosis making it easier for the tumour to spread
What is the lytic enzyme mechanism of metastasis?
malignant tumour cells secrete lytic enzymes to breakdown extra cellular matrix (ECM); decreases local pressure allowing tumour to invade local tissues
What is the decreased adhesion mechanism of metastasis?
cancer cells do not adhere due to lack of or defect in cadherins
What are cadherins responsible for?
adhesion of neighbouring cells
What is the increased motility mechanism of metastasis?
secretion of AUTOCRINE MOTILITY FACTOR (AMF) allows tumour cells to stimulate own movement
Cancer cells take the path of ____ _______.
least resistance
How do malignancies spread?
move through body cavities, lymph, or blood
What is a primary neoplasm?
the original neoplasm
What is metastasis?
a secondary neoplasm; subpopulation that has detached, spread, & formed secondary mass
Metastases often resemble the ____ _______ histology.
primary neoplasm
What are the pathways of metastatic spread?
- seeding across body cavity
- via lymph channels
- via blood vessels
What is lymphatic spread?
metastasis via lymphatic channels
What is hematogenous spread?
metastasis via blood vessels
What is trans-coelomic spread?
metastasis seeding across body cavities
Where is seeding likely to occur?
peritoneal cavity
What is a concern when surgically removing a cancer?
metastasis via seeding (in body cavities)
What is the most common route of metastasis?
lymphatics
Once metastatic emboli are in the lymph they travel to…
regional lymph nodes
What happens when cancer cells get lodged in lymph nodes?
- get KILLED (local inflammation or incompatible local environment)
- become DORMAT
- detach and enter afferent vessels
- grow into noticeable lump
What do manifestations typically depend on?(slide 41)
location and extent of metastasis
What are the 9 main manifestations?
- Local Effects
- Pain
- Fatigue
- Cachexia (general weakness)
- Anemia
- Leukopenia/ Thrombocytopenia
- Infection
- Paraneoplastic Syndromes
What is the local effect of cancer?
- ulcerations and necrosis
- when with a serous membrane commonly leads to effusion (excreting fluid or gas)
How many terminally ill patients feel pain?
60-80%
Is there pain in the early stages of cancer?
little to none
What about cancer causes pain?
- PRESSURE
- stretching visceral surfaces
- tissue destruction
- inflammation
Pain can be due to ____ factors, ___ and ____
psych factors
infections and necrosis
What is the most common symptom of cancer?
fatigue not releived by more sleep
What may fatigue involve?
- sleep disturbances
- biochmical changes due to disease or txt
- nutritional disrution
- LEVEL OF ACTIVITY
- psych factors
What is cachexia?
most severe form of malnutrition associated with cancer
What percentage of cancer patients die from cachexia?
20%
What percent of patients present with cachexia?
80%
What is involved in cachexia?
ANOREXIA ANEMIA (low RBC count) ASTHENIA (weakness) taste alterations altered metabolism of nutrients
What is the anorexia due to in cachexia?
pain, depression, chemo- or radiation-therapy
Define emaciation
to be come very thin, loss of ~80% of adipose tissue and skeletal muscle
Does food decrease with cachexia?
food intake may increase
Why does the same or decreased fluid intake not effect the decrease in weight of cancer patients?
protein synthesis and protein degradation in some cells (skeletal muscle) – more like patients suffering from sepsis or severe trauma
How is cachexia treated?
high calorie intake
Why do we see anemia in cancer patients?
chronic bleeding severe malnutrition medical therapies impaired production malignancies of blood-forming tissues
How do we treat anemia?
EPO- erythropoietin
What is leukopenia?
decreased WBC’s
What is thrombocytopenia?
decreased platelets
What about cancer causes leukopenia and thrombocytopenia?
direct tumor invasion of bone marrow
chemotherapy or radiation of bone marrow
Why is infection risk increased when you have cancer?
- decreased WBCs, increased immune function - immunosuppression due to chemo/radiation
- decreased resistance due to surgery
- age
What are paraneoplastic syndromes
When mutations result in PRODUCTION OF HORMONES (such as ADH (leads to SIADH), ACTH (leads to Crushing syndrome)
PTH (leads to hypercalsemia)
- procoagulants (increase venous thrombosis)
- come cause weakness or pigmentation
What is preformed to screen for cancer?
observation palpation imaging histologic sampling blood tests
Cancer generally has a ________ prior to treatment.
headstart
After how many doublings is the tumour at 1 billion cells and approx 1cm
30 doublings
After 35 doublings how many cells does the tumour contain?
1 trillian
What are 6 treatment options for cancer?
- Surgery
- Radiation
- Chemotherapy
- Hormone Therapy
- Immunotherapy
- New possibilities on the horizon
What roles can surgery play in management of cancer?
diagnosis
prognosis
treatment
prevention
Surgery to obtain viable neoplasm tissue allows ____ diagnosis and obdservation needed for ___ and ___
histologic diagnosis
staging and grading
What ways may we retrieve tissue from cancer.
- aspiration biopsy
- needle (core) biopsy
- incisional biopsy (remove a piece of tumor)
- excisional biopsy (remove the entire tumor)
- endoscope methods
Surgery is used for treatment of…
solid cancer
(may have necrotic centres and poor vascular supply rendering radiation and chemo less effective
How can surgery be used preventatively?
to remove congenital some times cancer causing parts of the body
What is debulking?
(remove as much as possible – increases success of alternate therapies)
What is radiation?
Utilizes high energy radiation from a variety of sources which can be precisely aimed at neoplastic; without excessive toxixity
What kind of rays are caused for radiation?
xray and gamma rays
How does radiation work?
generates free radicals leads to tumour cel death
What percentage of cases is radiation useful for?
50-60%
How many doses are typically used to minimize damage to healthy cells and increase chance cell dividing?
30+
How is radiation typically used?
- vital or inaccessible areas
- in combination with surgery and or chemo
What is the device used in radiation treatment?
linear accelerators
What is palliative radiotherapy used for?
- painful bone and soft tissue metastases
- brain metastases
- malignant spinal cord compression
- airway obstruction, hemoptysis, ulcerating or bleeding lesions, etc.
What percentage of palliative radiotherapy patients notice a significant difference in symptoms
60-80%
When is chemotherapy used?
- widespread
- rapidly growing
- at high risk of micro- metastatic deposits (clinically undetectable)
Chemotherapy is a _____ treatment.
systemic (effecting the whole body)
Chemotherapy is typically done with a combination of drugs because…
- ONE type may NOT BE EFFECTIVE
- AVOID RESISTANCE
- allows individual doses to be smaller, which typically produces LESS SIDE EFFECTS
What are cytotoxic drugs?
they target viral cellular machinery or metabolic pathways required for malignancy
Most chemo agents interfere with ____ and _____ of DNA
synthesis or function
What are cytotoxic drugs more toxic too?
proliferating cels
What 4 main things does chemo do?
- prevents vessel growth
- stops cels division/replication
- causes spontaneous cell death
- creates a non-dividing cell by altering cell structre
Different chemo drugs stop replication in different ____, making it more effective
stages
Define therapeutic index.
refers to the relative amount of the drug required to kill cancer cells, compared to the dose that is harmful to normal cells
Chemo treats proliferating cells, however cells responsible for persistence and growth is often largely in __ ___ ____.
cell cycle arrest
Cells that are in cell cycle arrest ___ ___ _.
stimulate later growth
Define first order kinetics.
a dose of the drug kills the same percentage of cells are not the same number of cells each time is it given
What impact does first order kinetics have on cancer treatment?
must use multiple courses of therapy
What effect does tumour heterogeneity and chemotherapy have?
creates sub-clones making cancer more heterogenous and adapts to host defences making it MORE AGGRESSIVE
What are some side effects of chemo and radiation?
- aging
- discomfort
- fatigue and anemia
- risk of infection
-risk of hemorrhage - effect on rapidly dividing cells
(bone marrow, GI, skin and nails, and reproductive system)
What are the GI effects of chemo and radiation?
- ULCERS
- INFECTION
- malabsorption
- diarrhea
- nausea
What are the skin and nail side effects of chemo and radiation?
- alopecia
- dryness
What are the reproductive system effects of chemo and radiation?
- decrease number of gametes
- affects indirectly through the hypothalamus
How does hormone therapy work?
alters hormonal environment through suppression or receptor changes which may slow cancer
How does immunotherapy work?
- use bacterial strains locally induce immune response
- or antibodies injected directly (antibodies injected with radioactive isotopes)
How do interferons effect tumours?
They are
- Anti-proliferative (prevent cell division but prolonging cell cycle, making cells more susceptible to chemo.)
- Pro-apoptotic (initiate cell death pathways)
Immunostimulatic (trigger immune response)
- Anti-angiogenic (stop new blood vessel formation)
What are some potentially new cancer therapies?
- block angiogenesis
- initiate apoptotic pathways
- virus
What are the components responsible for blocking angiogenesis?
anti-VEGF compounds to block angiogenesis
- EGFR (epidermal growth factor receptors)- tyosine kinase inhibitors
to block angiogenesis
What apoptotic pathways could be initiated for cancer therapy?
Gemin X- INITIATES APOPTOSIS regardless of their p53 status
currently in phase 2 of clinical trials under the name obatoclax
How can viruses be used as cancer therapy?
Viruses are able to infect human cells and replicate, induce cell death, and release viral particles that spread through tissues (self-amplifying dose)
- cancer cells are extremely vulnerable to viral attach
Viruses that are extremely sensative to ___ pathwayss of normal cells are able to only effect cancer cells
interferon
What is the down side to cancer treatment?
become immune to the virus