Chapter 10 - Biology of Cancer Flashcards
How is cancer a form of Darwinian evolution?
tumour development has cells with a heritable change that have a survival advantage, so outcompete their neighbours
What is the leading cause of suffering and death worldwide?
cancer
Cancer is a collection of more than ___ diseases
100
Is cancer age related?
yes, the longer we live, the greater chance DNA replication has a mutation
Is cancer genetic or epigenetic?
it can be both
Epigenetic
how behaviours and environment cause changes that affect gene function
What 3 factors influence risk and development of cancer?
environment, heredity, behaviour
Cancer is derived from the Greek work Karinoma meaning ____. Why?
crab; describes the projections of the tumour into near tissues
Original Tumour Definition
any swelling caused by inflammation
Current Tumour Definition
new growth or neoplasm (abnormal growth)
Are all tumours cancer?
no
Benign Tumour
non-cancerous
Malignant Tumour
cancerous
Well-differentiated Cells
normal tissues that grow and spread slowly
Undifferentiated Cells
made of abnormal cells that grow and spread quickly
What kind of cells do benign tumours have?
well-differentiated cells and connective tissue
Do benign tumour invade beyond its capsule?
no, they maintain a normal structure
Are benign tumours dangerous?
they can be
Benign Meningioma
tumour at the base of the skull that can compress the brain
Malignant tumour progress to ____
cancer
Malignant tumours grow ______ and have ______ organization
rapidly; abnormal
Anaplasia
loss of cellular differentiation
What type of cells do malignant tumours have?
undifferentiated
Pleomorphic
variability in size and shape
Stroma
supporting structure
Metastasis
ability to spread far beyond tissue of origin
What is the most deadly characteristic of malignant tumours?
metastasis
Carcinomas
cancers arising from epithelial tissue
Adenocarcinomas
cancers arising from ductal or glandular structures
Do benign tumours metastasize?
no
Benign tumours have a ____ mitotic index, malignant tumours have a _____ mitotic index
low; high
What is a carcinoma in situ (CIS)?
a pre-invasive epithelial tumour of glandular or squamous cell origin
What does “pre-invasive” mean?
the cancer develops incrementally as it accumulates specific genetic mutations
Are CIS considered malignant?
No, they have not broken the basement membrane or invaded surrounding stroma
Situ
in natural or original place
CIS remain _____ for a long time
stable
Can CIS progress?
yes they can progress into invasive or metastatic cancers
Can CIS disappear?
yes they may regress
CIS either…
remains, progresses, disappears
How to classify CIS?
vary from low-grade to high-grade
Which class of CIS are more likely to become an invasive carcinoma?
high-grade
Cancer is predominantly a disease of ______
aging
Mutation
cancer cells acquire characteristics that provide them an advantage over other cells
What is the advantage of cancer cells mutating?
increased growth rate and/or decreased apoptosis
Do cancer cells need growth factors to multiply?
no
Cancer cells lack contact inhibition meaning…
Anchorage independence
Do cancer cells undergo apoptosis?
no, they are immortal
How many mutations are required for cancer cells to form?
multiple
Tumour Microenvironment
mixture of cells (cancerous and not) and their secretions
Stage 1 of Cancer: Tumour Initiation
production of initial cancer cells, first stage of development
What does tumour initiation depend on?
specific mutations
Stage 2 of Cancer: Tumour Promotion
population of cancer cells expands with diverse phenotypes, the cells undergo additional mutations
Stage 3 of Cancer: Tumour Progression
tumour spreads to near (invasion) and far (metastasis), more mutations occur
Point Mutations
small-scale genetic changes, alteration of one or a few base pairs
Translocations
large-scale genetic changes
Driver Mutations (small-scale)
drive the progression of cancer forward
Passenger Mutations (small-scale)
don’t contribute to malignant phenotypes, just random events
Chromosome Translocations (large-scale)
large changes in chromosome structure
During chromosome translocation…
a section of one chromosome is translocated to another
Gene Amplification (large-scale)
rather than 2 normal gene copies, tens or hundreds are made
HER2 Proteins
too many receptors signalling cells to grow and divide too quickly
Clonal Proliferation Model
advantage of cancer cells that causes them to replicate faster than neighbours
What drives the accumulation of mutations?
rapid cell division and impaired DNA repair mechanisms
What does inactivation of the antigen presenting cell cause?
the cell seems normal but proliferates excessively
What does the mutation that activates K-ras cause?
normal cell that proliferates too much
What does a loss of DCC and an over-expression of COX-2 cause?
rapidly proliferating cell undergoing structural changes
What does a loss of TP53 and the activation of telomerase cause?
uncontrollable abnormal cell growth
Transformation
process by which a normal cell becomes a cancer cell
What directs transformation?
accumulation of genetic changes that drive it to malignancy
Do all cancer cells have the same mutations?
not necessarily, some have their own set of mutations
What is the result of transformation?
heterogenous mixture of cells that accumulate more and more mutations
Heterogenous
diverse in character
Which cancer cell triggers the initial pro-inflammatory response?
the initial cancer cells
Who is affected by the initial pro-inflammatory response?
the cancer cells that triggered it and the neighbouring nonmalignant cells
What is recruited during the pro-inflammatory response?
-Inflammatory and immune cells (macrophages, T and B cells)
-tissue repair cells (fibroblasts, adipocytes, mesenchymal stem cells, endothelial cells)
What do these recruited cells form?
a stroma/ tumour microenvironment
What does the stroma do?
surround and infiltrates the tumour
What % of the tumour mass may the stroma contribute to?
90%
What directs stroma growth?
-cancer cell proliferation
-cell additions
How does abnormal wound healing affect cancer cells?
increase proliferation and increases the diversity of said cells
Many cancer cells die but the surviving cells are more _______
aggressive and take on a metastatic phenotype
How do cancer cells gain the ability of uncontrolled growth?
sustained proliferation signals
What is pro-oncogene?
mutations that control sustained proliferation signals
What does pro-oncogene do?
blocks the body’s mechanism of stopping uncontrolled growth
What is the 1st hallmark of cancer?
uncontrolled cellular proliferation
When do normal cells enter proliferative phases?
in response to growth factos
What do growth factors do?
bind to receptors on the cell surface and activate signalling pathways to stimulate DNA synthesis and growth
Proto-oncogenes
normal genes that direct protein synthesis and growth
Oncogenes
mutated proto-oncogenes cells
Oncogenes are _______ of normal regulatory mechanisms
independent
How do stroma contribute to uncontrolled growth?
by producing their own growth factors
Which growth receptors are activated by cancerous oncogenes?
RAS, P13K, D-cyclins
What do translocations cause?
excessive and inappropriate oncogene production
What does Burkitt Lymphoma produce? How?
abnormal B-lymphocytes by translocation changing normal chromosomes
How do cancer cells stop tumour suppressor genes?
evading growth suppression by 2 mutations to inactivate tumour suppressor genes
What do normal tumour-suppressor genes do?
inhibit proliferation, stop cell division of damaged cells, prevent mutations
Anti-oncogenes
tumour suppressor genes
What must be inactivated for cancer to continue?
tumour suppressor genes
Tumour-Protein P53 is a…
classic tumour-suppressor gene
P53 aka ‘_______ of the genome’
guardian
What does P53 do?
monitor cellular stress and activates ‘caretaker genes’
What do caretaker genes do?
repair genetic damage and control apoptosis
How many mutations are required to inactivate P53?
2
What does only a single mutation of P53 result in?
increased cancer risk in offspring
How do cancer cells stop limits on their division?
telomere activation to provide unlimited “tickets” to divide
Hayflick Limit
limited number of divisions imposed on most body cells
What are telomeres?
protective caps on each chromosome
What happens to telomere caps as cells divide?
they shorten with each division
What happens when telomeres run out?
the cell can no longer divide so the cell dies (apoptosis)
What is telomerase?
an enzyme that maintains telomeres with cell division
Under normal conditions, where is telomerase active?
ovaries, testes, stem cells
What is the result of cancer cells activating telomerase?
unlimited telomeres (= unlimited division)
How do cancer cells gain their own blood supply to move around the body?
by angiogenesis – the irregular development of vessels
What does angiogenesis by cancer cells increase the risk of?
hemorrhage
Angiogenesis means cancer has access to…
the systemic blood system
What do advanced cancers secrete?
angiogenic factors to promote growth
What are the angiogenic growth factors produced?
vascular endothelial GF, platelet-derived GF, basic fibroblast GF
Are tumour vessels the same as healthy blood vessels?
no
Do tumour vessels branch the same as healthy blood vessels?
no, they branch irregularly from existing capillaries
Why are tumour vessels more prone to hemorrhage?
the cells are less tight together and are hence more porous so can leak
How do tumour vessels promote metastasize?
they allow the passage of tumour cells in the vascular system so it can spread
How do cancer cells gain the building blocks to gain more cells?
they program energy metabolism to increase cellular growth
Normal cells use ______ metabolism
aerobic (mitochondria ETC)
When normal cells have limited oxygen they undergo glycolysis and produce ____ _______.
lactic acid
Warburg Effect
Aerobic glycolysis: cancer cells, even in adequate oxygen presence, use only glycolysis
What does the Warburg effect allow cancer cells to do?
continually produce lactate
What is lactate used for?
lipid, nucleoside, amino acid, molecular building block production needed for growth
How do cancer cells resist apoptosis?
utilizing the intrinsic/extrinsic pathway to activate BAK and block apoptosis
Apoptosis: What does the intrinsic pathway do?
monitors cellular stress
What does the intrinsic pathway activate if a cell can recover?
BAX
What does the intrinsic pathway activate if a cell must be destroyed?
BAK
What do BAX and BAK regulate?
mitochondrial release of pro-apoptotic molecules (cytochrome C)
When is the extrinsic pathway activated from dormancy?
when BAK, the death receptor is activated
What does activation of both the intrinsic and extrinsic pathways result in?
Apoptosis induced by cytotoxic T-cells and natural killer T-cells
The dysregulation of apoptotic pathways in cancer cells means they do not…
undergo apoptosis
What is the major cause of death from cancer?
metastasis
Can cancer that has not metastasized be cured?
Often yes by surgery, chemotherapy, radiation
Are surgery, chemotherapy, and radiation effective against metastasized cancer?
not usually
How do cancer cells develop the ability to metastasize?
EMT - epithelial-mesenchymal transition
Where do carcinomas originate?
highly differentiated epithelial cells in sheets stabilized be adhesions to neighbouring cells
What prevents carcinomas from dissociating from the extra cellular matrix (ECM)?
their epithelial like characteristics
What must happen for cancer cells to metastasize?
dissociation from the extra-cellular matrix
Metastasis is achieved by a programmed transition from a partially epithelial-like carcinoma to a more ____________ mesenchymal-like carcinoma?
undifferentiated
When does epithelial-mesenchymal transition occur normally?
embryonic development and wound healing
Anoikis
apoptosis that occurs when normal cells are separated from their ECM
Intravasation: How do tumour cells enter circulation?
via leaky angiogenesis vessels created by the cancer
Where do tumour cells spread?
through vascular and lymphatic pathways
Extravasation: Where do tumour cells go after they exit circulation?
host tissue
What allows tumour cells to survive in circulation?
cancer clot: platelets that coat the tumour to provide protection
Tumour-Initiating Cells aka cancer stem cells
the few cancer cells required to form a tumour in a new location
Does metastasis guarantee proliferation?
No
Dormancy
stable, non-proliferating state
Is dormancy reversible?
Yes
2/3 of breast cancer deaths occur after a __ year disease-free interval
5
What are some viruses associated with cancer?
Human Papillomavirus (HPV), Epstein-Barr Virus (EBV), Hepatitis B and C
Oncolytic Viruses
a new cancer therapy that uses these virus to attack cancer cells
3 Ways Cancer cells avoid the immune response:
- don’t produce tumour antigen
- MHC gene mutation needed for antigen presentation
- immunosuppressive protein production or expressing inhibitory cell surface proteins
______ immune system protects against cancer
normal
__________ fosters cancer
immunosuppression (ie. non-hodgkin’s lymphoma, Kaposi sarcoma)
What does the release of immunosuppressive factors into the tumour microenvironment increase?
resistance to chemotherapy and radiation
They phenotype of a macrophage depends on the tumour m____e_______
microenvironment
What stage do ‘Classic Macrophages’ (M1) respond to?
inflammatory stage
What do classic (M1) macrophages do?
phagocytosis
What stage do M2 macrophages respond to?
healing
What do M2 macrophages do?
produce anti-inflammatory mediators to suppress inflammation
Do tumour-associated macrophages (TAM) perform like M1 or M2?
M2
What do TAMs do?
block T-cells and NK cells, produce cytokines that are advantageous to tumour growth and spread
What is analyzed microscopically to determine cancer staging?
present of metastasis
Stage I
no metastasis
Stage II
local invasion
Stage III
spread to regional structures
Stage IV
distant metastasis
Cancer Treatment: Surgery
-prevention
-biopsy for diagnosis and staging
-lymph node sampling
-palliative surgery
Palliative Surgery
used for pain relief rather than dealing with the cause of the condition
What does ionizing radiation do?
damage cancer cell’s DNA
Cancer Treatment: What is the goal of radiation?
eradicate cancer without excessive toxicity and damage to normal structures
What does chemotherapy target in cancer cells?
specific vulnerabilities
Cancer Treatment: Why is chemotherapy given in combinations?
it can be designed to attack many different weaknesses of the cancer at the same time
Paraneoplastic Syndromes
a group of rare disorders triggered by an abnormal immune response to a cancerous tumour
What causes paraneoplastic syndromes?
biological substances released by the tumour
What is usually the earliest symptom of unknown cancer?
paraneoplastic syndromes
Is pain a symptom of early malignancy stages?
usually no, if so it is influenced by fear, anxiety, sleep loss, physical deterioration
Cachexia Syndrome
weakness and wasting of body due to severe chronic illness
What is the most severe form of malnutrition?
cachexia syndrome
Cachexia Syndrome Symptoms
anorexia, early satiety, weight loss, anemia, asthenia, taste alterations, altered lipid, protein, carbohydrate metabolism
Asthenia
weakness, lack of energy and strength
What does direct tumour invasion of bone marrow cause?
leukopenia and thrombocytopenia
Leukopenia
reduced WBC count in blood
Thrombocytopenia
low platelet count in blood
What increases the risk of infection?
when neutrophil and lymphocyte counts fall
