Cancer Biology Flashcards
(204 cards)
1
Q
How common is cancer?
A
-Nearly 1 in 2 Canadians get it
-49% lifetime risk for men
-45% lifetime risk for women
-25% who develop cancer will die of it
2
Q
Cancer is a disease of the
A
-Cell
-While cancer is typically referred to by the type of tissue it originated in (breast cancer, lung cancer)
-When looked at more scientifically cancer is fundamentally a disease of the cell itself
3
Q
Cancer Cells are Defined by two Heritable Properties:
A
- Autonomy
- Anaplasia
-To understand what these terms mean got to understand - Cell proliferation
- cell differentiation
4
Q
Cell Proliferation
A
-Programmed generation of new daughter cells divided from a parent cell in the boys
-Under the control of genes
-A regulated balance of cell proliferation and cell death is needed to maintain body homeostasis
5
Q
Examples of Cell Proliferation
A
-Every day thousands of skin cells are sloughed off and replaced by new cells generated in the stratum basale
-After drinking a lot of alcohol your liver regenerates it’s damaged and destroyed hepatocytes using that same form of cell division
6
Q
Types of Cell Proliferation
A
Mitosis
Meiosis
7
Q
Mitosis
A
-Each cell ends up with two copies of a chromosome
-How the majority of the body undergoes cell proliferation
-46 chromosomes in the parent cell should result in 46 chromosomes in the two daughter cells
-Highly regulated process with multiple checkpoints
-Dependent on a variety of factors such as growth factors or hormones and signals from neighbouring cells
8
Q
Meiosis
A
-Each cell only has one copy of each chromosome
-46 chromosomes (23 pairs) in a normal cell becomes 23 total chromosomes with one copy each in the four new cells after meiosis
9
Q
Autonomy
A
-Altered cellular proliferation
-The loss of regulated balance of cell division may result in over proliferation and crowding of cells
-Cancerous cells exhibit excessive cellular proliferation
-They grow and reproduce uncontrollably
-They are said to be autonomous
10
Q
If a cell begins to undergo excessive mitosis or meiosis when not needed…
A
-then this can cause significant dysfunction of the tissue those new cells reside in
11
Q
When a cell becomes cancerous it …
A
-Loses the ability to stop the mitotic cycle and begin to reproduce uncontrollably disregarding signalling from neighbouring cells
-Thus they are termed autonomous
12
Q
A normal cell divides only when..
A
-Needed and only for as long as needed
-A cancerous cell no longer follows those rules and begins to reproduce far more than Is necessary to repair an injury
13
Q
Cell Differentiation
A
-The orderly process of cellular maturation to achieve a specific function
-A regulated balance of undifferentiated and differentiated cells is needed to maintain body homeostasis
14
Q
Cell differentiation under control of:
A
-Genes
-Growth factor
-Nutrients
-Stimulation from the external environment
15
Q
Second characteristic of cancer cells
A
-Anaplasia
-Described as uncontrolled cell differentiation
16
Q
When a stem cell matures..
A
-It differentiates from a pluripotent cell (a cell which can mature into a wide variety of different mature cells), Into a unipotent (it can only have one type of mature cell)
-This differentiation and maturation is under the control of all 4 factors
17
Q
Cell differentiation control: Certain Genes
A
-Which are turned on or off during maturation of a cell
18
Q
Cell differentiation control: Growth factors
A
Hormones such as HGH (human growth hormone), estrogen, testosterone, etc
19
Q
Cell differentiation control: Nutrients
A
Some cells require specific nutrients in order to differentiate into their proper, mature forms
-Immature T cells for instance require amino acid glutamine to differentiate into CD4+ T helper cells
20
Q
Cell Differentiation control: Stimulation from the external environment
A
-If you cut yourself, you stimulate production of new skin cells to repair the wound
21
Q
Undifferentiated Cells
A
-Can mature into any number of mature cells
-Thus they are flexible and adaptable to whatever the tissue they are differentiating in requires
22
Q
Differentiated Cells
A
-Have matured into a single type of cell
-Can not undifferentiate
-Eg. A differentiated cardiomyocyte for instance will not undifferentiate into an immature cell or spontaneously become a renal cell instead
23
Q
Anaplasia
A
-Altered cellular differentiation
-The loss of regulated differentiation renders the cell incapable of carrying out its designated function
-Cancer cells = this, they are too busy replicating that it often doesn’t mature enough to do it’s designated job
24
Q
Cancerous cells exhibit a loss of
A
-Cellular differentiation
-They lose their ability to carry out their specific functions and do not die when expected
-They are said to be anaplastic
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Eg Anaplasia
-If a hepatocyte in your liver becomes cancerous and loses differentiation then it will no longer be able to preform the metabolic function of a hepatocyte = too busy replicating cannot mature to do its job
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Not following the rules of differentiation =
Cancerous cells which have lost differentiation are unable to function as their differentiated, normal cells would
-Mature cells effectively act like immature cells
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Neoplasm =
Autonomy and Anaplasia
-When a cell has lost control of its proliferation and its differentiation it is said to be autonomous and anaplastic and can now be considered as a potentially cancerous tumour cell
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Difference between a tumour and a cancer ?
-Tumor: originally referred to as any swelling; now generally reserved for a new growth (neoplasm)
-Two types:
Benign, Malignant
-Cancer: a malignant neoplasm
so all cancers are tumours, but not all tumours are cancers
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The Root Cause of Cancer is:
DNA Damage
-Cancer is a disease of the cell where the cell has become autonomous and anaplastic = damage to the DNA of the cell in question
-This damage is called DNA mutation
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Mutations that lead to cancer are characterized as
Carcinogenic
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Transcription/Translation
-Genetic information is stored as genes in our double stranded DNA, which is transcribed into a single stranded mRNA via an enzyme called RNA polymerase
-The mRNA then leaves the nucleus, enters the cytosol and is used as a template for the ribosome to generate a protein from individual amino acid molecules
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Each Gene in the DNA begins with
-The 3 base start sequence “ATG”
-And when mRNA is made the RNA polymerase copies that into the sequence AUG
-Thyamine is replaced by uracil in RNA
-Every subsequent series of 3 bases of mRNA codes for a different amino acid
-These sequences of 3 mRNA bases are known as RNA codons
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The shape and function of the protein is dictated by
-the sequence of amino acids which in turn was determined by the sequence of RNA codons read by the ribosome
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RNA codons read by
-The ribosome
-The ribosome aligns the mRNA by looking for the AUG start codon (codes of methionine amino acid)
-Then starts adding other amino acids together based on the next 3 mRNA bases (codon)
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Eg. bases
-If next 3 bases is UUA then ribosome will add a leucine amino acid
-If it’s AGU the ribosome will add a serine
-In some cases 3 or 4 codons can call for the same amino acid
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How does the ribosome know when to stop and release the new chain of amino acids ?
It reads a UGA sequence, which is the stop codon
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DNA Point Mutations
-DNA is miscoded frequently during DNA replication
-DNA repair genes which can be thought of as “spellcheckers” for “misspelled” DNA, usually repair erroneous sequences
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Example DNA repair genes
-If DNA base sequence should AAA but is accidentally copied by DNA polymerase as CAA then DNA repair proteins correct this back to AAA by comparing it to complimentary DNA strand
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If DNA repair gene is damaged and made defective..
-Then mutations in the DNA of other genes may go uncorrected and begin to build up
-Proteins made from the RNA (as a result of mutant DNA) may have incorrect amino acid sequences and may not fold or function properly
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If enough critical cellular proteins cannot function properly..
-Cancer is often the result
-Eg. Xeroderma pigmentosa, an inherited disease with a predisposition to development of skin cancers, is caused by a faulty DNA repair apparatus that allows defective DNA to remain mutant
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What can a mutation do (positive)
-In many cases they may do nothing at all
-For instance if the RNA sequence called for in the DNA is CUA but changes to CUG then both still code for the amino acid leucine
-Even though the sequence has changed, the resultant protein is still the same and nothing happens to the cell
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What can a mutation do (negative)
-in many cases erroneous DNA mutations can have an effect
-if the RNA sequence called for in the DNA is UGU but changes into UGA, the amino acid called for goes from a cysteine to a “stop codon” which signals to the ribosome that this is the end of the protein
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DNA repair enzyme P53 mutation
-If DNA repair enzyme such as P53 has a mutation in it which causes a premature stop codon then when the P53 protein won’t be made at its normal, full, amino acid length and may not function anymore
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Consequences of DNA Mutation
-Produces abnormal mRNA
-results in defects carried over into translation
-interfere with proper protein synthesis
-suppress transcription (DNA—>RNA)
-Generation of abnormal/misfolded proteins
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DNA Mutation and Mitosis Control
-Some proteins involved in controlling the cell cycle (mitosis)
-If DNA mutations of these proteins = may not function properly or be made at all
-If those proteins are involved in preventing the cell from going from G1 phase to S phase of mitosis, then that mitosis checkpoint may no longer function
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RB protein
-Checkpoint protein frequently mutated in cancer cells
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If cell looses enough of these checkpoints
-Then it loses control of the cell cycle
-has become autonomous
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G1 phase
The cell grows and prepares to synthesize DNA
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S phase
-Synthesis phase, cell copies it’s DNA
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G2 phase
Cell prepares to divide
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M phase
Or mitosis
The cell divides
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Checkpoints
G1 checkpoint (stops it from progressing to S phase)
G2 checkpoint (stops from progressing to M phase)
M checkpoint (stops from entering M)
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The human genome is over ___ nucleotides
3.2 billion
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Base Human Mutation Rate
-Actual mutation rate is about 1 mutation in ever 10 billion nucleotides (even after accounting for DNA repair mechanisms)
-Result is about 1 mutation for every 3 replications of the entire genome
-Why Metaplasia/dysplasia can result in Anaplasia/autonomy
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How do these mutations happen?
-DNA is mutated every time a cell goes through 3 rounds of mitosis because of mistakes made by our DNA polymerase enzyme
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DNA Polymerase Enzyme
-Enzyme that does check for errors when replicating DNA
-occasionally one slips past
-may not matter much for neurons which rarely ever replicate
-but matters for cells which may be forced to replicate frequently such as epidermal cells
-this alone may introduce many harmful mutations over the course of a patients life
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Mutations and stressing a cell
-Stressing a cell to the point of triggering Metaplasia and then dysplasia requires a cell to replicate many more times than it normally would in a healthy patient
-= cells more likely to become cancerous than others
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Carcinogens
-Any substance, radionuclide, or radiation that is an agent directly involved in causing cancer
-Any agent capable of causing genetic mutation
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Some Carcinogens and the Cancers they Cause
-Sunlight (UV radiation); skin cancer
-Inhalation carcinogens (cigarette smoke); lung cancer
-Excretory carcinogens (industrial chemicals); bladder cancer
-Human Pap (unprotected sex); cervical cancer
-Contact carcinogens; skin cancer
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UV radiation
-UV radiation in sunlight is capable of altering DNA sequences and thus altering the final proteins made from those sequences
-Why UV radiation is linked to skin cancer
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Cigarette smoke
-Contains many chemicals which have been show to be carcinogenic
-Benzene for instance can become benzene oxide in the cell and bind to DNA thus damaging it During DNA replication
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HPV
-intentionally degrades DNA repair enzymes like P53 as well at mitosis checkpoint proteins such as RB in order for virus to increase the infected cells mitosis and thus it’s replication and spread
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Examples contact carcinogens
-ethidium bromide, arsenic
-been found to bind to DNA and affect its ability to properly replicate triggering mutations
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The origins of skin cancer
-UV radiation at a wavelength 254.7nm can damage DNA
-It can cause cross-linking of the pyramidine based (thyamine and cytosine) neighbouring each other where the UV photon strikes the chemical bond
-In many cases DNA repair enzymes will detect these mutations and repair this cross linking causing no problems and no increased risk of cancer
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But what happens if cross-link is in the DNA encoding for that DNA repair enzyme, or HPV has damaged that DNA repair enzyme ?
-Now suddenly these mutations can build up
-If they build up sufficiently to damage the proteins involved in cell proliferation and cell differentiation then the result may be malignant melanoma, a common form of skin cancer
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What in alcohol causes cancer?
Aldehydes
-Can directly damage DNA
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Genetic Predisposition to Cancer
-A small % of cancer patients have an inherited mutation in their germ cells that predisposes them to development of certain types of cancers
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BRCA1
-BReast CAncer 1 gene
-Most widely known genetic predisposition to cancer
-Normal BRCA1 is a gene which codes for DNA repair protein
-A mutated version of BRCA1 gene increases the chance of DNA mutations building up and encourages, but does not guarantee the development of breast and ovarian cancer in women
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Genetic Influence of Cancer Examples
-Non-smoking relatives of lung cancer patients develop lung cancer with a greater frequently
-Children who inherit a defective copy of the retinoblastoma gene are almost certain to develop retinoblastoma = malignant tumour of the retina
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Carcinogenesis
-multistep process
-Cancer pathogenesis describes the process by which a mutated cell proliferates into an undifferentiated population of cells capable of metastasis
-no single mutation of any gene type is sufficient to produce a neoplasm (tumour), arises from multiple mutations
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The average breast or colon cancer has __ different mutations
90
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Cells become cancerous due to a cycle of repeated …
Injury and mutation
-Eg, smoking: one cigarette isn’t enough, one pack for 35 years is
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Monoclonal Origin Theory
-Cancer is thought to originate from a single mutated cell
-In most/all cases, cancer begin with mutations developing in several genes in a single cell, eventually culminating in that cell becoming autonomous and analplastic
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Mutations that affect ___ genes can lead to cancer r
Regulatory
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Most mutations are
Spontaneous alterations in DNA replication
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Majority of mutations …
-Have no consequences
-Many cells will develop many mutations throughout the life of the person and most will be completely harmless
-It requires just a single cell to have enough mutations built up to damage the cell cycles “stop” and “go” protein checkpoints, DNA repair enzyme, apoptosis triggering proteins and growth inhibitors to result in cancer
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Genes that can cause cancer when altered
-Mutator genes
-Oncogenes
-Tumour suppressor genes
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Mutator Gene
-Code for proteins that repair mutated DNA
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Oncogenes
-Code for proteins involved in cell growth
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Tumour suppressor genes
-Code for proteins that prohibit over proliferation of cells and regulate apoptosis
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Mutant genes associated with cancer are first discover and named because
-They are associated with a particular cancer
-Name give to the gene usually is related to the abnormal (defective/cancer causing) form of the gene not the normal gene or it’s usual function
-Often leads to the mistaken assumption that the abnormal gene is the only one that exists
-Eg. BRCA gene associated with breast cancer is named for the cancer with which it is associated, even though it’s purpose is to repair DNA and not mutate it to cause cancer
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All cells contain genes encoding for proteins that function as
Mitotic “go” or “stop” switches stimulating or restraining cell growth
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Mitotic “go” genes
-are proto-oncogenes
-promote normal cell girth but when mutated become oncogenes
-Eg, HER2 gene is a proto-oncogene that produces human epidermal growth factor 2 that promotes normal cell growth, the mutant HER2 gene promote uncontrolled growth
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Mitotic “stop” genes
-Tumour suppressor genes
-opposite of oncogenes
-restrain normal cell growth by producing proteins that inhibit cell division
-If a growth suppressing gene is mutated and loses ability to function, it leaves cell growth uninhibited
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Example of these genes which promote apoptosis
-Such as p53 gene
-normal p53 gene triggers DNA repair (thus can be considered mutator gene)
-but if DNA damage is too extensive then it stimulates apoptosis in the damaged cell
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Most common genetic defect in human cancers
-Mutation in p53 gene
-About half of all cancers have a defective p53 gene
-Without the p53 gene to signal for apoptosis, cells with damaged DNA remain alive, capable of dividing indefinitely and on a road to malignancy
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Caspases
-another example of tumour suppressor genes
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Pathogenesis of Cancer
-Process is unique for each cancer type
-Process often takes years
-Pathogenesis of cancer typically goes through several stages
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Process of cancer cell development
-Most DNA mutations are successfully repaired by DNA repair enzymes unless the target of the mutation happens to be the DNA repair enzyme itself, it’s co-factors or it’s regulatory processes
-Eventually mutations build up in the cell, allowing for activation of growth promoting oncogenes which stimulate mitosis, and suppression of anti-oncogenes which wouldve acted as check points to prevent uncontrolled mitosis
-Once this has occurred the cell is said to have transformed and become a neoplastic cell (one with autonomy and anaplastic characteristics)
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Chance of process of cell cancer happening
-While most mutations are harmless or dont significantly affect crucial proteins, over time the chances of a mutation striking a critical protein increase just via random chance
-This is why most cancers unless hereditarily triggered, occur as patients get older
-Their cells simply need the time for those random mutations to occur
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Initiation-promotion-progression theory
-because not all cells divide lots
-states that once a cell mutated enough to become cancerous it will require an additional signal in this form of promoter exposure to trigger that primed, mutated cell to begin mitosis
-Having sufficiently mutated, once it receives that promotion signal to enter mitosis it will progress into continual mitosis without mitosis checkpoints or stop signals to cease = generates a tumour
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Initiation
-The irreversible alteration of a cancer-related gene
-Initiating event causes cell mutation
-Initiating event may eventually be identified, but often is not
-example of an initiating event: exposure to a carcinogen
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Promotion
-The proliferation of the initiated (mutated) cell due to promoter exposure (mitogen exposure)
-Requires continual exposure to a “promoter” to stimulate growth of initiated cells
-If the promoter is a chemical substance either made within the cell or something external the cell is exposed to then the promoter is also known as a MITOGEN
-Promoters include mitogens, growth factors, hormones, environmental toxins, chronic inflammation, compensatory hyperplasia (caused by necrosis or cell removal/surgery)
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Progression
-the autonomous proliferation of the mutated cells
-does not require promoter to continue cell proliferation
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Tumour Growth
-a single neoplastic cell is about one billionth of a gram
-the smallest detectable mass is about the size of a grape (about 1 gram)
-this usually take 10-20years or more
-If doubling continues at the same rate, the mass will reach football size in only a fraction of the time it took to each grape size
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Tumour growth fraction
-in most tumours the majority of cells are usually resting and only a fraction of them are dividing at any given time = growth fraction is the main determinant of total growth rate
-for example if 80% of cells in a tumour are dividing, that tumour will grow much more rapidly than a tumour in which 20% of cells are dividing
-How frequently the cells are dividing is important but in the end how many of the cells are dividing at a given time is more important
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Growth fraction is clinically important because
-chemotherapy drugs work by interrupting or slowing the growth cycle of dividing cells
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Tumours with a high growth fraction are more likely to
-(many cells that are actively dividing)
-more likely to be successfully affected by various chemotherapy agents
-but without effective treatment that same high growth fraction tumour will be more likely to metastasize and kill the patient faster than a slower growing tumour on average
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Tumour characteristics: Neoplasms
-Characterized by two main features:
1) abnormal and rapid proliferation (autonomy)
2) loss of differentiation (Anaplasia)
-there are structural and functional consequences to these changes
-when a cell looses control of the cell cycle and enter mitosis when it shouldn’t there are characteristic changes in the cell which can be visualized in a lab
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Tumour cell morphology
-Cells and nuclei are pleomorphic
-nuclei often considerably larger than normal
-nuclei often have bizarre shapes
-chromatin is coarse and clumped
-nuclei often contain abnormal numbers of chromosomes (aneuploidy)
-more cells in mitosis than normal
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Pleomorphic/pleomorphism
-Refers to cells and nuclei that are variable in their size and shape
-they no longer resemble the cells of the tissues they’re derived from
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Aneuploidy
-Refers to the proportion of cancer cells which have too many or too few chromosomes
-When cancer cells are rapidly dividing, mistakes in the distribution of chromosomes can result
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Aneuploid cancer vs diploid cancer
-aneuploid cancer cell is usually more aggressive than diploid cancer
-diploid cancers are the cancer cells those that have the same number of chromosomes as normal healthy cells and tend to be slower- growing, less aggressive cancers
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Karyotyping and cancer
-lab test called karyotyping can show if a tumour cell is diploid or aneuploid
-the number of chromosomes in cancer cells can very considerably
-in a single tissue biopsy you many find some cells that have 20 chromosomes and others with 150
-reason for this: cells having lost the mitotic checkpoints at which they’re supposed to make sure the chromosomes have been properly duplicated in S phase and have all been successfully pulled to opposite sides of the cell during anaphase
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Neoplasia is…
New, uncontrolled growth of cells that is not under physiologic control
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Benign tumour
-usually not life-threatening
-not cancerous
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Malignant tumour
-more likely to cause death, one that has the capacity to cause death
-cancer is caused by malignant tumours
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Benign neoplasms characteristics
-Grow slowly
-Low mitotic index
-Well-differentiated
-Have a well defined capsule
-Not invasive
-Do not metastasize
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Malignant neoplasms characteristics
-Grow rapidly
-High mitotic index
-Poorly differentiated
-Usually unencapsulated
-Invasive
-Spread distantly through the bloodstream and lymphatics
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Mitotic Index
-A measure for the proliferation status of a cell population
-defined as the ratio between the number of cells in mitosis and the total number of cells
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Encapsulated
-The growing mass of cells is still surrounded and contained by the basement membrane of the tissue
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Unencapsulated
-The growing mass has burst out of or degraded the capsule around it and is free to spread
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Meningioma
- a potentially fatal benign tumour
-benign neoplasm of the meninges surrounding the central nervous system
-can kill by compressing the brain
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Excepts to benign tumours being harmful
-brain tumours, benign cardiac tumours
-May grow slowly but can cause death by virtue of their critical location
-Eg. Compressing the brain
-Eg. Several myxomas and lipomas which may interfere with proper cardiac function
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Tumour nomenclature (naming)
-Because malignant cancer cells are so poorly differentiated, they are named according to their type of origin cell, adding the suffix oma to the parenchymal tissue type from which the cancer originated
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Examples of tumour nomenclature: Carcinomas
-Carcinomas = Arise from endothelial and epithelial tissue
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Examples tumor nomenclature: sarcomas
-Arose from mesenchymal (connective) tissues
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Examples tumour nomenclature: Adenocarcinomas
-carcinomas arising from glandular or ductal epithelium
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Examples of tumour nomenclature: Teratocarcinoma
-arise from germ cells
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Example sarcomas
Eg. Osteogenic sarcoma
-an aggressive malignant neoplasm that arises from mesenchymal tissue and that exhibits osteoblastic differentiation
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Examples adenocarcinomas
Eg. Mammary adenocarcinoma = the proper term for breast cancer
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Tumours are usually named according to
The cells from which they arise, for every benign tumour there is a matching malignant variety
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Naming benign vs malignant example
-For example, a benign tumour of a gland is usually called an adenoma, while a benign tumour of fibrous connective tissue is a fibroma
-An malignant tumour of epithelium (breast duct epithelium, prostate epithelium, bronchial epithelium) is a carcinoma
-a malignant tumour of a mesenchymal tissue (bone, cartilage, fat, muscle, or fibrous CT) is a sarcoma
-Combining these two naming conventions, a malignant tumour of gland epithelial cells is an adenocarcioma and a malignant tumour of fibrous tissue is a fibrosarcoma
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There are no benign granulocyte or lymphocyte tumours because:
-these are unencapsulated, circulating cells by default so every tumour of that cell type is malignant
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CT, Granulocytes, Lymphocytes, Melanocytes
-CT = connective tissue
-Granulocytes = eosinophils and basophils
-Lymphocytes = B and T white blood cells
-Melanocytes = the melanin producing cells of the skin, but are also found in the inner ear, meninges, bones, and heart
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7 hallmarks of neoplasia
1.) self-sufficiency of growth signals
2.) evasion of growth suppression signals
3.) unlimited proliferation
4.) avoidance of apoptosis
5.) recruitment of nutrients via angiogenesis
6.) tissue invasion and spread (malignant neoplasms only)
7.) evasion of immune surveillance
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Malignant neoplasm characteristics
-Are not encapsulated
-Grow rapidly
-Can compress blood vessels and outgrow their blood supply
-Rob normal tissues of essential nutrients
-Liberate enzymes and toxins that destroy normal tissues
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Invasion/Metastasis
-Invasion is the movement of tumour cells into adjacent tissue (different between benign and malignant)
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Invasion/metastasis benign
-Benign tumours grow slowly and push aside nearby structures using blunt force
-Compressed fibrous tissue usually forms a capsule around the tumour
-slow growth usually gives time for nearby tissues to adapt, so that tumour often does not affect function
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Invasion/metastasis malignant
-Malignant tumours invade nearby tissue with streams of destructive cells
-No capsules limit the advancing army of cells or that capsule is degraded and destroyed
-The invasion nature allows them to invade blood vessels and spread discontinuously to distant tissues or organs
-Some tumours May be locally aggressive = tumours that invade but do not metastasize to distant locations in the body
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Angiogenesis
-formation of new blood vessels and a critical step in the growth and spread of cancer
-tumours require a dedicated blood supply to provide oxygen/essential nutrients in order to grow beyond 1-2mm or it begins to starve
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Angiogenic growth factor
-if a tumour is able to release this, such as VEGF (vascular endothelial growth factor) then it may stimulate blood vessel extension, expansion, providing the tumour with a new source of the nutrients and oxygen it requires
-This is why many chemotherapeutic agents are angiogenesis inhibitors, if they can halt the production of new blood vessels, you can starve the cancer
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Local spread
-Malignant neoplasm proliferates within tissue of origin sending out crablike projections into the surrounding tissue
-This occurs when no capsule is present or when encapsulation has failed
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Direct Extension
-infiltration of malignant neoplasm into adjacent tissues
-Aided by secretion of enzymes that breakdown adjacent tissues
-Most often occurs via direct extension as the neoplasm moves into adjacent tissues
-malignant cells escaping the basement membrane after many mutations in the cells genome causes it to begin producing and secreting enzymes it wouldn’t = beginning to spread
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Metastasis
-the discontinuous spread of tumour from one site to another is the most reliable sign of malignancy
-results in cancer spread beyond adjacent tissues
-the presence of metastases greatly reduced the chances of a cure
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Types of Metastasis
1. Lymphatic spread
2. Hematogenous spread
3. Seeding (aka transcoelomic spread)
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Lymphatic Spread
-Spread via lymphatic channels
-Favoured by most carcinomas
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Hematogenous spread
-spread via blood vessels
-typical of sarcomas and some carcinomas that originate in the kidneys
-because of their thinner walls, veins are more frequently invaded than arteries and the spread is via veins
-tumour cells follow natural venous flow and lodge into distant capillary bed (for intestinal malignancies this is usually the liver, for remainder it is usually the lungs)
-surprisingly despite the great blood flow the muscle and spleen are rarely sites of metastasis
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Seeding (Transcoeiomic spread)
-Spread via body cavities
-The cancer cells seed onto peritoneal, pleural, meningeal, and pericardial spaces
-Occurs as tumour cells detach from one organ and attach to a neighbouring one
-Most often seen in intra-abdominal spread of ovarian cancer on the surface of the peritoneum
-Less often seen in the meningeal, pericardial, and pleural spaces
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When tumours invade blood vessels it’s called
Hematogenous spread
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About 1/3 of patients with malignancy have ___ at the time of diagnosis
-metastases
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Seeding the Soil Theory
-States that it is difficult for cancer cells to survive outside of their region of origin, so in order to metastasize they must find a location with similar characteristics
-provides a good guideline for where to examine a patient for the most frequent areas of neoplasm spread
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Seeding the Soil theory Example
-Breast tumour cells (which gather calcium ions from breast milk) metastasize to bone tissue where they can gather calcium ions from bone
-Malignant melanoma spreads to the brain, presumably because neural tissue and melanocytes arise from the same cell line in the embryo
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Staging/Grading
-Staging/grading evaluates degree of invasiveness and metastasis
-important for treatment decisions
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Cytologic/histologic grading of tumours
-based on degree of abnormal proliferation and differentiation
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Grade I
Well differentiated
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Grade II
Moderately differentiated
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Grade III
Poorly differentiated
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Grade IV
Undifferentiated
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The grading scheme is based on
The microscopic appearance of a malignant neoplasm
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The degree of differentiation of the neoplasm refers to
-The degree to which it resembles normal tissue in function and appearance
-perfectly differentiated tissue is normal
-neoplasm are judged to be well differentiated or poorly differentiated according to the degree they deviate from normal
-clue to their likely behaviour
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Well differentiated vs Poorly differentiated tumours
-Benign tumours are well differentiated
-Highly malignant tumours are poorly differentiated
-Well differentiated malignant tumours grow slowly and are slow to invade and late to metastasize
-Poorly differentiated tumours grow rapidly, invade aggressively, and metastasize early, they also have cells that are difficult to recognize as to their cell of origin
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In general a higher grade means
-There is a lesser degree of differentiation and the worse the biologic behaviour of a malignant neoplasm will be
-Most tumours well or poorly differentiated, also show little or no normal physiological function
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Staging: TNM system
-This grading scheme focuses on a cancers spread more than its physiological characteristics
-Commonly used when diagnosing lung cancer
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T score
-Tumour
-Based on the size and/or extent of invasion
-T0 = no evidence of primary tumour
-Tis = Carcinoma in situ
-T1-4 = Progressive increase in tumour size
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N Score
-Nodes
-Score indicates the extent of lymph node involvement
-N0 = no evidence of regional node metastasis
-N1-3 = increasing involvement of regional lymph nodes
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M Score
-Metastasis
-Score indicates whether distant metastases are present
-M0 = no distant metastasis
-M1 = distant metastasis present
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TisN0M0
- is the diagnostic staging for carcinoma in situ, also known as pre cancer
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Other grading systems
-There are many grading systems used in cancer diagnosis
-Eg. Gleason grading system for staging prostate cancer
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Gleasons grading system
-system for prostate cancer
-similar to cytologic grading system but focuses on cell density in addition to differentiation
-named after pathologist who developed it at Minneapolis veterans affairs hospital
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Genetic Staging
-Based on changes in nucleus/chromosome morphology
-If often used as the basis for many staging diagnosis = determine the type of cancer, it’s likelihood to metastasize, and which chemotherapeutic agents should be used
-Karyotyping
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Cell-to-cell adhesion diagnostics
-Reduced tendency of cancer cells to stick together permits shedding of tumour surface cells into surrounding body fluids or secretions
-Can be detected using cytologic methods (Eg Pap test)
-If a tumour is likely to seed into a cavity or spread to the bloodstream it must be able to detach
-Most cells are stuck together with bonds such as tight junctions, gap, desmosomes = keeps tissues/ organs whole
-Because cancer cells have a tendency to enter into mitosis so quickly they no longer form these junctions
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Cell to cell adhesion diagnostic example
-In Pap smear nurse or doctor looks for cells which have begun to loose their cell to cell adhesion characteristics
-typical of cervical intraepithelial neoplasia
-if they begin to become dysplastic and cancerous they slough off much more readily
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Antigen Expression and Cancer
-A number of antigens that are immunologically foreign may be expressed by cancer cells (tumour markers)
-Diagnostics can test for presence/absence of these antigens in blood or urine
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Cancer and antigen immune system
-Once a normal gene is altered via mutation, it and the resultant protein of that gene become non self and subject to immune attack
-immune system antineoplastic function is referred to as immune surveillance = mutant cells that may develop into neoplasms are eliminated
-sometimes mutant cells escape immune attack to perpetuate themselves as neoplasms
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Immunodeficient patients and cancer
-patients with immunodeficiencies suffer from more neoplasms than those with a normal immune system
-AIDS patient and those on immunosuppressive therapy for organ transplants or other reasons also have a higher than expected occurrence of malignant neoplasms
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Antigens that can be treated for cancer
-CA-125
-PSA
-CEA
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CA-125 Antigen
-Cancer antigen 125
-Sometimes called MUC16 protein
-Mucin protein that may be found in transmembrane or secreted forms
-The transmembrane form can adhere to the peritoneum, facilitating metastasis of cancerous cells to the peritoneal cavity
-If a cell is expressing this transmembrane protein it is much more likely to be able to seed and adhere to other areas of the body
-Often expressed in lung cancer, skin cancer, breast cancer, pancreatic cancer, and ovarian cancer
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PSA Antigen
-Prostate specific antigen
-The protein which forms this antigen is known as a gamma-seminoprotein, and is usually produced in the ejaculate to allow semen to swim freely
-If this protein is found anywhere other than seminal fluid then it’s an indication that a cell has lost control of its protein manufacturing and potentially become anaplastic
-Often seen in metastasized prostate cancers
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CEA antigen
-Carcinoembryonic antigen
-normally produced in GI tissue during fetal development but production stops before birth
-If a cell is expressing it after birth then that cell is likely anaplastic
-Often seen in lung cancer, gallbladder cancer, breast cancer, stomach cancer, pancreatic cancer, and colon cancer
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Clinical manifestations of cancer how they manifest
-No single body function is unaffected by cancer
-Initial manifestation usually reflects the primary site of involvement (eg. Lung cancer typically causes resp impairment first)
-No regard for normal anatomical boundaries
-Eg. Cervical cancer is often detected after causing menstrual irregularities
-Eg. Prostate cancer if often detected after causing erectile dysfunction
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Clinical manifestations of cancer
-Lymphadenopathy
-Fever
-Anemia
-Anorexia and cachexia
-Fatigue
-Venous thrombosis
-Paraneoplastic syndromes
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Lymphadenopathy
-Abnormality in the size or character affecting one or more lymph nodes
-In many cases, especially with carcinomas, the first tissue invaded is the local lymph nodes
-Most commonly caused by infection, but can also be a sign of cancer
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Lymph nodes that are hard and painless..
-Have increased chance of malignant or granulomatous disease and typically merit further investigation
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Pain or swelling in the area of the lymph nodes..
-is common symptom of cancer that starts in the lymphatic system
-such as non-hodgkin lymphoma and Hodgkin lymphoma
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Spread to local lymph node and subsequent lymphadenopathy is also part of
TMN cancer staging system
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Cancer and Fever
-Unexplained fever is a very frequent symptom of cancer
-Fever from underlying malignancy accounts for up to 25% of fever of undetermined origin
-Almost all patients with cancer will have fever at some time, especially if the cancer or it’s treatment affects the immune system
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Reason for fever with cancer
-Release of cytokines from tumour cells or infiltrating mononuclear cells (Eg. Tumour necrosis factor and interleukin-1)
-Necrosis of tumour tissue
-Obstruction of a hollow duct or viscus resulting in proximal infection (Eg. A cholangiocarcina causing bile duct obstruction)
-Drug fever (Eg. Reactions to antibiotics, chemotherapy drugs)
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Anemia
-Common in many types of cancer
-May be defined as a lack of sufficient RBC’s to maintain adequate tissue oxygenation
-Develops when the demand for new RBC’s exceeds the capacity of the bone marrow to produce them
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Anemia can be related to
-Blood loss
-Hemolysis
-Impaired RBC production
-Bone marrow failure
-Hypoxia
-Treatment effects
-Nutritional deficiencies
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Anemia often results in
-Reduced treatment effectiveness
-Increased mortality
-Increased transfusion requirements
-Decreased quality of life
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Mild anemia
-May not be detected by the patient
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Moderate anemia
Causes fatigue and headache
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Severe anemia
Life threatening
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Anemia and Leukemia, lymphoma, and myeloma
-Can interfere with or destroy the marrows ability to produce RBC’s
-Other cancers that spread to the bone marrow may also result in anemia
-A patient with cancer typically produces much less erythropoietin than expected and cannot compensate for impaired RBC production
-Inflammation and infection can exacerbate this situation
-Anemia in patients with cancer appears to behave much like in patients with chronic renal failure because of the inability of kidneys to produce erythropoietin
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If cancer effects and damages the kidneys or walls of intestines ..
-May cause bleeding into those areas and the resultant blood loss can cause anemia
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Cancer and Anorexia/Cachexia
-Many cancers are associated with weight loss and wasting
-Common in solid tumours with the exception of breast cancer
-Results in poor response to chemotherapy and increased toxic side effects
-Cause is likely multifactorial not simply explained by decreased food intake
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Causes of anorexia/cachexia in cancer
-In many cases it’s the cancer treatment rather than the cancer
-Both chemotherapy and radiation therapy cause a variety of side effects that can cause anorexia/weight loss such as nausea and vomiting, changes in taste, dry mouth
-In addition body releases tumour necrosis factor and interleukin in attempt to fight cancer which can cause anorexia
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Destruction of cancer cells by radiation therapy increases ____ levels
-Tumour necrosis factor and interleukin 1 = anorexia and weight loss
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Cancer and Venous thrombosis
-Blood clot formation in a vein
-Often form in leg and break off and travel to lungs = pulmonary embolism
-Some adenocarcinomas release thromboplastin activating the clotting system
-Sometimes unexplained thrombotic events are the first sign of an undiagnosed malignancy, particularly pancreatic
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Malignancy increases the risk of Venous thromboembolism by a factor of
-At least 4
-Cancer patients constitute 15-20% of the patients diagnosed with venous thrombosis
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Tumour cells not only release thromboplastin but also
-inflammatory cytokines, hypoxia inducible factor, and early growth response 1 which may increase risk of DVT’s
-Some tumour cells can also directly adhere to platelets, leukocytes, and endothelial cells, further increasing the risk of clotting
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Adenocarcinomas and DVT’s
-Adenocarcinomas are glandular or duct tissue cancers, and there is a substantial amount of glandular and duct tissue in the pancreas
- = association between DVT’s and pancreatic cancer
-Lung and stomach cancer also have high DVT risks for the same reason
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Paraneoplastic
-The result of hormones or cytokines secreted by cancer cells
-Can also be caused by an immune response against the tumours = immune system begins to attack normal cells
-Common among middle aged to older patients with cancers of the lungs, breast, ovaries, or lymphatic system
-Particularly devastating form are Paraneoplastic neurological disorders
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Paraneoplastic syndromes cause
-dozens identified
-Mental aberration
-Neurologic disease
-High blood calcium
-Low blood glucose
-High blood cortisol or other hormones and other problems
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Sometimes appearance of Paraneoplastic May..
-preceed diagnosis of the neoplasm and May give a clue to its presence
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Paraneoplastic Neurological Disorders (PND)
-Can cause difficulty walking, dizziness, rapid uncontrolled eye movements, difficulty swallowing, loss of muscle tone, loss of fine motor coordination, slurred speech, memory loss, vision problems, sleep disturbances, dementia, seizures, sensory loss
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Paraneoplastic syndromes: Cushing’s syndrome
-Also known as hypercortisolism
-Due to prolonged exposure to cortisol
-Results in abdominal obesity along with thin arms and legs, round red face, fat lump between shoulders, weak muscles and bones, acne, reddish stretch marks, and fragile skin
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Paraneoplastic Syndromes: Hypercalcemia
-Excess calcium in the blood
-Leads to kidney stones, bone pain, abdominal distress, depression, cognitive issues
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Paraneoplastic Syndromes: Hyponatremia
-ADH Is antidiuretic hormone
-Results in low sodium levels causing nausea, vomiting, headache, short term memory loss, confusion, lethargy, fatigue, loss of appetite, irritability, muscle weakness, spasms or cramps, seizures, decreased conciousness/coma
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Paraneoplastic Syndromes: Polycythemia
-Too many RBCs in a given blood volume which may result in kidney damage
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Paraneoplastic Syndromes: Trousseau syndrome
-Causes inappropriate blood clots
-Can be an early sign of gastric or pancreatic cancer
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Paraneoplastic Syndromes: Hypoglycemia
-Low blood sugar
-Can result in neural dysfunction, brain damage, and death
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Paraneoplastic Syndrome: Carcinoid syndrome
-Caused by too much sertatonin
-Overwhelms the livers ability to metabolize it
-Includes flushing and diarrhea, less frequent HF and bronchoconstriction
