Ch. 10 Flashcards
Cancer
Leading cause of suffering and death in the developed world
How is cancer a form of Darwinian evolution
Tumor development has cells with heritable change that have a survival advantage, so they outcompete their neighbors
Cancer is a collection of more then _ diseases
100
Is cancer age related
yes
what modifies the risk of developing cancer and the response to treatment
-Environment
-Heredity
-Behavior
Epigenetic
Study of how behavior and environment cause changes that affect gene mutation
Cancer is derived from the greek word
Karkinoma (Crab)
Karkinoma/hippocrates use crab to describe
projections extending from tumors into adjacent tissues
Tumor used to
refer to any swelling caused by inflammation
Tumor now
reserved for describing new growth or neoplasm
Are all tumors cancer?
No
what is a non cancerous tumor
Benign
what tumors contain cancer
malignant
What kind of cells do benign tumors have
-well-differentiated cells
-well-organized stroma
Benign tumors retain
-normal tissue structure
-don’t invade beyond capsule
Can benign tumors be dangerous
yes
-eg. benign meningioma at eh base of the skull can compress brain tissue
what tumors have cancer
malignant tumor
Malignant tumors grow
-rapidly
-abnormal organization
Hall mark of cancer
Anaplasia
Anaplasia
loss of cellular differentation
Pleomorphic
vary in size and shape
Malignant tumor structure
large, disorganized stroma, with an abnormal structure
Metastasis
ability to spread far beyond the tissue of origin/most deadly characteristic of malignant tumors
Characteristics or malignant tumors
-Rapid growth
-Anaplasia
-Pleomorphic
-Large stroma
-Metastasis
Cellular differentiation
process in which a stem cell alters from one type to a differentiated one
-usually more specialized
Malignant tumor types
-Carcinomas
-Adenocarcinomas
Carcinomas
Cancers arising from epithelial tissue
Ademocarcinomas
cancers arising from ductal or glandular structures
Benign
-Grow slow
-well-defined capsule
-not incisive
-well differentiated
-low miotic index
-don’t metastasize
Malignant
-grow rapidly
-not encapsulated
-invasive
-high mitotic index
-can metastasis
Situ
in natural or original place
Carcinoma in situ
preinvasive epithelial tumors of glandular or squamous cells origin
cancers develop- and accumulate
incrementally
genic lesions (mutations)
CIS: 3 fates
- Remain stable for a long time
- Progress to invasive/metastatic cancers
- regress and dissapear
high grade lesions are more likely
to become invasive
CIS cancer cells
have not broken through basement membrane or invade surrounding stroma
-not considered malignant
CIS vary from
low grade to high grade dysplasia
What is a disease of aging
Cancer
what is required for cancer to develop
multiple mutations
Mutation
cell acquires characteristics that provide an advantage overing neighboring cells
advantage of mutations
increased growth rate and/or decreases apoptosis
Result of mutation
-decreased need for growth factor to multiply
-anchorage independence to spread through body (metastasis)
-immortality
immortality in cells means
no apoptisis
Fundamental cancer concepts
- cancer is a genetic disease arising from multiple mutations
- tumor microenvironment is a mix of cells (cancer and benign) and their secretions
3 cancer stages
- tumor initiation
- tumor premotion
- tumor progression
Tumor initiation
-producing initial cancer cell
-first stage of development
-depends on specific mutations
Tumor premotion
-population of cancer cells expands with diversity of phenotypes
- additional mutatuions
Tumor progression
-spread of tumor to adjacent and distal sites
- governed by more mutations and changing microenvironments
2 types of mutations
-small scale changes
-large scale changes
Small scale changes are also
point mutations
large scare changes are also
translocations
Point mutations
Alteration of one or a few nucleotide base pairs
result of point mutations
profound effects on activity of resulted proteins
Driver mutations
mutations that drive the progression of cancer
passenger mutations
mutations that don’t contribute to malignant phenotype
-random events
small scale includes
driver mutations and passenger mutations
large scale: chromosome translocations
-large changes in chromosome structure
-section of one chromosome is translocate
gene amplification
-instead of two normal copies of a gene 10s-100s of copies are present
Why does gene amplification make some many copies
One section of chromosome is translocated reshuffling the order of nucleotides making new sections
Gene amplification example
gene expression of HER2 proteins
Clonal proliferation model
selective advantage cancer cell has over neighboring cells
what’s an advantage of clonal proliferation model
it can replicate faster than nonmutant neighbors
What is the action of clonal proliferation model
increasingly rapid cell division and impaired DNA repair mechanisms of cancer cells
what does the rapid dividing and repairing mechanisms of clonal proliferation create
continuing accumulation of mutations throughout progression to mist aggressive metastatic lesion
Transformation definition
process by which a normal cell becomes a cancer cell
Transformation causes malignancy
by progressive accumulation of genetic changes that alter basic nature of cells
Individual cancer cells develop
its own set of mutations
Result of individual cell mutations
-Gnomically heterogeneous mix of cells
-Subsets accumulate more mutations increasing the cells malignant potential
Cancer cells that don’t accumulate a critical set of mutations
lose to competition and die
How is cancer similar to wound healing
it has an initial proinflammatory response
cancer cell proliferation triggers
proinflammatory response by itself and adjacent nonmalignant cells
Like with wound healing mediators recruit
-inflammatory or immune cells (T+B, Macrophages)
-Cells associated with tissue repair (Fibroblasts, adipocytes, mesenchymal stem cells, and endothelial cells)
What causes abnormal wound healing
recruited cells form a stroma (tumor microenvironment)
Effect of Abnormal wound healing
-cancer cells increase proliferation
-become more heterogeneous (Diverse)
Process of abnormal wound healing
-great deal of cancer cell death
-surviving cells are more aggressive
-Many take of a monastic phenotype
Cancer cell needs uncontrolled growth through
sustained proliferation signals
sustained proliferation signals
-Pro-oncogene control
-oncogene mutations
result of sustained proliferation signals
blocking of body’s mechanism to stop uncontrolled growth
First hallmark of cancer
uncontrolled cellular proliferation
Normal cells proliferative phase
runs in response to growth factor
Growth factor
binds to specific receptors on cells surface and activates intracellular signaling pathways affecting DNA synthesis and cellular growth
Proto-oncogenes
normal genes that direct protein synthesis and cellular growth
Oncogenes
mutated pro-oncogenes cells
Oncogenes cells
-independent or normal regulatory mechanisms
-Mutations allow uncontrolled growth
-in addition various stoma cells produce their own growth factors that contribute to uncontrolled growth
Growth receptors
-RAS
-P13K
-MYC
-D-cyclins
what activates growth receptors
oncogenes
Translocations cause
excessive inappropriate production of oncogenes
Translocation eg. burkitts lymphoma
normal chromosomes get changed into Burkitt’s lymphoma which produces abnormal B cells
Cancer cells stop tumor suppressor genes by
2 mutations which inactivate tumor suppressor genes
Tumor suppressor genes in normal cells
-inhibit proliferation
-stop cell division when cells are damaged
-prevent mutations
Abnormal wound healing
-Recruited cells form stroma
-Stroma surrounds and infiltrates tumor
Stroma cells can make up to _of the tumor mass
90%
Stroma growth is affected by
-rapid cancer cell proliferation
-various cell additions
Extensive paracrine signaling affects
-Stromal cells
-Cancer cells
Abnormal wound healing effect
-cancer cells increase proliferation
-cells become more heterogeneous (diverse)
Abnormal cell growth process
-great deal of cancer cell death
-surviving cells are more aggressive
-many cells take on a metastatic phenotype
Tumor suppressor genes are called
anti-oncogenes
Tumor suppressor genes
Must be activated for cancer proliferation to occur
Classic tumor suppressor gene
tumor-protein P53
guardian of the genome
classic tumor suppressor gene P53
P53
-Monitors cellular stress and activates “care taker genes” to repair genetic damage
-controls apoptosis
Inactivation of P53
requires at least 2 mutations
-single mutation increases risk of children developing cancer
Cancer wants to stop the limit to its division
Cancer activates telomeres to provide unlimited division
Is there a limit to body cell division
yes
What’s the limit to division called
Hayflick limit
what are telomeres
protective caps on each chromosome
When cells proliferate
telomere caps shorten each time it divides
When telomeres run out
-cells can’t divide anymore
-cell death
Telomerase
enzyme that maintains telomeres and stops them from shortening
Telomerase is active
in ovaries and testes germ cells and stem cells
cancer activates telomerase causes
unlimited telomeres
unlimited telomeres causes
unlimited proliferation/immortality
Cancer needs its own blood supply to move around the body
yes
cancer making its own blood supply is called
angiogenesis
Angiogenesis
-irregular development of vessels
-increased risk of hemorrhage
result of angiogenesis
cancer has access to systemic blood system
cancer activates production of new blood vessels
angiogenesis
advanced cancer secretes
angiogenic factors
GF- growth factor
-vascularized endothelial GF
-platelet-derived GF
-Basic Fibroblast GF
how do vessels within tumors differ from healthy vessels
-irregular branching from existing capillaries
-cell contact between endothelial cells are less tight
-tumor created vessels allow passage of tumor cells
passage of tumor cells into vascular system
metastasize
less tight cell contact in tumors
vessels are more porous and prone to hemorrhage
Cancer needs more building blocks to make more cells
programming energy meta olism
Programming energy metabolism
-Warburg effect/lactic acid
-increased risk of hemorrhage
-rapid cell growth
Reprogramming energy metabolism- Normal cells
-oxygen use aerobic metabolism
-limited oxygen use glycolysisd
glycolysis produces
lactic acid
Reprogramming energy metabolism- cancer cells
-only use glycolysis even with oxygen available
-warburg effect
Warburg effect
aerobic glycolysis
Cancer benefit of warburg effect
-shift in glycolysis allows continual production of lactate
Lactate
used for production of lipids, amino acids, and other molecular building blocks for growth
resisting apoptosis
-intrinsic/extrinsic pathways
-activate BAK
-results in blocked apoptosis
intrinsic pathway
-monitors cell stress
IP if cell can recover
activation of BAX
IP if cell can’t recover
destroy cell with activation of BAK
BAK and BAX
regulate mitochondrial release of pro-apoptotic molecules (Cytochrome c)
Cytochrome c
proapoptotic molecule
Extrinsic pathway
dormant till death receptor is activated (BAK)
Both IP and EP activation cause
T-cells (cytotoxic) and Natural killer (NK) cells to induce apoptosis
Apoptotic pathways in cancer
are dysregulated
Mechanism for cancer to travel through the body
EMT
EMT
the ability to metastasize
Metastasis
spread of cancer cells from site of original tumor to distant tisseues and organs
The defining characteristic of cancer
Metastasis
Major cause of death from cancer
Metastasis
Example of metastasis
Breast cancer
Localized breast cancer
five year survival >90%
Metastasized breast cancer
30% survival rate after 5 years
Non-metastasized cancer
can often be cured by surgery, chemotherapy, and radiation
Surgery, chemo, radiation
often ineffective against metastasized cancer
Model for transition to metastasized cancer
EMT
EMT
Epithelial-mesenchymal transition
Carcinomas
From highly differentiated epithelial cells that form sheets stabilized by adhesions from neighboring cells
Initial carcinomas
can complete local tumor expansion, retain epithelial characteristics that prevent disassociation from ECM
ECM
extracellular matrix
Metastasized cells must
dissociate from ECM
Degree of De-differentation
Cells ability to differentiate and produce the phenotype that can separate from the primary to flourish in a hostile secondary site
undifferentiated mesenchymal-like carcinoma
comes from the programmed transition from a partially epithelial-like carcinoma which initiates epithelial-mesenchymal transition process
epithelial-mesenchymal transition process occurs
in embryonic development and wound healing
cell separation from ECM
under go Anoikis
Anoikis
induction of apoptosis in cells loss of ECM attachment
Cancer cells avoid
Anoikis instead they enter circulation and spread
EMT steps
- Intravasation
- Extravasation
- Survival in circulation
Intravasation
Entry of tumor cells into circulation
Intravasation occurs from
-Leaky angiogenesis vessels cancer created
-Spread through both vascular and lymphatic pathways
Extravasation
Exit of tumor cells from circulation to host tissue
Survival in circulation
Platelets coat tumor providing protection (Cancer clot)
Cancer clot
Platelets coating and protecting tumor cells
Survival in new location
-Few cancer cells needed to establish new tumor (TICs)
-Metastasis don’t mean proliferation
-Dormancy
TICs
-Tumor initiating cells
-Cancer stem cells
Dormancy
Stable non-proliferating state that is reversable
2/3 breast cancer deaths
occur after 5 year disease free interval
Deceased individuals have been studied and found to have
dormant cancer cells even with no cancer history
Viruses associated with cancer
-Human Papillomavirus (HPV)
-Epstein-Barr Virus (EBV)
-Hepatitis B + C
New cancer therapy
development of oncolytic viruses that specifically attach cancer cells
How do cancer cells evade immune detection
- Failure to produce tumor antigen
- Mutation in MHC genes needed for antigen presentation
- Production of immunosuppressive proteins or expression of inhibitory cell surface proteins
Normal immune system
protects against cancer
Immunosuppression
fosters cancer
Immune suppressed eg.
-Non-Hodgkin’s lymphoma
-Kaposi sarcoma
-Release of immunosuppressive factors into tumor microenvironment increase resistance of tumor to chemotherapy and radiation
Tumor Associated Macrophages
Different phenotypes depending on environment
Macrophage phenotypes
-Classic Macrophage (M1)
-M2
-Tumor associated macrophages (TAM)
Classic macrophage
responds to inflammatory stage to perform phagocytosis
M2
During healing produces anti-inflammatory mediators to suppress inflammation
Tumor-associated Macrophage (TAM)
Act like M2
-block Tcells and NK cells and produce cytokines advantageous to tumor growth and spread
Cancer Staging
Microscopic analysis based of presence of metastasis
Stage I
No metastasis
Stage II
Local invasion
Stage III
spread to regional structures
Stage IV
Distant metastasis
Cancer treatments
-Surgery
-Radiation
-Chemotherapy
Surgery
-Prevent cancer (colon polyps)
-Biopsy for diagnosis and staging
-lymph node sampling
-Palliative surgery
Palliative surgery
-relieving pain
-doesn’t deal with cause of condition
Radiation
-Ionizing radiation damages cancer cell’s DNA
-Goals
~eradicate cancer w/o excessive toxicity
~Avoid damage to normal structures
Chemotherapy
-Takes advantage of specific vulnerabilities in target cancer cells
-Usually given in combination designed to attack cancer from many different weaknesses at the same time
Clinical manifestations of cancer
-Paraneoplastic syndromes
-Pain
-Cachexia
-Leukopenia
-Infection
-Asthenia
Paraneoplastic syndromes
-group of rare disorders triggered by an abnormal immune system response to a cancerous tumor
-caused by biological substances released by tumor
-may be earliest symptom of unknown cancer
Pain
-little or no pain is associated with early stages of malignancy
-Influenced by fear, anxiety, sleep loss, fatigues, and physical deterioration
Cachexia
Weakness and wasting of body die to severe chronic illness
-Most severe form of malnutrition
Cachexia includes
-Anorexia
-Early satiety
-Weight loss
-Anemia
-Asthenia
-Taste alterations
-Altered protein, lipid, carbohydrate metabolism
Leukopenia + Thrombocytopenia
-Direct tumor invasion to bone marrow causes leukopenia and thrombocytopenia
Leukopenia
Reduced WBC
Thrombocytopenia
Reduced platelets in blood
Infection
Risk increases when absolute neutrophil and lymphocyte count falls
Asthenia
Weakness, lack of energy and strength
