Neoplasia IV: Cancer Pathogenesis - WordPress.com · 2018-10-11 · Neoplasia Outline • Tumor...
Transcript of Neoplasia IV: Cancer Pathogenesis - WordPress.com · 2018-10-11 · Neoplasia Outline • Tumor...
Kristine Krafts, M.D.Neoplasia IV: Cancer Pathogenesis
Neoplasia Outline
• Tumor nomenclature
• Tumor characteristics
• Epidemiology
• Cancer pathogenesis
Neoplasia Outline
• Tumor nomenclature
• Tumor characteristics
• Epidemiology
• Cancer pathogenesis• Overview• Genes• Steps• Chromosomes• Agents• Grading and staging
Neoplasia Outline
• Tumor nomenclature
• Tumor characteristics
• Epidemiology
• Cancer pathogenesis• Overview
What causes cancer?
What causes cancer?
Non-lethal genetic damage.
Normal Genes Damaged in Cancer
• Genes that promote growth (�proto-oncogenes�)
• Genes that inhibit growth(�tumor suppressor genes�)
• Genes that regulate apoptosis
• Genes that repair DNA
Cancers acquire new genetic defects along the way.
Neoplasia Outline
• Tumor nomenclature
• Tumor characteristics
• Epidemiology
• Cancer pathogenesis• Overview• Genes
Characteristics of Cancer Cells
• Autonomous growth
• Insensitivity to growth-inhibitory signals
• Evasion of apoptosis
• Limitless replication
• Sustained angiogenesis
• Invasion and metastasis
Characteristics of Cancer Cells
• Autonomous growth
Autonomous Growth
• Proto-oncogene: a normal gene whose product promotes cell growth.
• Oncogene: a mutated proto-oncogene. Causes tumor cell to grow autonomously.
• Oncoprotein: the product of an oncogene.
Growth Signals in Normal Cells
Cell divides
• Growth factor binds to receptor• Receptor activates signal-transducing protein• Signal-transducing protein activates 2nd messenger• 2nd messenger talks to nuclear transcription factors• Nuclear transcription factors start DNA transcription• Cyclins move the cell through the cycle
Growth Signals in Cancer Cells
Cell divides on its own!
• Growth factors may be made by cell itself• Receptor may be overexpressed• Signal-transducing protein may always be on• Nuclear transcription factors may be overexpressed• Cyclins may be overactive
Example: RAS
• RAS is a signal transduction protein
• Mutated RAS is always on…
• …therefore, always transducing signals…
• …therefore, cell is always dividing.
Characteristics of Cancer Cells
• Autonomous growth
• Insensitivity to growth-inhibitory signals
Insensitivity to Growth-Inhibitory Signals
• Tumor suppressor genes: normal genes whose products act like “brakes” on the cell cycle.
• Mutate these guys, and you lose the brakes!
• Must mutate both copies of the gene to cause tumors.
Example: RB
• RB gene product stops cell at G1 checkpoint
• Mutant RB is inactive; lets cells pass through G1!
• Patients with two mutated RB genes have way, way high risk of retinoblastoma (and increased risk of other tumors).
The Cell Cycle
Patient with retinoblastoma
Orbit filled with retinoblastoma
Retinoblastoma
Retinoblastoma: characteristic �rosettes�
Another example: p53
• Nickname for p53: “guardian of the genome”
• If a cell’s DNA is damaged, p53 causes a pause in
the cell cycle (via RB), so DNA can be repaired.
• If DNA damage is irreparable, p53 causes the cell
to undergo apoptosis.
• Most human tumors have p53 mutations!
p53 activated
cell cycle arrest
p53 not activated
no cell cycle arrest,no DNA repair
Characteristics of Cancer Cells
• Autonomous growth
• Insensitivity to growth-inhibitory signals
• Evasion of apoptosis
Evasion of Apoptosis
• Many proteins are involved in apoptosis:• Fas (the “death receptor”)• Executioner caspases • BCL2 protein family• p53 (the “guardian”)
• If genes for these proteins are mutated, the call becomes immortal.
Characteristics of Cancer Cells
• Autonomous growth
• Insensitivity to growth-inhibitory signals
• Evasion of apoptosis
• Limitless replication
Limitless Replication
• Normal human cells: only 60-70 doublings
• Telomeres keep getting shorter…
• …leading to cell cycle arrest (via p53 and RB).
• Stem cells and cancer cells use telomerase to maintain telomere length and keep replicating.
Characteristics of Cancer Cells
• Autonomous growth
• Insensitivity to growth-inhibitory signals
• Evasion of apoptosis
• Limitless replication
• Sustained angiogenesis
Sustained Angiogenesis
• Tumor cells need blood too!
• Can’t grow >1-2 cm without new vessels
• Tumor cells eventually learn how to stimulate angiogenesis
• Lots of cytokines involved (i.e., VEGF)
• Tumor vessels are fragile and abnormal
Characteristics of Cancer Cells
• Autonomous growth
• Insensitivity to growth-inhibitory signals
• Evasion of apoptosis
• Limitless replication
• Sustained angiogenesis
• Invasion and metastasis
Invasion and Metastasis
• To invade, tumor cells must:• Loosen contacts between cells• Degrade extracellular matrix• Migrate away from the original site
• Some tumors lodge in nearest capillary bed
• Some tumors show tropism
clonal growth
intravasation
metastatic subclone
tumor cell embolus
extravasation
Tumor cells surrounding and invading vessel
Tumor cells now within vessel
How do all these genetic mutations arise?
• We are constantly exposed to mutagenic agents.
• But we don’t get many cancers because normal cells are able to repair DNA damage.
• Many systems for DNA repair exist.
• If you inherit a defect in any of these systems, you’ll be more likely to get cancer.
Number of cell divisions/day
Spontaneous mutation rate
Number of mutations/day
1011
10-6
105
Neoplasia Outline
• Tumor nomenclature
• Tumor characteristics
• Epidemiology
• Cancer pathogenesis• Overview• Genes• Steps
Steps to Cancer
• Every tumor results from the accumulation of a bunch of mutations
• Average: 90!
• Normally, body fixes or gets rid of mutated cells (using RB, p53)
• For a tumor cell to grow, one of its mutations must be within these checkpoint/guardian genes.
Neoplasia Outline
• Tumor nomenclature
• Tumor characteristics
• Epidemiology
• Cancer pathogenesis• Overview• Genes• Steps• Chromosomes
Chromosomal Changes
• Genetic damage can be subtle, invisible on a karyotype (point mutation)
• …or obvious, visible on a karyotype
• Some karyotypic abnormalities occur predictably in certain tumors (leukemias, lymphomas, solid tumors)
Chromosome banding
prophase
metaphase
anaphase
metaphase spread
Normal male karyotype
Balanced Translocations
• Common!
• Either put a proto-oncogene next to a promoter…
• …or create a fusion gene that makes a bad, growth-promoting product
• Most common in hematopoietic tumors
• Example: Philadelphia chromosome
Deletions
• Deletion of part or all of a chromosome
• Usually, deletion of a tumor suppressor gene
• Most common in solid tumors
• Example: del 13q14 in retinoblastoma
Neoplasia Outline
• Tumor nomenclature
• Tumor characteristics
• Epidemiology
• Cancer pathogenesis• Overview• Genes• Steps• Chromosomes• Agents
Carcinogenic Agents
• Chemicals
• Radiation
• Bugs/viruses
Chemicals
• Direct-acting agents, e.g., chemotherapy drugs
• Indirect-acting agents (require conversion to become carcinogenic), e.g., hydrocarbons, aflatoxin B, nitrites
• Mechanism: electrophile groups bind to DNA
RadiationIonizing radiation• Causes chromosome breakage, translocations• Examples: miners (lung cancer), atomic bomb
radiation (leukemia), therapeutic head/neck radiation (thyroid cancer)
UV light• Causes formation of pyrimidine dimers• Repair pathways usually fix – but can become
overwhelmed• Examples: squamous cell carcinoma, melanoma
normal DNA
DNA with pyrimidine dimers
Bugs
• HTLV-1: T-cell lymphoma
• HPV: Cervical cancer
• EBV: various lymphomas
• HBV and HCV: hepatocellular carcinoma
• H. pylori: gastric cancer, lymphoma
Neoplasia Outline
• Tumor nomenclature
• Tumor characteristics
• Epidemiology
• Cancer pathogenesis• Overview• Genes• Steps• Chromosomes• Agents• Grading and staging
Grading and Staging
• Used for malignant tumors• Helps determine treatment and prognosis• Grading
• Tells you how nasty the tumor looks (use microscope)
• Somewhat useful• Staging
• Tells you how far the tumor has spread (use imaging)
• Very useful
Tubuleslots of tubules some tubules rare tubules
Mitoses0-9 mitoses/10 hpf 10-19 mitoses/10 hpf≥20 mitoses/10 hpf
Pleomorphismsmall, uniform cells larger, less uniform cellsmarkedly pleomorphic cells
Grading system for breast cancer
Low gradeIntermediate gradeHigh grade
123
123
123
3-56-78-9
add all points together
Grade Score 5y survival>95%80%60%
Breast carcinoma low grade
Breast carcinoma high grade
T=TumorTis – in situ tumor T1 – small tumorT2 – larger tumorT3 – larger or invasive tumorT4 – very large/very invasive
N=NodesN0 – no lymph node involvement N1 – a few regional nodesN2 – lots of regional nodesN3 – distant nodes
M=MetastasesM0 – no metastases M1 – metastases
TNM staging system for non-small cell lung cancer
Overall stageStage 0
Stage I
Stage II
Stage III
Stage IV
TNM staging system for non-small cell lung cancer
TTis
T1 or T2
T1T2T3
T1 or T2T3
Any TT4
Any T
NN0
N0
N1N1N0
N2N1 or N2
N3Any N
Any N
MM0
M0
M0M0M0
M0M0M0M0
M1
TreatmentSurgery only
Surgery � radiation
Surgery and radiation
� chemotherapy
Chemotherapy �radiation to debulk
Maybe surgery
Palliative careMaybe chemo or radiation
5y prognosis75%
50%
30%
10%
<2%
Grading and Staging
Grading = microscopic
Staging = clinical
Staging is more useful.