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.