Neoplasms: Behavior, Etiology, Pathogenesis

Front 1

Neoplasm

Back 1

= disorder of cell growth triggered by a series of acquired mutations affecting a single cell and its clonal progeny

Hamartoma: abnormally arranged tissue

Choristoma: cells in an abnormal setting

Front 2

Malignant neoplasms

Back 2

Carcinoma: epithelium; 80% - surface coverings, glands; all 3 germ layers

Sarcoma: mesenchymal (CT) - fibroblasts, Sm, bone, cartilage, adipose tissue

Lymphoma: lymphoid tissue - lymph nodes, etc.

Leukemia: bone marrow-derived cells - in blood & other tissues

Front 3

Combines tumors

Back 3

Mixed tumor:

= divergent differentiation of a single neoplastic clone

Teratoma:

= A tumor that contains recognizable cells/tissues belonging to more than one germ cell layer (sometimes all three)

Front 4

Dysplasia

Back 4

= disordered growth in epithelia

- premalignant change, might evolve to carcinoma

Front 5

Malignant histologic features

Back 5

Pleomorphism - variation in size & shape

Hyperchromasia - ↑ density of chromatin

Chromatin distribution - clumped, condensed along nuclear membrane

↑ Nuclear to Cytoplasmic ratio (N:C ratio)

Abnormal mitoses (tripolar)

Loss of polarity

Necrosis (esp. w/o angiogenesis)

Front 6

Morphologic features =/=> biologic behavior

Back 6

1. "An innocent face may mask an ugly nature"

2. Continuum of genetic changes & morphologic features: benign-malignant

Front 7

Grade

Back 7

= degree of differentiation: well-poorly

- number of mitoses

- necrosis

- 1-4 ~ aggressiveness

Front 8

Stage

Back 8

= extent of involvement by malignant neoplasm

- more predictive than grade

- TNM (Tumor size, Nodes involved, Metastases) system

- 0-IV

Front 9

Prognosis

Back 9

- Growth rate:

-- cell production > loss

-- fraction of cells in replicating pool

-- doubling: 30 -> 10^9 ~ 1g; 40 -> 10^12 ~ 1kg

- Predicting behavior: variable

Front 10

Metastases

Back 10

1° tumor formation

-> localized invasion

-> intravasation

-> circulation

-> extravasation

-> colonization (limiting step)

Front 11

Chemical carcinogens

Back 11

- exposure to chemical (mutagen) -> cancer

-> mutagenicity measured by Ames test (his-)

- direct vs. indirect (<- metabolic activation)

=> types of DNA dmg:

-- alkylation -> mismatches in base pairing

-- depurination/depyrimidination

-- bulky DNA adducts --| base pairing

-- ds breaks

Front 12

Viral carcinogens, radiation, stochastic events

Back 12

Viruses (papova, adeno, herpes hepatitis)

-> genome integration -> viral protein expression

Radiation

-> DNA dmg, chromosomal breakage, abnormal.

Stochastic events

- during DNA replication, oxidative dmg, IC event

Front 13

DNA repair & defective repair

Back 13

- repair mechanisms: prereplicative (↑ fidelity), post-replicative (↑ & ↓ fidelity); examples:

-- Xeroderma pigmentosum - deficiency in nucleotide excitosol repair -> ↑ UV mutation rate

-- Hereditary nonpolyposis colon cancer (HNPCC) - DNA mismatch repair defect (MLH1,...)

-- Bloom's syndrome: chromosomal instability by defect in homologous recombination repair

Front 14

Modifiers of carcinogenesis

Back 14

Enzyme induction - indirect usually activated by CYP (cytochrome P450), detoxification

Genetic polymorphisms -> ↑ predisposition:

-- activating enzymes

-- protective & DNA repair enzymes

Diet: antioxidants, VitA, caloric intake

Cell cycle: dividing cells; labile cells in cycle

Front 15

Steps in chemical carcinogenesis

Back 15

2 steps:

Initiation = exposure to a mutagen

Promotion = subsequent events -> neoplasms (epigenetic events favoring tumor development)

Progression = additional genetic events required to confer a malignant phenotype

Front 16

Properties of tumor cells

Back 16

- foci are clonal outgrowths

- altered morphology

- ability to proliferate indefinitely

- loss of contact inhibition

- reduced requirement for GF's

- increased IC transport of glucose

- tumorigenicity (ability to make timors in vivo)

Front 17

Gene classes deregulated by oncogenesis

Back 17

- proto-oncogenes (gain of fxn)

- tumor suppressor genes (loss of fxn)

- genes regulating apoptosis/cell cycle

- DNA repair genes (also telomerase)

Front 18

Metastatic invasion

Back 18

- loss of adherens jxns (loss of e-cadherin)

- conversion -> fibroblast-like morphology

- expression of matrix degrading enzymes

- ↑ motility

- molecular changes in invasion:

-- loss of e-cadherin

-- loss of Merlin (NF2 product) - couples e-cadherin to TrkR's (EGF-R)

-- TS regulations of Snail, Slug, Twist, Zeb1/2

Front 19

Types of oncoproteins

Back 19

- GF's (c-sis -> PDGF-β)

- GF-R's (TM R Trk's; EGF-R)

- signal transduction proteins (RAS)

- nuclear regulatory factors (TF's: MYC, FOS, JUN)

- cell cycle proteins (cyclins, CDK's)

Front 20

Hereditary cancer syndromes:

Autosomal dominant

Back 20

Retinoblastoma - Rb mutation

Li-Fraumeni syndrome - p53

Familial adenomatous polyposis - APC gene

Neurofibromatosis - Neurofimbrin

Familial breast/ovarian cancer - BRCA1/2

Familial atypical multiple mole melanoma syndrome - p16

Hereditary Non-polyposis Colon Cancer (HNPCC) - DNA mismatch repair

Front 21

Hereditary cancer syndromes:

Autosomal recessive

Back 21

Xeroderma Pigmentosum - DNA excision repair

Ataxia-telangiectasia - DNA repair "sensor"

Bloom syndrome - Recombination repair

Fanconi anemia - Recombination repair

Front 22

Metastatic requirements

Back 22

- Detachment & ↓ cellular cohesion: ↓ Cadherins

- ECM degradation: ↑Metalloproteases, ↓TIMPs

- Cell-matrix attachments: Integrin switching

- Angiogenesis: ↑ VEGF, ↑ bFGF

- Motility & migration: GF's, MMP's, cytokines

- Vascular extravasation

- Avoiding immune surveillance: "cloaking"

- Survival & Proliferation in a new environment