Lecture 32: Neoplasia

Question 1

What are the three fundamental principles of carcinogenesis?

Answer 1

1. Genetic changes (mutations) lie at the heart of carcinogenesis.
2. Two major classes of genes are the targets of this damage.
   -oncogenes and tumor suppressor genes
3. Carcinogenesis is often a multistep process with multiple genes involved.

Question 2

What are the two major classes of genes that are targets of genetic damage during carcinogenesis?

Answer 2

Oncogenes: genes encoding proteins that promote cancer.

Tumor suppressor genes: genes encoding proteins that inhibit cancer.

Question 3

What is the “two-hit” hypothesis for tumor suppressor genes?

Answer 3

Developed by Alfred Knudsen in 1971 using mathematics.

Most tumor suppressors are recessive and need both alleles (homozygous deletion/mutation)
-heterozygous mutations can be inherited: families show increased susceptibility to cancers

Question 4

Why does cancer risk increase with age?

Answer 4

Accumulation of somatic mutations

Decline in immune function

Question 5

How do inherited mutations in DNA repair genes contribute to increased cancer risk?

Answer 5

The loss of DNA repair causes increased mutation rate and increased tumor incidence.

EX: BRCA 1/2 repair of double stranded DNA breaks. Inherited mutations lead to breast and ovarian cancer.

Question 6

How do environmental factors increase DNA damage?

Answer 6

Environmental factors such as smoking increase the speed of mutation rate median.

Chemical carcinogens react with DNA, leading to mutations and DNA damage.

Ionizing radiation (x-rays) cause genetic lesions (mutations, translocations, breakage) by inducing DNA strand breaks.

Ionizing radiation (alpha, beta, gamma particles) from unstable isotopes induce DNA strand breaks.

UV light causes genetic lesions by cross-linking DNA bases. LOF mutations in tumor suppressors or GOF mutations in oncogenes.

Question 7

What are the six hallmarks of cancer cells?

Answer 7

Self-sufficiency in growth signals

Resistance to growth inhibitory signals

Evade apoptosis

Limitless replicative potential

Tumor cells can trigger angiogenesis

Invade surrounding tissues and metastasize to distant locations

Question 8

What is important to know about Hallmark 1: Self-sufficiency in growth signals

Answer 8

Activation of kinase signal transduction pathways that respond to mitogenic signaling.

Cancer mutations are common in receptor tyrosine signaling pathways. EX: thyroid cancer

Question 9

What is important to know about Hallmark 2: Resistance to growth inhibitory signals

Answer 9

Cancer may arise through loss of expression (mutation) of growth inhibitory proteins.

Question 10

What is important to know about Hallmark 3: Evade apoptosis

Answer 10

Disruption of apoptotic pathways prevents cell death upon DNA damage or cell cycle checkpoint activation.

EXs: Loss of p53, Loss of p21, Loss of BAX

Question 11

What is important to know about Hallmark 4: Limitless replicative potential

Answer 11

Telomere shortening leads to chromosomal abnormalities and cell death as they get shorter each division.

Tumor cells overexpress telomerase leading to cell immortalization (limitless replicative potential)

Question 12

What is important to know about Hallmark 5: Tumor cells can trigger angiogenesis

Answer 12

Solid tumor larger than 1-2 mm diameter need blood supply.

Tumor cells produce VEGF (vascular endothelial growth factor) promoting angiogenesis.

Question 13

What is important to know about Hallmark 6: Invade surrounding tissues and metastasize to distant locations

Answer 13

First there is adhesion and invasion of basement membrane beneath tumor.

Migration through extracellular matrix.

Invasion of vascular basement membranes and vascular ingress (intravasation).

Travel via the vasculature.

Adhesion to basement membrane at destination.

Invasion of vascular basement membrane and vascular exit (extravasation).

Migration through extracellular matrix.

Formation of metastatic deposit and cell proliferation.

Question 14

How is the cell cycle regulated and monitored?

Answer 14

There are checkpoints throughout the cell cycle.

The cell cycle clock determines when the cell moves from one phase to the next.
-driven by cyclins paired with CDKs

R point is critical point during G1 where cell determines to enter cell cycle or not

Cell cycle checkpoints will inhibit passage to the next stage if the cell isn’t ready to move on.

Question 15

What is important to know about receptor tyrosine kinase signal pathway?

Answer 15

Cancer mutations are common in RTK signal pathways

EX: thyroid cancer

Question 16

How do growth stimulatory proteins encoded by oncogenes and growth inhibitory proteins encoded by tumor suppressor genes play into receptor tyrosine kinase signal pathway?

Question 17

How can genetic alterations in about receptor tyrosine kinase signal pathway lead to cancer?

Answer 17

DNA polymerase could copy multiple copies of a gene and you have abnormally high levels of the protein through amplification.

At high level of receptors, receptors will encounter each other more frequently and can produce ligand independent phosphorylation.

Question 18

How does telomerase overexpression lead to cell immortalization?

Answer 18

Increasing the ends of the chromosomes through telomerization gives a protective seal to the DNA allowing for limitless replicative potential.

Question 19

How do tumors induce angiogenesis?

Answer 19

Solid tumor larger than 1-2 mm diameter need blood supply.

Tumor lacks adequate oxygen and lack of metabolite supplies and lack of way to remove metabolism products.

Tumor cells produce VEGF (vascular endothelial growth factor) promoting angiogenesis.

Question 20

What is the sequence of events required for cancer cells to metastasize?

Answer 20

First there is adhesion and invasion of basement membrane beneath tumor.

Migration through extracellular matrix.

Invasion of vascular basement membranes and vascular ingress (intravasation).

Travel via the vasculature.

Adhesion to basement membrane at destination.

Invasion of vascular basement membrane and vascular exit (extravasation).

Migration through extracellular matrix.

Formation of metastatic deposit and cell proliferation.

Question 21

How does inflammation increases cancer risk?

Answer 21

Inflammation results in persistent regenerative cell proliferation or hyperplasia (increase in cell number) and DNA damage as a result of reactive oxygen and nitrogen species produced by immune cells.

Question 22

How can viruses cause cancer?

Answer 22

3 mechanisms.

-Integration into the genome (retroviruses) can cause modulation of oncogenes or tumor suppressor genes.

-Chronic inflammation (HBV and HCV) cause hepatitis (chronic liver inflammation) increasing the risk of liver cancer.

-Expression of viral genes that alter cellular pathways.

Question 23

What is the sequence of genetic changes associated with colon carcinogenesis?

Answer 23

Loss of APC gene (resulting in hyperproliferative colonic epithelium)

DNA methylation (promoter) results in loss of expression of other APC gene (2nd hit) resulting in translocation of catenin protein to nucleus stimulating Myc and Cyclin D transcription. resulting in early adenoma tumor.

GOF mutation of ras gene resulting in intermediate adenoma

LOF mutation of DCC, SMAD2 and SMAD4 tumor suppressor genes. DCC is a growth inhibitory cell adhesion protein. SMAD2 and SMAD4 are part of the growth inhibitory TGF signaling pathway. result large polyp

Loss of mutation of p53 gene and subsequent additional genetic changes. Result is carcinoma (malignancy)

Question 24

What is neoplasia?

Answer 24

The abnormal growth of cells or tissues.

Neoplasms (tumors) are an abnormal mass of tissue characterized by dysregulated cell proliferation

Question 25

What is the difference between malignant tumors (cancers) and benign tumors?

Answer 25

Cancers are less differentiated

Cancers are invasive

Cancers are metastatic

Question 26

What is grading related to cancer?

Answer 26

The estimate of aggressiveness or level of malignancy based on microscopic examination of tumor cell morphology.
-grading is based on the differentiation state and number of mitoses of the tumor
-largely qualitative in nature

Question 27

What is staging related to cancer?

Answer 27

The estimation of aggressiveness of level of malignancy based on size of primary lesion, spread to lymph nodes, and presence of absence of metastases.
-stage is largely quantitative
-staging is of greater clinical value