Cancer Cell Biology

Question 1

What is the process of normal cell proliferation?

Answer 1

Question 2

What is the Ras pathway?

Answer 2

Question 3

What is the cell cycle clock?

Answer 3

Question 4

What are the cyclins and CDKs?

Answer 4

Question 5

What is the cell cycle–dependent phosphorylation of Rb?

Answer 5

• The phosphorylation state of Rb (red circle) is closely coordinated with cell cycle advance.
• As cells pass through the M/G1 transition, virtually all of the existing phosphate groups are stripped off Rb, leaving it in an unphosphorylated configuration.
• As cells progress through G1, a single phosphate group is attached at any one of 14 different phosphorylation sites (by cyclin D-CDK4/6 complexes), yielding hypophosphorylated Rb
• However, when cells pass through the restriction (R) point, cyclin E– CDK2 complexes phosphorylate Rb on at least 12 more sites, placing it in a hyperphosphorylated state.
• Throughout the remainder of the cell cycle, the extent of Rb
  phosphorylation remains constant until cells enter into M phase

Question 6

What are the functional consequences of phosphorylation?

Answer 6

Non-phosphorylated Rb:

• Binds transcription factors collectively called E2Fs
• Prevents E2F-mediated transcriptional activation of many genes whose products (e.g., DNA polymerase) are required for DNA
  synthesis

Phosphorylated Rb:

• Cyclin D–CDK4/6 kinase activity phosphorylates Rb starting in mid- G1.
• Complete phosphorylation inactivates Rb and disassociates E2Fs to turn on genes required for transition to S and for DNA synthesis, irreversibly committing the cell to DNA synthesis.
• Deregulation of the cell cycle and genome maintenance pathways can cause cancer.
• Mutations that promote unregulated passage from G to S phase are oncogenic in ~80 percent of human cancers.

Rb loss-of-function mutations contribute to cancer:

• Childhood retinoblastoma, a relatively rare type of cancer
• More common cancers that arise later in life (e.g., carcinomas of lung, breast, and bladder)

Question 7

What are the functions of p53?

Answer 7

p53 inhibits neoplastic transformation by three interlocking mechanisms:

• activation of temporary cell cycle arrest (quiescence)
• induction of permanent cell cycle arrest (senescence)
• triggering of programmed cell death (apoptosis)

Question 8

What are the classes of genes in the onset of cancer?

Answer 8

Question 9

What mutant forms of proteins can cause cancer?

Answer 9

Question 10

How can a proto-oncogene become mutated?

Answer 10

Question 11

What are tumour viruses?

Answer 11

Question 12

What are examples of DNA tumour viruses?

Answer 12

Question 13

What is the process of viral integration?

Answer 13

Question 14

What is DNA methylation and its roles?

Answer 14

Roles of DNA methylation

• Long term silencing of genes
• X-chromosome inactivation
• Establishment and maintenance of imprinted genes
• Silencing of repetitive elements ( eg: transposons)
• Suppression of expression of viral genes and other deleterious elements that have been incorporated into the genome of the host over time
• Carcinogenesis

Question 15

What are the patterns of DNA methylation in normal vs cancer tissue?

Answer 15

Question 16

What are the barriers for indefinite replication?

Answer 16

Two barriers prevent cultured cells from replicating indefinitely in culture – senescence and crisis
• Senescence involves cells existing long-term in a non- growing but viable state
• Crisis involves the apoptotic death of cells. Cells can escape crisis by activating hTERT telomerase, thus staving off mitotic catastrophe and achieving immortality. hTERT is specialized to elongate telomeric DNA by extending it in hexanucleotide increments

Question 17

What is the multi step model of cancer development?

Answer 17

First mutation – gives one cell a slight growth advantage

Second mutation – in a progeny cell causes its descendants to grow more uncontrollably and form a small benign tumour

Third mutation – in a cell within the tumour allows it to overcome constraints imposed by the tumour microenvironment and outgrow the others to form a mass of cells, each of which has all three genetic changes

Fourth mutation – in one cell allows its progeny to escape into the bloodstream and establish daughter colonies at other sites (hallmark of metastatic cancer)

Question 18

What are the main routes of metastasis?

Answer 18

• Lymphatic spread

Mainly carcinomas – pattern of lymph node involvement follows the natural routes of drainage.

Carcinoma of breast (upper outer quadrant) spread to axillary lymph nodes, the inner quadrant drain through the nodes along the internal mammary artery.

Regional nodes act as a barrier to further spread of the tumour, at least for a time.

The cells, after arrest within the node, may be destroyed.

• Blood-borne (haematogenous) spread

Typical of sarcomas, but also seen in carcinoma.

Arteries: due to thicker walls are less readily penetrated.

Venous invasion follow venous flow draining the site of neoplasm: e.g. liver and lung (all portal drainage to the liver and all caval blood flows to the lungs).

Cancers arising in close proximity to the vertebral column often embolise through the paravertebral plexus: e.g. thyroid and prostate carcinomas.

Lung cancer commonly metastasizes to the skeletal system, including the spine

• Transcoelomic spread – metastasis across a body cavity

Peritoneal cavity

Pleural cavity

Pericardial cavity

Subarachnoid cavity

Joint space

Diagnostic paracentesis of ascitic/pleural fluid

Breast and lung tumours commonly involve pleural space and cause pleural effusion.

Ovarian and gastric tumours are responsible for peritoneal involvement and cause malignant ascites.

• Perineural spread

Spread along the course of nerve bundles.

Common in prostate carcinoma and some basal cell carcinoma.

Question 19

What happens in the invasion of the epithelial basement?

Answer 19

Question 20

Intra vs extravasation

Answer 20

Question 21

What is the invasion-metastasis cascade?

Answer 21

Question 22

What happens in an EMT transition?

Answer 22