W4L3 Fri: Human Cancer

Question 1

Normal cell grow vs cancer growth in cultre

Answer 1

normal human breast cells grown in culture:
* divide in an orderly fashion
* organise themselves into spheroids of polarised epithelial cells
Breast cancer grown in the same conditions:
* divide aggressively
* become migratory
* lose epithelial structure and form disorganised clumps

Question 2

What is cancer

Answer 2

-Disease featuring abnormal and improperly controlled cell division resulting in invasive growths, or tumours, that may spread throughout the body.

Question 3

Type of cancer

Answer 3

• Cancer are classified based on the tissue of origin:
  o Carcinoma: cancers of epithelial cells. Account for about 80% of human cancers (eg. lung, breast, bowel, prostate, etc.)
  o Sarcoma: cancers of connective tissue (eg. bone, cartilage, fat, muscle, vascular tissues).
  o Melanoma: cancer of melanocytes (pigment producing cells in the skin)
  o Leukaemias: Cancers of white blood cells
  o Lymphomas: Cancers of the lymphatic system
  o Retinoblastoma, Glioblastoma, Medulloblastoma, Neuroblastoma. Cancers of the cells of the nervous system (neurons & glia)

Question 4

Benign tumours vs malignant tumours (cancers)

Answer 4

• Benign, or noncancerous, tumours - generally stop growing, do not spread to other parts of the body, and do not create new tumors.
• Malignant, or cancerous, tumours can invade healthy tissues, interfere with body functions, can draw in blood vessels (angiogenesis) to get nutrients and oxygen for more growth, can spread to other parts of the body, and create new tumours.

Question 5

Type of cell proliferation and death

Answer 5

• Apoptosis: The process of programmed cell death.
• Cell proliferation: The increase in cell number by division.
• Senescence: A cell which is still alive but not actively proliferating (dividing), therefore in a state of arrest which is normally irreversible.

Question 6

Metastasis

Answer 6

The spread of cancer cells from one site in the body to another site.
-occur through the capillary system

Question 7

Cancer rate ad age

Answer 7

-Multiple mutations are needed to create a cancerous cell.
-This requires long periods of time or higher mutation rates.

Question 8

Genetic and epigenetic cause of cancer

Answer 8

Cancer is, at heart, a genetic disease. It is caused by genetic (or epigenetic) changes that affect gene expression or function.
Genetic changes can be caused by:
* mutations (e.g. due to DNA damage),
* chromosomal abnormalities such as translocations, or * introduction of genes by viruses.

Question 9

What is oncogene

Answer 9

A gene that, when mutated or expressed at high levels, helps turn a normal cell into a CANCER cell
* The “normal” version of an oncogene is referred to as a proto-oncogene
* Only one copy of the proto-oncogene need be “activated” to develop cancer.

Question 10

Tumour suppressor gene:

Answer 10

A gene that acts to prevent a normal cell from turning into a CANCER cell.
* Mutations in tumor suppressor genes may lead to cancer, but one must lose both copies of the gene (Knudson “two hit” theory).

Question 11

Way that proto-oncogene can be activated

Answer 11

-Deleation or point mutation in coding sequences > hyperactive protein made in normal amount
-Regulatory mutation> overproduction
-Gene amplification> overproduction
-Chromosomal rearrangement > either change in regulator sequences that lead to overproduction or fusion of gene lead to hyperactive protein

Question 12

Burkit lymphoma

Answer 12

-An aggressive cancer of the lymphatic system involving over-proliferation of B lymphocytes
- due to a proto-oncogenes translocation lead to higher transcriptional activity
-90% of cases of Burkitt’s lymphoma involve a reciprocal translocation between chromosomes 8 and 14
-enhancer from chromosome 14 transfer to proto-oncogene c-myc

Question 13

Why does higher level of cmyc lead to burkit lymphomia

Answer 13

-Myc is a transcription factor, which promotes cell growth and proliferation by controlling expression of target genes in response to many signaling pathways.
-Excessive Myc levels leads to hyper-proliferation of the lymphocytes.

Question 14

Chronic myeloid leukaemia

Answer 14

-a cancer in which the bone marrow produces too many granulocytes (a type of white blood cell)
* reduced numbers of healthy white blood cells, red blood cells and platelets.
* This leads to increased infection, anemia, & easy bleeding
-Most cases of CML involve a reciprocal translocation between chromosomes 9 and 22.
-lead to the creation of Philadelphia chromosome

Question 15

The Philadelphia chromosome

Answer 15

a fusion between the c-abl (c-abelson) gene which encodes a kinase and the Bcr (Breakpoint cluster region) genes.
-Bcr-abl fusion Have an increase in kinase activity
-The BCR-ABL fusion protein oligomerizes through the BCR coiled-coil domain and, as such, undergoes auto-activation of the ABL tyrosine kinase domain. This results in a constitutively active kinase, therefore mis-regulation of the cellular signaling pathway that it mediates.

Question 16

Melanoma and its cause

Answer 16

-a skin cancer in which melanocytes overproliferate and become metastasise
-MAPK pathway is activated by extracellular ligands binding to the Receptor Tyrosine Kinase, which in turn activates Ras, binds to and activates the BRAF kinase and the rest of the MAPK cascade.
-Activation of this pathway causes cell growth and proliferation.
Almost 50% of melanomas harbour mutations in BRAF, (most commonly V600E) which result in a constitutively active kinase.
This means the MAPK pathway is activated all the time.

Question 17

Loss of heterozygosity

Answer 17

-A person can inherited a god and a bad copy of tumor repression gene
- loss of fuction in the remaining good gene gene

Question 18

Retinoblastoma

Answer 18

Retinoblastoma is a rare (1 in 20,000) childhood tumor which develops from neural progenitor cells in the immature retina

Question 19

Rb – the first tumor suppressor gene discovered

Answer 19

1. E2F promotes cell-cycle progression by activating transcription of S-phase genes.
2. It is normally held in an inactive complex by Rb.
3. G1-Cdk phosphorylation of Rb inactivates it, liberating E2F and triggering S-phase.

Question 20

Rb and retino blastoma

Answer 20

-Children that inherit a faulty copy of Rb are predisposed to retinoblastoma (and other cancers) and usually develop multiple tumors affecting both eyes.
-Non-hereditary retinoblastoma is extremely rare because it requires two successive hits to the Rb gene (ie. the knudson two-hit model), and typically only produces a tumor in one eye.

Question 21

p53 - the guardian of the genome

Answer 21

• p53 is one of the most important tumour suppressor genes in human cancers. It is a DNA-binding transcription factor.
  *Homozygous loss of p53 is found in many carcinomas (eg. 70% of colon cancers, 30–50% of breast cancers, and 50% of lung cancers),
  -leukemias, lymphomas, sarcomas, and neurogenic tumors

Question 22

Fuction of p53

Answer 22

-Cells are subjected to various stresses such as hyperproliferation (e.g. due to excess Myc), DNA damage, telomere shortening, or lack of oxygen (i.e. hypoxia). These increase the levels/activity of p53.
-p53 can then respond by stopping the cells from dividing, causing them to die (undego apoptosis), and have them repair damaged DNA.
p53 is a transcriptional activator. It controls cell-cycle arrest, senescence, apoptosis, DNA repair, and invasion by turning on other genes

Question 23

p53 germline mutations - Li-Fraumeni syndrome (LFS)

Answer 23

-Greater risk of cancer, at a much younger age.
-at risk for many type of cancer

Question 24

Control of p53

Answer 24

-Levels of p53 are normally kept low in cells through the action of a ubiquitin ligase called Mdm2
-DNA damage lead to phosporilisation of p53, mdm2 can no longer bind
-p53 level increase
-Similarly, excessive amounts of Myc leads to increased levels of another protein Arf, which can stop Mdm2 binding to p53.