Biology 311 - Cancer

What is cancer?

• a disease of uncontrolled cell division.

• its development and progression are usually linked to a series of changes in the activity of cell cycle regulators.

• abnormal growth, division and survival of cells.

• rapid division: typical of cells that have taken their final cell fates

  • Apoptosis

• all cancers have shared hallmarks

• altered cellular physiology

What are the six hallmarks of cancer?

1. resist cell death

2. sustain proliferative signaling

3. evade growth suppressors

4. induce angiogenesis

5. enable replicative immortality

6. activate invasion and metastasis

what is the genetic disease of cancer cells?

• altered karyotypes (aneuploidy) and mutations

  • Aneuploidy is the presence of an abnormal number of chromosomes in a cell due to abnormal growth

  • A karyotype is an individual's complete set of chromosomes.

What pathway does cancer undergo?

cancer undergoes aerobic glycolysis even in the presence of oxygen

what is angiogenesis?

• when tumors induce growth of blood vessels

describe the evolution of a tumor

1. Initiation

   1. a mutational event targets a somatic cell

2. Cancer progression

   1. during proliferation of cells, mutation and genome destabilization occurs, as well as, dysregulation of growth control pathways.

3. Evasion of cancer cell elimination

   1. at the precancerous phase, apoptosis no longer occurs, and cancer cells prevent their elimination by blocking T-cells which leads to a cytotoxic T-cell

4. Tumor growth and dispersal

   1. When it has become a tumor, angiogenesis occurs and metastasis

what is metastasis?

• the ability for cancer cells to migrate to other parts of the body

• epithelial to mesenchymal transition = backwards development

  • cells lose their terminal differentiation (uncontrolled mitosis)

  • switch back to aerobic glycolysis (even in the presence of O2)

• tumor cells degrade the basement membrane underlying epithelia

What are oncogenes?

• cells that promote cell division and growth

• found in cancerous cells

• mutated to higher levels of activity: always dividing

• gain-of-function

what are tumor suppressors?

• cells that serve to inhibit cell division and growth

• mutated to lower levels of activity

• cancerous mutations are loss-of-function

• tends to be recessive which requires both mutant alleles

what promotes uncontrolled cell growth?

• activation of oncogenes

  • ras

• inactivation of tumor suppressors

  • p53

oncogenic ras

• cell division and proliferation will still occur even in the absence of a growth factor and growth factor receptor complex.

• Ras is a G-protein, meaning it can switch back and forth between active and inactive form.

• cancer-causing mutations often change Ra’s structure so that it can no longer switch to its inactive form, or can do so only very slowly, leaving the protein in the “on” state.

tumor suppressors in healthy cells

• tumor protein p53

  • acts primarily at the G1 checkpoint (controlling the G1 to S transition)

  • functions to block cell cycle progression in response to damaged DNA and other unfavorable conditions

• when a cell’s DNA is damaged, a sensor protein activates p53, which halts (pauses) the cell cycle at the G1 checkpoint by triggering production of a cell-cycle inhibitor

• the pause from above serves to buy time for DNA repair, which also depends on p53, whose second job is to activate DNA repair enzymes.

• If damage is fixed then p53 released the cell, allowing it to continue through the cell cycle.

• If damage cannot get fixed, p53 will plays its third role and final': triggering apoptosis so that damaged DNA is not passed on.

tumor suppressors in cancer

• in cancer cells, p53 is often missing, nonfunctional, or less active than normal.

• when p53 is defective, a cell with damaged DNA may proceed with cell division.

• the daughters cells of such a division are likely to inherit mutations due to the unprepared DNA of the mother cell.

how does p53 act?

p53 acts by biding to target genes and activating their transcription, the non-binding mutant protein is unable to do its job.

what do oncogenes and tumor suppressors lead to?

oncogenesis via activation of cyclin D and acceleration of the cell cycle.

oncogenesis

the development of a tumor to tumors

describe the Philadelphia chromosome

• occurs due to a 22 and 9 translocation

• generates a fusion of two genes BCR-ABL

  • Creates a mutant form of ABL kinase that phosphorylates the wrong substances (cancer cells) which results in uncontrolled myeloid growth

  • formation of BCR-ABl and the Philadelphia chromosome allows cell to bypass signals controlling growth and differentiation

• Gleevec serves to inhibit

  • done by binding to the ATP binding site on BCR-ABL complex to competitively inhibit the activity of BCR-ABL and greatlyreeduce cancer

hereditary retinoblastoma

• typically inherit one inactive copy of a gene

  • passed on to the next generation in germ cells

  • about 10 percent of human cancer

  • 2nd it mutations gives rise to tumors

sporadic retinoblastoma

• develops 2 inactive copies of tumor suppressor in the same cell

  • typically derived from a single somatic cell

  • is not passed on