Neoplasia IV: Cancer Pathogenesis Cancer Pathogenesis Lecture - - PowerPoint PPT Presentation

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Neoplasia IV: Cancer Pathogenesis Cancer Pathogenesis Lecture - - PowerPoint PPT Presentation

Aug 16, 2022 230 likes •662 views

Neoplasia IV: Cancer Pathogenesis Cancer Pathogenesis Lecture Objectives Briefly answer, in your own words, the question What causes cancer? List the eight characteristics (or hallmarks) of cancer cells that make them different from

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Neoplasia IV: Cancer Pathogenesis

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Cancer Pathogenesis Lecture Objectives

  • Briefly answer, in your own words, the question “What

causes cancer?”

  • List the eight characteristics (or hallmarks) of cancer cells

that make them different from normal cells.

  • Explain what proto-oncogenes and oncogenes are.
  • Describe what the RAS protein normally does, and explain

how it causes cancer when it is mutated.

  • Describe what tumor suppressor genes are.
  • Describe what the RB protein normally does, and explain

how it causes cancer when it is mutated.

  • Describe the normal functions of p53, and explain why it’s

mutated in most tumors.

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Cancer Pathogenesis Lecture Objectives

  • Describe the normal function of telomeres, and explain how

tumor cells exploit this function.

  • Describe the basic steps involved in invasion and metastasis.
  • Explain what the Warburg effect is, and explain why tumor

cells opt to use it.

  • List some ways tumor cells can evade immune detection.
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What causes cancer? Non-lethal genetic damage.

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Autonomous cell proliferation Resistance to growth-suppressing signals Evasion of apoptosis Immortality Ability to invade and metastasize Altered metabolism Evasion of immune detection

Hallmarks of Cancer

Angiogenesis

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Autonomous cell proliferation

Hallmarks of Cancer

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Autonomous Cell Growth

  • Proto-oncogene: a normal gene whose product

promotes cell growth.

  • Oncogene: a mutated proto-oncogene.

Causes tumor cell to grow autonomously.

  • Oncoprotein: the product of an oncogene.
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  • RAS is a signal transduction protein
  • Mutated RAS is always on…
  • …therefore, always transducing signals…
  • …therefore, cell is always dividing.

The RAS Gene

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Autonomous cell proliferation Resistance to growth-suppressing signals

Hallmarks of Cancer

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Resistance to Growth-Suppressing Signals

  • Tumor suppressor gene: a normal gene whose product

suppresses the cell cycle (like brakes on a car).

  • Mutate these guys, and you lose the brakes!
  • Must mutate both copies of the gene to cause tumors.
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  • RB gene product stops cell at G1 checkpoint
  • Mutant RB is inactive; lets cells pass through G1!
  • Patients with two mutated RB genes have very high

risk of retinoblastoma (and an increased risk of getting other tumors).

The Retinoblastoma (RB) Gene

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The Cell Cycle

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Retinoblastoma

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Autonomous cell proliferation Resistance to growth-suppressing signals Evasion of apoptosis

Hallmarks of Cancer

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Evasion of Apoptosis

  • Many proteins are involved in apoptosis:
  • p53
  • Fas (the “death receptor”)
  • Executioner caspases
  • BCL2 protein family
  • If genes for these proteins are mutated,

the cell will be able to avoid killing itself.

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  • Nickname for p53: “guardian of the genome”
  • If a cell’s DNA is damaged, p53 causes a pause in

the cell cycle (via RB), so DNA can be repaired.

  • If DNA damage is irreparable, p53 causes the cell

to undergo apoptosis.

  • Most human tumors have p53 mutations!

The p53 Gene

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p53 activated cell cycle arrest p53 not activated no cell cycle arrest, no DNA repair

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Autonomous cell proliferation Resistance to growth-suppressing signals Evasion of apoptosis Immortality

Hallmarks of Cancer

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Immortality

  • Normal cells can only undergo 60-70 doublings
  • Main reason: telomere shortening!
  • Stem cells and cancer cells use telomerase to

maintain telomere length and keep replicating.

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Telomeres

As cells divide over time...

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Autonomous cell proliferation Resistance to growth-suppressing signals Evasion of apoptosis Immortality Angiogenesis

Hallmarks of Cancer

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Angiogenesis

  • Tumor cells need blood too!
  • Can’t grow >1-2 cm without new vessels
  • Tumor cells eventually learn how to stimulate angiogenesis
  • Lots of cytokines involved (i.e., VEGF)
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Tumor cells surrounding new vessel

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Autonomous cell proliferation Resistance to growth-suppressing signals Evasion of apoptosis Immortality Ability to invade and metastasize

Hallmarks of Cancer

Angiogenesis

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Ability to Invade and Metastasize

To do this, tumor cells must:

  • Loosen contacts between cells
  • Degrade extracellular matrix
  • Migrate away from the original site

Some tumors lodge in nearest capillary bed;

  • ther tumors show tropism.
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clonal growth intravasation metastatic subclone tumor cell embolus extravasation

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Tumor cells surrounding and invading vessel

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Autonomous cell proliferation Resistance to growth-suppressing signals Evasion of apoptosis Immortality Ability to invade and metastasize Altered metabolism

Hallmarks of Cancer

Angiogenesis

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Altered Metabolism

  • Normal cells, when oxygen is around, use oxidative

phosphorylation to generate ATP.

  • Cancer cells are different!
  • They take up tons of glucose, and convert it to lactate

via the glycolytic pathway.

  • This is called aerobic glycolysis, or the “Warburg effect.”
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Normal cells Rapidly dividing cells Tumor cells O2 present O2 absent Oxidative phosphorylation

36 ATP per glucose

Anaerobic respiration

2 ATP per glucose

Anaerobic respiration

2 ATP per glucose

O2 present or absent

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Normal cells Rapidly dividing cells Tumor cells O2 present O2 absent Oxidative phosphorylation

36 ATP per glucose

Anaerobic respiration

2 ATP per glucose

Anaerobic respiration

2 ATP per glucose

O2 present DNA RNA structural proteins lipids

  • rganelles
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Autonomous cell proliferation Resistance to growth-suppressing signals Evasion of apoptosis Immortality Ability to invade and metastasize Altered metabolism Evasion of immune detection

Hallmarks of Cancer

Angiogenesis

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