Neoplasia Growth Survival

What is the Warburg effect?

• What is it?

• Why?

Warburg Effect

• What is it

  • Metabolic phenomenon where cancer cells preferentially convert glucose -> lactate via glycolysis

    • even if there is enough O2 to perform more efficient mitochondrial respiration 

• Why?

  • Provides Meta. intermediates needed for cellular components 

    • (AA)

  • Faster energy production

Describe IDH:

• What is it?

• How is it related to cancer?

• Importance?

• Mech

• Example?

Isocitrate dehydrogenase (IDH)

• What is it?

  • Krebs cycle Enzyme

• Related to cancer

  • IDH mutation -> production of dif. Metabolite -> (2-hydroxyglutarte)

• Importance:

  • (2-hydroxyglutarte) = oncometabolite

    • Alters gene expression -> Cancer

• Ex:

  • Gliomas of the brain: astrocytomas

[REVIEW] Apoptosis

Describe the two Apoptosis Genes and their function

• P53:

  • Promote apoptosis when DNA damage detected

• BCL2 

  • Inhibits apoptosis

  • Overexpressed in 85% of follicular B cell lymphoma 

    • t(14,18)

How do cancer cells avoid mitotic crisis?

• Mitotic crisis due to progressive shortening of telomeres

• Cancers express telomerase

  • enzyme responsible for maintaining telomeres

  • Normal cells do not express this

How can Cancer transform into stem-like cells

How can Cancer transform into stem-like cells

• Mutations in Trxn factors -> Somatic cells reprogramming via epigenetics -> pluripotent stem cell

Describe how Clonal Evolution and CSCs can occur

Describe Cancer’s ability to create blood vessels:

• Angiogenesis/Hypoxia Relation:

• Mech:

Angiogenesis/Hypoxia Relation:

• Hypoxia  -> Trxn of basic fibroblastic growth factor + VEGF (vascular endothelial growth factor) 

NOTE: VEGF inhibitors are used in treatment of some cancers

Describe the mechanism for Cancer Invasion

• Mech:

  • Release intercellular adhesion molecules

    • E-cadherin

      • Invasive lobular carcinoma and diffuse gastric carcinoma

  • Degrades ECM via enzymes

  • Has Integrins -> ECM attachment

  • ECM migration via cytokines

Describe Metastasis

• Targets

• Metastasis by blood

  • Typical of?

  • Location most common?

• Metastasis by lymph

  • Typical of?

  • Direction?

Metastasis

• Targets:

  • To first capillary bed encountered (lung or liver)

  • Some has specific receptors -> organ tropism

• Metastasis by blood:

  • Typical of Sarcoma/Carcinoma

  • Liver/lungs most frequently involved

• Metastasis by Lymph:

  • Common in Carcinoma

  • Follow Lymphatic Drainage

List and describe the 3 ways in which tumor antigens originate

How does the body protect against cancerous cells?

Cancer protection Method

1. DCs and macrophages consume tumor cells -> lymphnodes

2. Presentation via MHC to  CD8+ CTL 

3.  CD8+ CTL Activation

Describe CAR-T cells

• What is it?

• Method of Creation?

• Clinical Approval for?
  

• What is it?

  • Programmed targeting of tumor associated antigens

• Method of Creation:

  • Pt. T cells removed -> reprogramed -> re infused

    • Reprogram via transgene

  • Result:

    • Act. T cells attack tumor and expand

• Clinical Approval:

  •  for targeting CD10 on B lymphocytes

    • Can treat B cell malignancy (lymphoma)

  • Other in Dev:

    • EGFR, HER2, CEA, CA125, mesothelin

List/Describe three ways Cancer cells Evade the Immune system

Cancer Immune Invasion:

• Evolve w/o antigens or changes antigens

• Loss of MHC 

• Immunosuppression

  • TGF-B Secretion

    • Potent immunosuppressant

  • Expression of PDL-1

    • Inhibits T Cells

Describe PD-L1/PD-1

• Gene location

• What/Where is it?

• Function:

How does Cancer use this?

Treatment Against this mech?

PD-L1/PD-1

• Gene Location: 9p24

• What/Where is it?

  • Cell membrane receptor

    • lymphocytes, macrophages, Tumor Cells

• Function:

  • Down regulate Immune Response

  • Important part of functioning placenta

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Tumor Escape

• Tumor -> increase PD-L1 expression -> protection against immune

  • Act. T Cells Bind -> disabled 

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Treatment against PD-L/PD-1

• Abs block PD-L1 or PD-1 receptors

  • Tumor can no longer inactivate

    • Immune attacks Tumor (immune surveillance)

Describe Tumor Markers:

• What are they?

• Usefulness:

• What are they?

  • Proteins released by tumors into blood

• Usefulness:

  • Tumor Screening

    • BUT low sensitivity and specificity

    • BUT: Can be elevated in nonneoplastic conditions

  • monitor response to therapy

Describe Paraneoplastic Syndrome

• What is it?

• symptoms?

Paraneoplastic Syndrome

• What is it?

  •  first sign of cancer

    • Symptoms = Clinically sign.

    • Occurs in ~10% of pts. w/ cancer

  • Specific Symptoms correlate w/ specific cancers

• Symptoms:

  • Hypercalcemia = most common

    • squamous cell carcinoma of the lung

  • Cushing syndrome

    • small cell carcinoma of the lung

  • Acanthosis nigricans

    • gastric carcinoma