3. Week 2: Cancer and Apoptosis

Lecture 3 - 643 - Dr. Faridi

The biology of cancer

• Define it

• Example image of cancer cell liver:

  • Abnormal - liver in image does not reflect normal liver structure

  • Uncontrolled growth - expanded/cluster of nodules

  • Spread - not called cancer until it develops the ability to spread

    • the nodules on the liver are stomach metastasis - liver unable to function as liver

• Cancer is a group of diseases, not one thing or one type of treatment- all have different etiology and cause

  • “Breast cancer (BC)”

  • “Estrogen receptor + BC”

What are the 6 basic properties of cancer cells

Explain how cancer leads to the loss of growth

Explain how cancer leads to the loss of contact inhibition and anchorage independence

Explain how cancer leads to no limited capacity for cell division

What is an angiogenesis inhibitor

• Name the agent

• MOA

  • what does the MOA result in

How do cancer cells appear under the microscope

List what increases/decreases the risk of cancer

Which virus increases the risk of cancer? And how does it increase the risk of cancer?

• PDGFR activation → RAS/MAPK → Cyclin D↑ → CDK4/6 activation → Rb inhibition → cell proliferation

Describe the MOA of Human papillomavirus (HPV)

1. E6 inhibits p53 (a tumor suppressor)

   1. Causes cells to display uncontrolled growth called immortalization

   2. Also causes an increase in telomerase - adds repeats, they are not shortened, leads to immortalization (uncontrolled growth)

2. E7 inhibits RB (a tumor suppressor)

   1. If you inhibit a suppressor of growth, get uncontrolled growth - immortalization

3. E5 causes an increase in PDGR (the PDGF receptor)

   1. More uncontrolled growth

Understand how a a tumor suppressor gene and transcription factor (TF) acts in a normal cell vs an HPV infected cell

• That means E2F now is a transcription factor that is free.

• And it will go bind the promoter region of genes. It's a transcription factor, it turns on transcription.

• It turns on the promoters for certain genes, and these are genes involved in growth.

• And the cell will undergo mitosis, and you see growth.

  • This shows how increase risk for cancer

The genetics of cancer - what is tumorigenesis

How does cancer involve multiple mutations over time?

Pink cell - normal

Green - mutation that inactivated a tumor suppressor gene

The genetics of cancer - what are tumor suppressor genes?

Tumor suppressor genes

• List the genes involved

• Primary tumor associated with the gene

• Proposed function of the gene

• Inherited syndrome

only need to know the highlighted

What is the function of p53?

Distinguish between a proto-oncogene and an oncogene

• 3 diff point mutations in Ras

• Her2 is breast cancer and ovarian, sometimes stomach

  • Not a modified version, it is the gene product that is amplified

• CYCD1

MOA of Trastuzumab (Herceptin)

What is Genentech’s T-DM1 Kadcyla (Ado-Trastuzumab Emtansine)

• Kadcyla (also called T-DM1 or ado-trastuzumab emtansine) is a targeted breast cancer drug made by Genentech. It is used mainly for HER2-positive breast cancer.

• It is an example of an antibody–drug conjugate (ADC):

  • part antibody

  • part chemotherapy

• What is it made of?

  • T-DM1 combines:

    • Trastuzumab (Herceptin) - a monoclonal antibody that targets HER2 receptors on cancer cells

    • DM1 (emtansine) - a potent chemotherapy drug that blocks microtubules

• Kadcyla (T-DM1) is an antibody–drug conjugate that starts by using trastuzumab to bind HER2-positive breast cancer cells and deliver the attached chemotherapy drug DM1 directly inside them. Once internalized, DM1 disrupts microtubules, blocking mitosis and causing cancer cell death.

  • T-DM1 = trastuzumab (HER2 targeting) + DM1 (microtubule inhibitor)

Process of normal colon cells to malignancy

Tumorigenesis - multistep process involving what?

What are cancer stem cells (CSC) responsible for? Define circulating tumor cells (CTCs).

Cancer stem cells:

Circulating tumor cells:

Cell death - define necrosis and apoptosis

• Necrosis - not planned

  • Passive consequence of gross injury to a tissue

  • resulting from

    • tissue damage

    • other pathology

  • Marked by

    • swelling

    • burst of cells

    • release of their contents

      • damages neighboring cells

• Apoptosis

  • actively driven by the cell

  • “programmed cell death”

    • organism is better off

  • Marked by

    • cell shrinking

    • membrane blebbing

    • cell fragmented in small membrane bound, apoptotic bodies

    • chromatin compaction

    • nuclear fragmentation

What diseases may occur with altered apoptosis

Understand the apoptotic signaling pathway - extrinsic pathway

Understand the apoptotic signaling pathway - intrinsic pathway

Define Caspases and Bcl-2 Family

Explain the normal pathways of:

• Absence of trophic factor - caspase activation

• Presence of trophic factor - inhibition of caspase activation

Restoration of apoptosis