26. Cancer 2

MIT OpenCourseWare

12 May 202048:37

EducationalLearning

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TLDRIn this lecture, Adam Martin celebrates the achievements of James Allison and Tasuku Honjo, Nobel Prize winners for their work on harnessing the immune system to fight cancer. Martin explores the mechanisms of cancer development, emphasizing the body's barriers to tumor formation, such as apoptosis and immune responses. He delves into the breakdown of growth survival signaling and the role of the tumor microenvironment. The discussion further covers the process of epithelial-to-mesenchymal transition (EMT), crucial for cancer cell migration and invasion. Through insights into cell adhesion, motility, and the actin cytoskeleton, Martin provides a comprehensive overview of cancer's complexity and the body's multifaceted response to it.

Takeaways

😀 The Nobel Prize for Physiology or Medicine was awarded to James Allison and Tasuku Honjo for discovering how to harness the immune system to fight cancer.
😃 Tumor cells can recruit surrounding cells to provide growth signals that promote tumor growth.
🤔 Oncogenic mutations reduce a cell's dependency on growth signals but do not eliminate it completely.
😯 Cancer cells undergo EMT (epithelial-mesenchymal transition) to become more mobile and invasive.
😮 Master regulator transcription factors like Twist and Snail repress cadherin to reduce cell-cell adhesion in EMT.
🧐 Integrins help cancer cells adhere to substrates as they migrate.
🤓 Actin filaments generate protrusive force at the leading edge of migrating cells.
😀 Signals from the environment direct the migration of cancer cells.
👍 Normal developmental programs like EMT are co-opted by cancer cells.
🥳 New cancer therapies like Herceptin target growth signaling dependencies.

Q & A

What did James Allison and Tasuku Honjo win the Nobel Prize for?
-They won the Nobel Prize for figuring out a way to release the brakes on the immune system to allow it to better fight cancer.
What are some barriers the body has in place to prevent cancer?
-Some barriers are regulation of cell division and death through signaling, apoptosis or programmed cell death, the immune system identifying and eliminating abnormal cells, and physical barriers like basement membranes that separate tissues.
How does the tumor microenvironment promote cancer growth?
-The tumor microenvironment includes surrounding cells that get recruited by the tumor and secrete growth factors and survival signals that the tumor depends on to grow.
What is Herceptin and how does it treat cancer?
-Herceptin is an antibody developed to target HER2 receptors, which are overexpressed in 30% of breast cancers. It blocks HER2 function or recruits immune cells to kill HER2 positive cancer cells.
What is epithelial-to-mesenchymal transition?
-Epithelial-to-mesenchymal transition (EMT) is a process where epithelial cells lose their cell-to-cell adhesion and become more migratory like mesenchymal cells. This allows cancer cells to spread.
What transcription factors regulate EMT?
-Transcription factors like Twist, Snail, Slug, and Escargot regulate EMT by repressing cadherin to reduce cell-cell adhesion and promote motility genes.
How do integrin receptors facilitate cell migration?
-Integrins connect the cell's actin cytoskeleton to the extracellular matrix. They help cells adhere and generate traction to translocate their cell bodies during migration.
How does the actin cytoskeleton enable cell movement?
-Globular actin subunits polymerize into long filaments that push the cell membrane outward. The growing filament ends exert protrusive force while integrins anchor the leading edge to pull the cell body along.
What is a lamellipodium and how is it formed?
-A lamellipodium is a broad, sheet-like protrusion at the front end of a migrating cell formed by outward growth of the dense actin filament network underneath the cell membrane.
Why do confined cells migrate differently than cells on a flat surface?
-Confined cells can use actin polymerization to push directly against surroundings instead of relying on integrin adhesion for traction, so loss of integrins doesn't impede their migration.

Outlines

00:00

😀 Introducing Nobel Prize Winners and Key Barriers to Tumor Formation

The instructor congratulates the students on regenerating their intestines since the last class. He introduces the recent Nobel Prize winners for discovering how to harness the immune system to fight cancer, which will be relevant later when discussing the immune system. He outlines key barriers the body has to prevent tumor formation: regulation of cell division/death, avoiding immune system detection, and lack of cell migration.

05:06

😊 Reviewing Epithelial vs. Stromal Cell Types and the Basement Membrane Barrier

The instructor reviews key differences between epithelial cells that line organs and stromal cells in connective tissue. Epithelial cells have high cell adhesion and low migratory potential. Stromal cells have the opposite properties. He emphasizes the importance of the basement membrane underlying epithelia as a barrier to invasion.

10:10

🧐 Oncogenic Mutations and Tumor Suppressor Loss Disrupt Normal Cell Regulation

The instructor explains how oncogenic mutations reduce dependency on external growth signals, while loss of tumor suppressors disables failsafe apoptosis. This disrupts normal cell regulation and tissue homeostasis. An experiment showing basal cell carcinoma relies on surrounding stroma highlights tumor cell dependence on external growth factors.

15:11

😮 HER2 Overexpression in Breast Cancer Enables Targeted Treatment

The instructor gives the example of HER2 overexpression in 30% of breast cancers. This growth factor receptor dependency enables targeted treatment with the drug Herceptin. Herceptin blocks HER2 function, showing cancers still rely partially on external growth signals.

20:12

🤯 Cancer Cells Undergo EMT to Reduce Cell Adhesion and Increase Motility

The instructor explains that epithelial-to-mesenchymal transition (EMT) is required for cancer cells to detach from surrounding tissue. Master regulator transcription factors like Twist repress E-cadherin adhesion. Signaling with stroma can induce EMT and genes involved in motility like integrins.

25:17

😲 Watching Cells Undergo EMT in Fly Development

The instructor shows a video of EMT occurring in fly development, enabled by Twist and Snail expression. The cells invade the embryo interior and undergo EMT to reach their final differentiation site. Cancer corrupts this normal developmental program.

30:24

🏋️‍♀️ Molecular Mechanism of Cell Motility and Migration

The instructor explains how actin polymerization generates protrusive force at the cell front. This pushes the membrane forward until anchoring with integrins. Repeated cycles of protrusion, adhesion, and traction enable net migration across a substrate.

35:26

🚶‍♂️ Various Mechanisms of Cell Motility in 2D vs. 3D Environments

The instructor notes that besides tractional migration, cells can use other mechanisms like chimneying to migrate in 3D/confined spaces without integrins. The environment impacts the motility mechanism.

Mindmap

Keywords

💡cancer

Cancer is characterized by uncontrolled cell growth and division. The video discusses barriers that prevent normal cells from becoming cancerous, such as regulated cell division and death. It also covers how mutations, gene regulation changes, and interactions with surrounding cells can lead to breakdowns in these barriers and tumor formation.

💡oncogene

Oncogenes are genes that have the potential to cause cancer when mutated or overexpressed. As the video describes, oncogenic mutations can reduce a cell's dependency on external growth signals, allowing it to divide uncontrollably.

💡tumor suppressor

Tumor suppressor genes normally promote controlled cell growth or initiate cell death when something goes wrong. Mutations in these genes remove safeguards against cancer development. The video gives loss of pro-apoptotic genes as an example.

💡epithelial-to-mesenchymal transition (EMT)

EMT is the process where epithelial cells lose cell-cell adhesion and gain migratory properties, switching to a mesenchymal cell state. The video explains how EMT allows cancer cells to become motile and metastatic through changes in gene regulation.

💡transcription factor

Transcription factors like Twist and Snail are regulators of gene expression that trigger EMT in cancer cells by repressing cadherins and activating migratory genes.

💡stroma

The stroma is the supportive tissue surrounding organs and tumors. As the video describes, stromal cells can secrete growth factors that cancer cells recruit for their own proliferative needs.

💡HER2

HER2 is a growth factor receptor often overexpressed in cancer cells, indicating some retained dependency on external signals. The video discusses how the drug Herceptin specifically treats HER2+ breast cancers.

💡actin

Actin is a protein that forms polarized filaments important for cell motility and force generation. The growth of actin networks facilitates cancer cell invasion into surrounding tissues.

💡integrin

Integrins are adhesion receptors that connect migrating cells to surrounding extracellular matrix or substrates. The video describes how integrin-mediated adhesion allows a cell to pull itself forward.

💡metastasis

Metastasis is when cancer cells spread from a primary tumor to distant sites throughout the body. The video overviews multiple cellular changes necessary for a localized tumor to become invasive and metastatic.

Highlights

First significant research finding

Introduction of innovative methodology

Key conclusion and practical application

Transcripts

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