Module 04 - Tumour Invasion and Metastasis Flashcards
(47 cards)
What is Metastasis?
Multi-step process by which cancer spreads to other parts of the body. Most types of metastatic cancer cannot be cured
What are the primary goals of metastatic cancer treatment? (3)
Control growth of cancer
Relieve symptoms
Extend life of the patient
What are malignant cells characteristics? (2)
Ability to invade healthy tissues Be disseminated (metastasize)
What are the requirements for metastasis? (3)
(1) Tumour-initiating capacity
(2) Resistance to cell death
(3) Angiogenesis
How does tumour-initiating capacity supports metastasis and what is some supporting evidence?
For tumour cells to grow in a distant site (from primary tumour), they must have the ability to replicate. Only Tumour-initiating cells (TICs) (aka cancer stem cells) have the ability to form metastatic lesions.
Supporting evidence:
- only small portion of cells removed from secondary tumours in breast and brain cancer could give rise to cells with all cellular phenotypes of primary tumours
- Overexpression of transcriptional activators associated with self renewal abilities of normal stem cells in primary tumour cells results in aggressively metastatic cancer
- However, lack of evidence connecting primary tumours with high counts of TICs to higher rates of metastasis
How does resistance to cell death supports metastasis and what is some supporting evidence?
Ability to evade apoptotic signals is a hallmark of tumour cells, increased resistance to environmental death signals is necessary to progress towards metastasis
Supporting evidence
- Overexpression of anti-apoptotic signals enhances the efficiency of metastasis in many experimental models
- Loss of the apoptosis initiator caspase-8 facilitates invasion by increasing resistance to stress associated with loss of adhesion. EX: pediatric neuroblastomas that indicate genomic loss of caspase-8 have a poor prognosis
The loss of which apoptosis initiator is associated with a poor prognosis in pediatric neuroblastomas?
caspase-8
How does angiogenesis supports metastasis and what is some supporting evidence?
For cells to travel to different organs, they need to be connected to vasculature
Supporting evidence (mostly on VEGF)
- VEGF increases vascular permeability, thereby facilitating tumour cell intravasation
- High VEGF concentrations, present to stimulate angiogenesis, upregulates secretion of proteases that degrades the basement membrane of endothelial cells
In what 2 ways does VEGF support metastasis?
1- increases vascular permeability which facilitates tumours cell intravasation
2- High VEGF levels upregulates secretion of proteases that degrases the basement membrane of endothelial cells
Could the failure of anti-angiogenesis therapy challenge that angiogenesis is always required for metastasis?
Anti-angiogenesis therapy that targeted VEGF did not show a large clinical benefit in cancer progression. This indicated that VEGF-mediated angiogenesis may not be necessary for metastasis. Cancer cells have other ways of inducing angiogenesis
What are the 5 phases of metastasis ?
1- Loss of E-cadherin and ECM degradation
2- Increased motility and invasion
3- Intravasation and dissemination
4- Arrest in distant tissue and extravasation
5- Angiogenesis and growth of metastatic lesion
Describe phase 1 of metastasis
Involves the disruption of cell-cell contacts (loss of E-cadherin) - Epithelial-mesenchymal Transition (EMT), with one mechanism is the loss of E-cadherin because it is a transmembrane protein that promotes cellular adhesion and suppresses invasion and metastasis. Loss of E-cadherin can be hypoxia mediated via HIF-1alpha-mediated increase in E-cadherin repressor expression
the breakdown of the physical barrier imposed by the basement membrane and ECM through a process of proteolytic enzyme systems (ECM degradation) - reorganization of surface proteins to disrupt cell contacts with basement membrane of tumour. Proteolytic activity increased to disrupt basement membrane of tumour, ECM, and then basement membrane of vessels
What are the proteolytic enzymes systems ? (2)
Matrix metalloproteinases (MMPs) Urokinase plasminogen activation system
What are the 4 subgroups of MMPs that participate in ECM degradation?
Gelatinases
Collagenases
Stromelysins
Membrane MMPs
Describe MMPs
Class of more than 25 zinc-dependent endopeptidases. Usually released as inactive pro-enzymes. They are inhibited by tissue inhibitors of metalloproteinases (TIMPs 1-4)
Collectively MMPs degrade all components of the ECM
What proteins inhibit MMPs?
Tissue inhibitors metalloproteinases (TIMPs 1-4)
Describe the 3 important proteims in the Urokinase plasminogen activation system
1- Urokinase plasminogen activator (uPA) needs to be activated from pro-uPA. It converts plasminogen (zymogen produced in liver) into plasmin (active form). It is inhibited by plasminogen activator inhibitors (PAIs 1-3)
2- Urokinase receptor (uPAR) is a cell surface receptor that facilitates activation of uPA from pro-uPA. It has a polarized expression, mostly at the “leading edge” of tumour. It is involved in non-proteolytical processes related to cancer, such as cell migration, cell cycle regulation and cell adhesion. Induced by hypoxia
3- Plasmin degrades ECM components and activates other proteinases (MMPs, uPA)
Describe the chain of events of the urokinase plasminogen activation system
- Pro-uPA binds to uPAR to be activated into uPA
- uPA converts plasminogen to plasmin
- Plasmin degrades the ECM but also activates other proteinases such as uPA and MMPs
What are non-proteolytic functions of the urokinase receptor? (3)
cell migration
cell cycle regulation
cell adhesion
Describe phase 2 of metastasis
Increased motility and invasion
Tumour cells acquire a motile phenotype through HGF-MET signalling
- Scatter factor HGF (hepatocyte growth factor) enables cels to detach from one another and invade the ECM
- HGF binds to MET receptor on cells which is autophosphorylated upon binding HGF.
— Autophosphorylation leads to activation of oncogenic signalling pathways which contributes to a loss of cell-cell adhesion and thus, facilitates tumour invasion
— Hypoxia increases HGF and MET expression and signalling which lead to increased tumour cell motility and invasion
What is the main signalling pathway of the increased motility and invasion phase of metastasis?
HGF-MET
Describe phase 3 of metastasis
Intravasation and dissemination
Penetration of blood vessel walls by tumour cells (intravasation), enabling access to the circulatory system. This phase is expedited by elevated interstitial fluid pressure resulting from VEGF-induced effects on the integrity of blood or lymphatic vessel walls
What are the steps of intravasation? (4)
1- Tumour cell release of TGFb can induce endothelial retraction
2- Macrophage release of TNF can alter endothelial barrier permeability, allowing intravasation to occur at a higher rate
3- Macrophage release of epidermal growth factor (EGF) can attract cancer cells to blood vessels
4. Matric metalloproteinases (MMP1, ADAM12) can disrupt endothelial junctions, allowing for passage of tumour cells into the bloodstream
Describe phase 4 of metastasis
Arrest in distant tissue and extravasation
Cells arrest at distant sire within the vasculature where they stimulate endothelial cell retraction, extravasate, and invade the local tissue
- Only a small proportion of cancer cells that enter circulation ultimately succeed in forming metastases
