Metastasis
Lecture 9, F2019
Metastasis
• Metastasis (Meta: Something beyond, Stasis: State of inactivity)
Spread of cancer cells from the primary tumor to surrounding tissues
and to distant organs and is the primary cause of cancer morbidity
and mortality.
• Responsible for about 90% of cancer deaths
• All solid tumors can metastasize
Five-year survival rates (%) by stage at diagnosis, 2001-2007
Cancer type
Non-metastatic
Metastatic
Prostate
100
29
Breast
99
23
Colorectal
90
12
Stomach
62
4
Lung
52
4
Liver
28
2
Metastatic Process
1. Primary tumor growth
2. Angiogenesis
3. Dissemination of cancer cells
4. Intravasation
5. Survival in transition
6. Extravasation
7. Dormancy and Colonization
Metastatic Process: Dissemination of Cancer cells
Malignant tumor cells acquire traits that equip them with the ability to
leave the primary site and travel to distant tissues
Cell 2017 168, 670-691DOI: (10.1016/j.cell.2016.11.037)
Metastatic Process: Dissemination of Cancer cells
The epithelial-mesenchymal transition (EMT) is a developmental program that
is hijacked by cancer cells, endowing them with multiple malignant traits
associated with the loss of epithelial properties and the acquisition of certain
mesenchymal features
• Increased motility
• Invasiveness
• Ability to degrade components of the extracellular matrix
EMT in reality is not a binary switch
Phenotypic plasticity associated with
carcinoma cells inhabiting the middle
of the E-M spectrum is critical
metastasis
Cell 2017 168, 670-691DOI: (10.1016/j.cell.2016.11.037)
Metastatic Process: Dissemination of Cancer cells
Diversity of tumor invasion mechanisms
Friedl, P. et al. Nature Reviews Cancer volume 3, pages362–374 (2003)
Metastatic Process: Dissemination of Cancer cells
ECM
Mesenchymal Leading edge
cell in transition
Step 1: Protrusion of the leading edge
Growing actin filaments connect to adaptor proteins and push the cell
membrane in an outward direction.
Friedl, P. et al. Nature Reviews Cancer volume 3, pages362–374 (2003)
Metastatic Process: Dissemination of Cancer cells
Step 2: Cell-matrix interaction and formation of focal contacts
• Integrins come into contact with ECM ligands and cluster in the cell
membrane
• Clustered integrins recruit adaptor and signaling proteins via their
intracellular domains
Friedl, P. et al. Nature Reviews Cancer volume 3, pages362–374 (2003)
Metastatic Process: Dissemination of Cancer cells
Step 3: Recruitment of surface proteases to ECM contacts and
focalized proteolysis
• In close proximity to the cell surface, proteases cleave ECM components
Friedl, P. et al. Nature Reviews Cancer volume 3, pages362–374 (2003)
Metastatic Process: Dissemination of Cancer cells
Step 4: Cell contraction by actomyosin
• Active myosin II binds to actin filaments (previously known as actomyosin)
and generates actomyosin contraction
(contraction direction is indicated by arrows).
Friedl, P. et al. Nature Reviews Cancer volume 3, pages362–374 (2003)
Metastatic Process: Dissemination of Cancer cells
Step 5: Detachment of the trailing edge
• At the trailing edge, focal contact dissassembly occurs through several
mechanisms.
• Following focal contact disassembly, integrins detach from the substrate
and become internalized for recycling towards the leading edge or
deposited onto the substrate
Friedl, P. et al. Nature Reviews Cancer volume 3, pages362–374 (2003)
Metastatic Process: Intravasation
Cancer cells disseminate to other parts of the body by entering
the bloodstream in a process that is called intravasation.
Invading cancer cells first need to move to blood vessels, which can be within
the tumor (neovasculature) or close to the tumor.
Nature Reviews Cancer volume13, pages858–870 (2013)
Metastatic Process: Intravasation
• The lymphatic system carries lymph from tissues throughout the body
to lymph nodes then deposits the lymph into the blood stream.
• An immunological defense mechanism
• Cancer cells can get into the lymph and
drain into lymph nodes.
• Cancer typically spreads to regional
lymph nodes
American cancer society
Metastatic Process: In transition
The bloodstream represents a hostile environment for CTCs
• Rapid clearance by natural killer (NK) cells
• Fragmentation due to the physical stress
• Immune protection through the actions
of platelets, which coat CTCs
• Neutrophils can provide protection from NK
cell attacks as well
Modified from Cell 2017 168, 670-691DOI: (10.1016/j.cell.2016.11.037)
Metastatic Process: In transition
The more CTCs that are present in the blood of the cancer patient
the worse that patient's prognosis is
Breast Cancer Prognosis