Module 3 - Chapter 10 - Metastasis Flashcards
Metastasis
Spread of cancer cells from the site of the original tumour to distant tissues and organs through the body
What is the defining characteristic of cancer and common cause of death from cancer?
metastasis
What percentage of individuals with breast Ca mets are still alive 5 years after diagnosis?
30%
What can initiate the metastatic process?
= Change in the tumour microenvironment including stromal cell adaptation to increase tumour mass and intratumour hypoxia
- with increased diversity due to changing microenvironment, some cancer cells may develop new abilities that can facilitate metastasis
What is the model for transition to metastatic cancer?
Epithelial-mesenchymal transition (EMT)
When does the EMT process normally occur?
embryonic development, wound healing, and tissue repair
True or False: Metastasis is a highly efficient process
False - it is inefficient
Research in this provide much of what is known about EMT.
Carcinomas
Where does carcinomas originate from?
It originates from highly differentiated and polarized epithelial cells that form structured sheets. This is stabilized by multiple adherences to neighboring cells and to a basement membrane along the cell’s basal surface.
What prevents neoplastic cells from primary carcinoma from dissociating from ECM and metastasizing to distal site?
Retaining the epithelial like characteristics
What is needed for a phenotype to separate from the primary tumour and flourish in a potentially hostile secondary site?
A greater degree of de-differentiation
A greater degree of de-differentiation results from what factor?
Programmed transition of a still partially epithelial like carcinoma to a more undifferentiated mesenchymal-like phenotype.
During the EMT process, tumour cells develop a metastatic phenotype characterized by what factors?
suppression of adhesion molecules and reduced adherence to adjacent cells and extracellular matrix (ECM), increased local invasion, and access to the blood and lymphatic circulations.
This a major mediator of the EMT process
transforming growth factor-beta (TGF-β), which is secreted by the tumour stroma.
Thesef acilitate intravascularization of tumour cells into the circulation and tend to cluster at the leading edge of the invading cancer cells.
Protumourigenic tumour-associated macrophage (TAMs), and cancer-associated fibroblasts (CAFs)
What does Protumourigenic tumour-associated macrophage (TAMs), and cancer-associated fibroblasts (CAFs) secrete that promote digestion and remodelling of the surrounding ECM
matrix metalloproteinases
What are the functions of matrix metalloproteinases
promote digestion and remodelling of the surrounding ECM
What suppresses cytotoxic immune cells (T-cytotoxic cells and natural killer cells [NK cells])
myeloid-derived suppressor cells (MDSC).
What promotes the survival of matrix metalloproteinases
Their association with platelets promotes their survival in the circulation in addition to clotting factors that shield the cancer cells from cytotoxic immune cells
This is essential for the establishment of a metastatic site:
hematopoietic progenitor cells (HPC)
What provides a site for the influx of hematopoietic progenitor cells (HPC)
induction of fibronectin
What does HPC have?
receptors for vascular endothelial cell growth factor and sets the stage for the beginning of metastasis.
What happens at matastatic site?
- cancer cells will adhere to local vascular endothelium,
- undergo extravascularization facilitated by the effects of adenosine triphosphate (ATP) on the endothelium,
- mesenchymal-to-epithelial transition
What prepares site for metastasis?
Molecular signalling from the cancer and initiation of a favourable microenvironment
What are the characteristics of cells that have transitioned into a mesenchymal-like phenotype
- have suppressed expression of adhesion molecules with a loss of polarity
- increased migratory capacity
- elevated resistance to apoptosis,
- demonstrated the potential to redifferentiate into other cell types.
the transition to a mesenchymal-like phenotype is driven by these
cytokines and chemokines produced within the tumour microenvironment
This is an effective driver of carcinoma cells into EMT
IL-8
What is a prerequisite for metastasis?
Invasion, or local spread,
In its earliest stages local invasion may occur by
Direct tumour extension
Invasion is a multistep process within EMT that includes
(1) diminished cell-to-cell adhesion
(2) digestion of the surrounding ECM
(3) increased motility of individual cancer cells.
What is critical for invation?
Recruitment of TAMs and other cells of inflammation.
What creates pathways through which cells can move
Degradation of the surrounding ECM
What Degrades of the surrounding ECM?
proteases and protease activators that promote digestion of connective tissue capsules and other structural barriers.
What secretes proteases and protease activators that promote digestion of connective tissue capsules and other structural barriers.
TAMs and other stromal (or supporting) cells
Normal cells, when separated from their ECM, undergoes this process
anoikis, a form of apoptosis.
caspase 8
Enzyme that can be lacking in neuroblastomas which leads to avoidance of apoptosis. Cells lacking of this are able to metastasize than cells with normal levels of these enzymes. Low levels = poor prognosis.
What must cancer cells be able to do to be able to transition from local to distant metastasis?
cancer cells must also be able to invade local blood and lymphatic vessels
What facilitates the ability of cancer cells to invade local blood and lymphatic vessels?
It is facilitated by stimulation of neoangiogenesis and lymphangiogenesis by factors such as VEGF.
What can promote cancer cell survival in distant locations?
What mechanism where tumour cells bind to blood platelets. This gives them a protective coat of non-malignant blood cells that both shields the tumour cells and creates a small tumour embolus or cancer clot.
How are cancer cells spread?
vascular and lymphatic pathways
What offers malignant cells direct access into the venous blood and draining lymphatic vessels.
neovascularization of a cancer
What determines the pattern of metastasis.
venous and lymphatic drainage networks associated with the primary tumour
What can disseminate by these routes?
Single cells, clumps, and even tumour fragments
Cancers often spread first to :
regional lymph nodes through the lymphatics
How is cancer spread to other organs?
through the bloodstream.
Where does Breast Ca mets usually spread?
the bloodstream to bones but rarely to kidney or spleen,
Where is lymphoma usually spread?
ften spread to the spleen but uncommonly spread to bone.
What may cause selectivity of metastasis?
Specific interactions between the cancer cells and specific receptors on the small blood vessels in different organs
tumour-initiating cells (TICs) (or cancer stem cells).
Cells that establishes a tumour
A cancer’s ability to establish a metastatic lesion in a new location requires the following:
cancer needs to survive in the specific environment and be capable of forming complex and heterogeneous tumours.
Explain or describe when EMT is not a stable transition.
after taking residence in the metastatic site, the tumour tends to regain some characteristics of the primary tumour, thus reverting somewhat to its epithelial origins.
Dormancy
- cellular quiescence—a stable, nonproliferative state that is reversible.
- This is when some cancer cells survive at a new site but do not proliferate to form a clinically relevant metastatic site.
About what amount of breast cancer deaths occur after a 5-year disease-free interval
2/3
what can result in dormancy?
- may result from features of the cell: early cells may have developed inadequately to a metastatic phenotype and thus, cannot recruit cells into a supportive stroma or initiated angiogenesis.
- or the environmental niche -
