W8 Invasion and Metastasis (GN) Flashcards
What is Metastasis?
=Spread of cancer cells from a primary tumour to a distant site within the body to establish a secondary tumoral growth
Cancer hallmark → (metastasis is) only in malignant tumours
- Metastasis is responsible for 90% of the deaths in patients with cancer
- Important prognostic value (associated with poor prognosis)
o Impairing organ functionality
o Difficult to eradicate surgically
o Usually chemo-resistant
Metastasis - what are the routes of spread? (4)
- Lymphatic system- Spread first to the closest regional lymph nodes (sentinel lymph node) and then to other parts, following natural route of drainage
-
Circulatory system (hematogenous spread)- Because of thinner walls, capillaries are the favoured routes, then
following the pattern of cardiovascular flow. (most common route) - Transcoelomic (body cavities)- Spread by penetrating the surface of the body cavities (e.g. peritoneal, pleural, pericardial)
- Canalicular spread- Spread along anatomical canalicular spaces( e.g. the bile ducts, the urinary system)
The Anatomic Model vs “Seed and Soil” Hypothesis:
What are the 2 theories?
➢Anatomic theory
* Follow the blood/lymphatic flow
* Secondary tumours tend to occur in organs which are first encountered by the disseminating cancer cells
* the size and shape of capillaries influence cell arrest
➢“Seed and soil” theory
* metastases resulted only when the appropriate seed (primary tumour) was
implanted in its suitable soil (metastasis site)
* Microenvironment (growth factors and extracellular matrix stroma composition)
plays a critical role in supporting the successful colonisation of metastases
Metastasis development steps
What are the 5 major steps?
1) Tissue Invasion
2) Intravasation
3) Circulation & Survival
4) Extravasation
5) Colonisation
Cancer invasion
What is Local invasion?
- Events involving the detachment of cancer cells from a well-confined primary
tumour and their consequent infiltration and invasion of the surrounding tissue
Local invasion
Loss of cell-cell interaction
In normal cells:
- Epithelial cells adheres to adjacent
cells and the extracellular matrix
through cell junctions - Cell junctions are mainly mediated by E-cadherins
- E-cadherins are linked intracellularly to β-
catenin of the cytoskeleton
Local invasion
Loss of cell-cell interaction
In tumoral cells:
- Altered E-cadherin (or β-catenin) expression leads to weak cell-cell adhesion
-
Altered expression of integrins
▪ trans-membrane proteins provide interactions with components in the extracellular matrix
▪ establishing traction for cellular motility and invasion - These alterations make the cells free and contribute to cell mobility and invasiveness
Local invasion
- Expression of Matrix Metalloproteinases (MMPs) to disassembly the basement membrane and extracellular matrix→ creating a path to facilitate invasion
- MMPs are elevated in most cancer types → poor prognosis
Matrix degradation
Cancer cells
Cell motility
* Cytoskeletal changes → altering cell morphology and
forming cell protrusions (pseudopodia)
* Actin/myosin contractile forces drives cell motility
* Chemotaxis → growth factors guide cell movements
Epithelial-Mesenchymal Transition for invasion (summary):
Epithelial state:
* Defined Cell polarisation/shape
* Firm cell-cell adhesion
* No migratory/invasion potential
* Expressing E-cadherins
Mesenchymal state:
* Loss of cell polarisation/shape
* Loss of cell-cell adhesion
* Ability to migrate and invade
* Low level of E-cadherins
Angiogenesis:
What is it?
What is it a hallmark of, thus facilitating what?
Formation of new blood vessels from pre-existing vascular beds.
It is a cancer hallmark
- Essential to provide nutrients &
oxygen and remove metabolic wastes
It is needed to further grow tumoral
masses (>2mm)
- Facilitates metastasis
Angiogenesis switch in tumours
Is there angiogenesis in normal cells, when? (important)
In normal cells:
* Normally, angiogenesis is inhibited
* Or induced in wound healing or menstruation
(more anti-angiogenic factors)
In tumoral cells:
* Hypoxia & mutations stimulates cancer
cells to overexpress pro-angiogenic
factors (VEGF, PDGF, TNF-α, etc)
* VEGF induces the proliferation of
endothelial cells of blood vessels
VEGF is the target of Avastin (antibody
binding VEGF) to block angiogenesis
(more Pro-angiogenic factors (VEGF))
Angiogenesis steps: (no need to memorise)
- Resting endothelial cells, dormant tumour
- Endothelial cell activation and production of proteases
- Endothelial cell migration and start of sprouting
- Endothelial cell proliferation and sprout formation
- Endothelial cell maturation
Normal vs tumoral vasculature (extra material)
- Tumour vasculature is abnormal
(irregular, tangled, leaky) → leading to
hypoxic areas - Due to an excess of pro-angiogenic
factors
▪ Uneven chemotherapy drug delivery → suboptimal dosage →potential drug resistance
Intravasation, Circulation & Survival, Extravasation
2) Intravasation
* Cancer cells must attach, degrade the basement membrane and migrate between
endothelial cells to enter the bloodstream (or lymphatic system)
3) Circulation & Survival
* Single cells or aggregates (emboli) travel with the blood/lymph flow (hostile environment)
* Cells must avoid immune destruction and their movement is arrested at target sites
4) Extravasation
* Cell attachment to the endothelial lining and passage between cells
* Destruction of the basement membrane and cell escape into the surrounding stroma
5) Invasion and Micro-metastasis
* Cancer cells invade and replicates in the tissue and form small clumps/colonies
* MET Differentiation - from mesenchymal to epithelial cells (inverse of EMT)
* Angiogenesis is required to grow further or cancer cells could undergo dormancy
Colonisation
* Cell growth from micro-metastasis into macroscopic tumours (low success rate)
Cancer Staging
What does a tumour stage describe?
What are the Two types of cancer staging systems?
- Tumour STAGE describes the extent of the tumour growth and how far it has spread within the body:
▪ estimating a person’s chance of recovery or survival (prognostic factor)
▪ helpful to plan the appropriate treatment
▪ compare and standardise treatment results between clinical/research studies
➢TNM system
➢Number system
TNM - Staging System:
What are the 3 letters involved and what do they represent?
T= Tumor size (0-4)
N= Lymph nodes spread (0-3)
M= Metastasis spread (0-1)
T:
* TX: Tumor cannot be evaluated
* T0: No evidence of tumor
* Tis: Carcinoma in situ
* T1-T4: Size/extent of tumor
N:
* NX: Lymph nodes cannot be evaluated
* N0: No lymph node involvement
* N1-N3: Increasing degree of regional
lymph node involvement
M:
*MX: Metastasis cannot be evaluated
* M0: No metastasis
* M1: Metastasis is present
E.g. → a cancer with a T4 N3 M1 stage is more advanced than a cancer with a T2 N1 M0 stage
Number - Staging System
How many stages?
What do they mean?
Stage 0: Carcinoma in situ (Precancerous State)
Stage I, II, III- Higher numbers mean the disease is more extensive, such as larger tumor size and/or lymph nodes spread
Stage IV- Spread to distant tissues/organs
Tumour grading
What does it describe?
what does a low vs high grade mean?
- Tumour GRADE describes a tumour in terms of how abnormal the tumour tissue appears under a microscope when compared to normal cells. Based on:
▪ Level of cell differentiation → dysplasia
▪ Rate of cell growth
➢ low grade → cancer cells closely resemble
normal cells and exhibit slow growth.
▪ Better prognosis
➢ high grade → cancer cells are poorly
differentiated or undifferentiated and tend to grow rapidly.
▪ Worse prognosis
Which of the following best describes the seed and soil hypothesis of metastasis tropism?
Metastatic sites must offer a suitable microenvironment fo
=C
What is the key process involved in extravasation
Summary
- Metastasis consists of the spread of a primary tumour to a distant site within the body to establish a secondary tumoral growth. It is associated to a poor prognosis
- Metastasis can occur via blood vessels, lymphatics or movement within the body cavities
- Metastasis occurs through multi-step process requiring the disruption of local cell–cell interactions, invasion, penetration of blood or lymphatic vessels (intravasation), escape from those vessels (extravasation), migration and growth.
- Angiogenesis is the formation of new blood vessels from existing vascular beds and increases the chance of cancer metastasis
- Cancer grade assesses the appearance and differentiation of cancer cells, while cancer stage describes the extent and progression of the disease within the body.
- Both cancer grade and stage are crucial for determining the most suitable treatment options and predicting a patient’s outlook.
