tumour angiogenesis invasion and metastasis Flashcards
Describe the sequential process of metastasis and common sites of metastatic spread
Metastasis is the process by which cancer spreads from the place at which it first arose as a primary tumor to distant locations in the body
1) Local Invasion:
- Cancer cells invade local tissues
- This involves the detachment of cancer cells from the primary tumor, degradation of the extracellular matrix, and migration of the cells through the surrounding tissue
2) Intravasation:
- Cancer cells enter into the blood vessels (vasculature or lymphatics)
- They achieve this by disrupting the endothelial cell layer lining the blood or lymphatic vessels
3) Circulation:
- Cancer cells are transported throughout the body via the bloodstream or lymphatic system
- The circulating tumour cells (CTCs) need to survive shear forces and immune attacks in the circulation
4) Extravasation:
- Cancer cells exit the blood vessels and invade a new tissue
- Cancer cells adhere to the endothelium of blood vessels at a distant organ site, followed by extravasation into the surrounding tissue parenchyma
5) Colonisation:
- Cancer cells multiply in the new tissue (secondary site) to form small nodules
- For successful metastatic colonisation, cancer cells need to adapt to, and co-opt, the foreign microenvironments at the secondary site
Common sites of metastatic spread depend on the primary cancer type:
- Breast cancer: commonly mestastasises to the bones, lungs, regional lymph nodes, liver and brain
- Lung cancer commonly spreads to the adrenal glands, liver, brain, and bones
- Prostate cancer primarily spreads to the bones and lymph nodes
- Colorectal cancer is likely to metastasise to the liver and the lungs
These sites are common because they are rich in blood vessels and lymphatics, which allow for the transportation and sustenance of the cancer cells. In addition, certain tissues may produce signaling molecules that attract the cancer cells, and the cancer cells may have receptors that make them more likely to migrate to specific organs
Define angiogenesis and its role in tumour expansion
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels
This is a normal and vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, it is also a fundamental step in the transition of tumours from a benign state to a malignant one
1) Nutrient Supply:
- For a tumour to grow beyond a certain size (usually 2mm), it needs a blood supply to deliver the necessary nutrients and oxygen to the proliferating cancer cells
- Tumours trigger angiogenesis to meet these nutritional demands
2) Waste Removal:
- In addition to providing nutrients, the new blood vessels also help to remove waste products produced by the rapidly dividing and metabolising cancer cells
3) Metastasis Pathway:
- Angiogenesis also provides a pathway for tumor cells to enter the bloodstream and metastasize to distant sites in the body
Angiogenesis is primarily triggered by the release of angiogenic factors from tumor cells, with the most well-known being vascular endothelial growth factor (VEGF)
Under normal circumstances, angiogenesis is a tightly regulated process, balanced by pro-angiogenic and anti-angiogenic factors. However, in cancer, this balance is disrupted in favor of pro-angiogenic signals
Explain epithelial to mesenchymal transition in tumour cells and the role of adhesion molecules
Epithelial-to-Mesenchymal Transition (EMT) is a process by which epithelial cells lose their cell polarity and cell-cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells
It is a crucial mechanism during embryogenesis and wound healing. However, in cancer pathology, EMT contributes to the metastatic potential of tumour cells
In normal epithelial tissues, cells are tightly bound to each other through various types of cell-cell adhesion molecules, such as cadherins (e.g., E-cadherin) and integrins
During EMT, changes in the expression of these adhesion molecules occur
For instance, the downregulation of E-cadherin, a key protein involved in epithelial cell-cell adhesion, is a hallmark of EMT
The loss of E-cadherin function leads to the disruption of cell-cell contacts and contributes to the acquisition of a more motile, mesenchymal phenotype
This process is often triggered by signaling pathways activated by growth factors such as TGF-beta and Wnt
Simultaneously, there is upregulation of mesenchymal markers like N-cadherin (a process known as cadherin switching), vimentin, and fibronectin. These proteins promote cell migration and invasion, key steps in the metastatic process
Simultaneously, there is upregulation of mesenchymal markers like N-cadherin (a process known as cadherin switching), vimentin, and fibronectin. These proteins promote cell migration and invasion, key steps in the metastatic process
Explain how proteases facilitate tumour cell invasiveness
These enzymes are capable of degrading the components of the extracellular matrix (ECM), the complex network of proteins and other molecules that provide structural and biochemical support to cells
The ECM acts as a barrier preventing the spread of tumor cells, so the ability of cancer cells to produce proteases enables them to breach this barrier and invade surrounding tissues
There are several families of proteases implicated in cancer invasion, including matrix metalloproteinases (MMPs), serine proteases, and cysteine proteases
These proteases degrade various components of the ECM, including collagen, laminin, and fibronectin, allowing cancer cells to invade surrounding tissues and to migrate towards blood vessels
MMPs can not only degrade ECM components but also process a variety of bioactive molecules, contributing to the regulation of inflammation, cell growth, and cell death, all of which can impact cancer progression
Overexpression of certain MMPs has been associated with increased invasiveness and poor prognosis in several types of cancers
Plasminogen activators are another example of proteases involved in cancer invasiveness. They convert the inactive zymogen plasminogen into plasmin, a protease that can degrade various ECM components and activate MMPs
In addition to degrading the ECM, proteases can also facilitate invasion by promoting angiogenesis (the formation of new blood vessels), which provides the tumor with nutrients and oxygen and is a route for metastasis
Explain how targeted therapies can slow tumour progression
Targeted therapies work by interfering with specific proteins or processes that contribute to the growth, progression, and spread of cancer cells
1) Inhibiting growth signals:
- Many targeted therapies work by blocking the signals that tell cancer cells to grow and divide
- E.g. some therapies target the receptors on the surface of cancer cells that receive growth signals (like the HER2 receptor in some types of breast cancer), while others target the proteins inside the cell that carry these signals to the cell’s nucleus
2) Promoting cell death:
- Some targeted therapies aim to restore or enhance the cell’s ability to undergo apoptosis
3) Interfering with angiogenesis:
- Tumours need a blood supply to grow and spread
- Some targeted therapies work by inhibiting the formation of new blood vessels, a process known as angiogenesis
- Without a sufficient blood supply, tumors are starved of the nutrients they need to grow
4) Blocking cancer cell proliferation:
- Some targeted therapies inhibit the activity of specific enzymes or proteins that are crucial for cell division and proliferation
- E.g. tyrosine kinase inhibitors block the action of tyrosine kinases, enzymes that activate many proteins by signal transduction cascades and thereby influence cell proliferation
5) Enhancing the immune system’s response to cancer:
- Some targeted therapies, known as immunotherapies, work by boosting the body’s immune system to better recognise and attack cancer cells