Introduction to Cancer Metastasis:
Metastasis is the word for the growth of secondary cancers in an area of the body distant from the initial primary cancer. Cancer treatment is challenging because of metastases. If the treatment works in one region, there is a secondary spread in other regions.
The two main causes of cancer death and morbidity are invasion and metastasis. The direct extension and penetration of a tumor cell into adjacent tissues is known as invasion. Invasion damage or destroy vital structure surrounding it and is a prerequisite for metastasis. Whereas, metastasis is a spread of a tumor to sites that are physically discontinuous with that of a primary tumor. It is derived from the Greek word “Methistanai” which means to change. 30% of the solid tumor can present as metastasis tumors. Likelihood of metastasis correlates with the tumor cells which lack differentiation, aggressive local invasives, having rapid growth, and large size.
Cancer cells may separate from their initial site and travel through blood or lymphatic channels to populate a new area. So, there are different classification of cancer metastasis.
- Primary metastasis
- Secondary metastasis
Stages of cancer metastasis:
Metastasis is a complex and unpredictable process. Not every tumor cell undergoes metastasizes, there should be accumulation of complementary genetic and epigenetic alteration in some of these tumor’s cells. There is basically referred to s metastatic phenotype. The cell which will have a metastatic phenotype and will go through series of steps which is referred to a metastatic cascade. Moreover, tumor cells don’t move singly, the cell will migrate as a cohesive group and the successful metastasis occur only when the cell migrate as a cohesive group.
Epithelial to Mesenchymal Transition (EMT)
The initial phase of cancer metastasis is the change from epithelium to mesenchymal tissue. Epithelial cells are fixed on a basal membrane and it doesn’t move all around the body. In contrast, mesenchymal cells are dislodged from the basal lamina and move throughout the different regions of the body. So, the epithelial to mesenchymal transition is the first step of metastasis.
Invasion
Then, there would be the invasion where the mesenchymal cell would invade through the extracellular matrix and it would undergo a process known as intravasation. It is among the main factors contributing to cancer-related death and morbidity.
Intravasation, Circulation, Extravasation and Colonization
So, it would get through the blood vessel and enter the blood vessel or also lymphatic as well. Then, it would circulate through the lymphatic and its extravasation occurs just like a neutrophil or any immune cell. And it would populate a new location and it forms a colony. So, the probability of colonization and successful extravasation is very low, even after that metastasis happens.
Mechanism of cancer metastasis:
Most of the carcinomas spread via lymphatic while most of the sarcomas spread hematogenously through the blood vessel. Metastatic cancer spreads fast in the region at lymph nodes. The most frequent locations for metastases are the liver and the lung. In fact, 50% of brain tumors are from metastasis, commonly seen as multiple well circumstances tumors at gray/white matter junctions.
Molecular Mechanism of cancer metastasis:
In order to understand the molecular mechanism of cancer metastasis, we need to first understand the epithelial to mesenchymal transition (EMT). EMT is the process by which epithelial cells become mesenchymal by losing their cell polarity and cell-cell adhesion and acquiring migratory and invasive characteristics.
First, epithelial cells have special characteristics such as cell to cell adhesion and tight junction, they have hemidesmosomes which connect them to the basement. In addition, they also have apico- basal polarities. their apical sites and basal sites are quite different from each other based on the molecular marker expression. Now, all these features are disrupted in a mesenchymal cell. So, epithelial characters are now abolished and now new characters have acquired a cell which is undergoing EMT. EMT is
- Loss of cell adhesion
- Loss of apicobasal polarity
- Cleavage and invasion of basal lamina
- Gaining of migratory capacity
- Invasiveness
EMT is a common process in the human body because during the development of the nervous system, neural crest undergoes EMT which is completely normal. During the formation of mesoderm, there is also an endothelial to mesenchymal transition. In fact, the wound healing process requires this kind of transition as well. It is not harmful but in context to cancer this could be quite determinantal.
Factors involved in EMT:
There are several molecular and transcription factors that are involved in EMT such as TWIST, SNAIL, ZEB1 which are highly involved in the process of EMT. Experiment has shown that if we topically express these factors into an epithelial cell, it will eventually undergo transformation into mesenchymal. In cancer cells, it has been reported that these factors are upregulated or mutation of these factors are also associated with cancer. All of these factors
- Modulate integrity of tight and adherens junctions.
- It also modulates actin regulators that can allow change in cell shape
- It triggers cytoskeletal rearrangement
Another important factor is the matrix metalloproteinase (MMP) that can act on ECM and dissolve the ECM which would make the detachment easier. There are several signaling pathways which converge into these particular transcription factors generation. So, these are the signaling pathways that are implicated in terms of cancer metastasis. One of the common themes of these pathways is that they upregulate TWIST, SNAIL, ZEB1 that lead EMT.
- WNT/β-catenin pathway
- Receptor Tyrosine Kinase (RTK) pathway
- JAK/STAT pathway
- TGF-β (Transforming Growth Factor-beta) pathway
- Notch signaling pathway
Matrix metalloproteinases (MMPs) are the key factors that help in metastasis that are secreted by the cell they break the ECM which would make it easier for mesenchymal cell to invade.
Determinants of metastasis:
The most important determinants will be external signals that could be growth factors, chemokines, cytokines, etc. So, the cell-cell adhesion and cell-basement adhesion are very important for metastasis.
- Adhesion are generally dissolved during the metastasis
- MMPs are the key factors which can dissolve or modify the ECM.
- There are several different additional factors such as genetic mutation that make it more susceptible or more likely that would cause cell metastasis.
And ultimately these days it can be shown that epigenetics modification could be also leading causes for cancer metastasis.