Metastasis is a process that occurs when a pathogenic agent (usually a cancerous tumour) spreads from an initial site of the body to another location. Like an enigmatic odyssey, the process of cancer metastasis unravels before our eyes, taking us on a cellular voyage from invasion to intervention by travelling through the circulatory or lymphatic system. The ability of cancer cells to metastasize not only exacerbates the severity of the disease but also serves as a significant obstacle to cancer treatment research; understanding the cellular perspective of cancer metastasis may hold the potential to unlock groundbreaking insights into cancer biology and open new avenues for therapeutic intervention.
The metastatic cascade can be separated into three main stages: invasion, intravasation and extravasation. The direct expansion and penetration of cancer cells into nearby tissues is referred to as invasion. The multiplication of altered cells and the steady growth in tumour size ultimately result in a breach in the tissue barriers, allowing the tumour to spread into the surrounding tissue. The invasion stage during the metastasis cascade is a result of epigenetic factors (including circadian rhythm disruptions and aging), adhesive signals from ECM components, and cell-to-cell interactions. When these cells are ready to migrate, clusters of the tumour cells utilize a transdifferentiation process called epithelial–mesenchymal transition (EMT) to group together and to a nearby extracellular matrix. This transportation mechanism can occur through single-cell dissemination or collective migration, as seen below.
Figure 1: EMT can occur through single-cell dissemination by originating as a partially mesenchymal cell or through collective migration.
While the EMT process consists of many transitional stages regulated by similar growth factors and signalling pathways, RNA sequencing proves that these various stages exhibit unique cellular characteristics and differences in gene expression as a result of separate transcription factors. EMT is also a mechanism that plays a critical role in contributing to the development of chemoresistance, the ability of cancer cells to adapt or become immune to the presence of therapeutics.
The second stage, intravasation, describes the process of the movement of a cell into the blood or lymph system by passing through a vessel wall. The cells that contribute to the process of intravasation help the tumour cells pass through the endothelial cell junctions so that they can travel through the circulatory or lymphatic system. Once they reach these systems, they are known as circulating tumour cells (CTCs). Tumour cells may also undergo changes that alter their cellular metabolism and heterogeneity during intravasation. One protein that regulates cancer metabolic reprogramming is the cytokine transforming growth factor beta (TGFB). TGFB acts as an EMT inducer, allowing the cancer cells to adopt a more migratory behaviour that detaches them from the primary mass. Additionally, TGFB also influences the cellular microenvironment during intravasation; regulatory T cells (Tregs), which are a specialized subpopulation of T cells that suppress defensive physiological reactions, are promoted by TGFB and help deter cells that are a part of the body’s natural immune system.
When CTCs pass through tiny capillaries (the delicate branching blood vessels that transport blood, nutrients and oxygen to cells in your body), the cells either undergo microvascular rupture or pass through the third stage of cancer metastasis: extravasation. If the cells go through extravasation, then depending on the location of the secondary cancer site, they will travel through the cell walls into the tissue. This process may differ in permeability, as some body systems are highly permeable while others may require additional genetic/molecular regulation to transmigrate. Extravasation consists of two main events: tumour cell arrest on the endothelium (the tissue lining of many vessels in the body) and tumour cell transendothelial migration (TEM). After the cancer cells have stabilized, they either form secondary tumours at the site or remain dormant in the tissue. Dormancy, which describes the inactive form of cancer cells, can only occur when the rate of cellular proliferation is equal to the speed of cellular death. This balance is usually only achievable through suppressive gene signalling. Otherwise, if the cancer cell cluster does not become dormant, CTCs utilize multiple extravasation mechanisms to create adhesion to the endothelium. Then, it will use available growth factors or vesicles to integrate into the endothelial cells and begin metastatic colonization.
Figure 2: The bottom left demonstrates the factors and proteins that adhere CTCs to the endothelium. The bottom right visualizes the process of transmigration into the endothelial barrier.
To prevent cancer metastasis, future research should focus on blocking pre-metastatic niches' pre-development rather than fighting the cells after they have already established a secondary site. Although there have been recent developments in the identification of several suppressor genes that may prevent the proliferation of metastatic cancer – some examples being G-protein-coupled receptors, cytoskeletal signalling, and adhesion proteins like KAI1, CD44, and E-cadherin –, treatment methods have remained consistent. Chemotherapy, targeted therapy, and immunotherapy are treatments used to treat metastatic cancer after the cancer cells have spread. Recent research has indicated that microRNA, highly conserved non-coding RNA, could also potentially be used to treat metastatic tumours. Furthermore, more localized research is also being conducted to investigate how cancer metastasis can be treated differently in specific body regions. In the branch of brain metastases in particular, new studies demonstrate that drugs that block PPAR-gamma activity prevent cancer cells from spreading further. Similarly, radiofrequency ablation (RFA), a minimally invasive heat procedure, is also being investigated for its ability to cause tissue fever and cell necrosis in bone metastases. To conclude, no matter the type, stage of cancer, location or extent of metastases, exploring cancer metastasis is paramount in oncology and medical research. Understanding the intricate cellular processes that underlie metastasis is essential for devising effective strategies to halt its progression and improve patient outcomes.