By Anny Wang
Cancer is a deeply confusing disease. One could even say it is an injustice to call it by one name, just due to the sheer amount of diversity each cancer can have. Here, it is important to realize that cancer is individualized. Cancer is a disease of the genes, usually caused by mutations that occur with time. The more genes that promote the survival of the cell itself, rather than the body, the more dangerous a potential cancer can become. Of course, there are certain mutations that if inherited, can make an individual more disposed to certain types of cancers. Yet, it is no coincidence that the median age of cancer diagnosis is 66 years old. However, the mutations themselves are the cause of death. It is estimated that metastasis causes 90% of all cancer related deaths. These secondary tumors caused by metastasis can inhibit many vital functions that the body needs, and hence it is very important to have a thorough understanding of this phenomenon for both therapy and research. Perhaps it is even more relevant today, than ever; with the world living longer, well into people's senior years, cancer is a major obstacle yet to be overcome.
Metastasis is a multistep process in which cells escape the primary tumor and establish a new colony of tumor cells. More specifically, in this case, the metastatic processes here are ones of carcinomas, or cancers of epithelial cells. Epithelial cells are surface lining cells, such as the lining of the stomach, and account for the majority of cancers.
Before the tumor can spread into different locations of the body, the tumor first starts spreading the surrounding tissue, generally prescribed as the change from the intraepithelial carcinoma Tis tumor stage to T1 tumor stage. As the tumor grows larger and larger, some cells are subject to constant pressures, including a state called hypoxia. To combat this, some cells develop much more aggressive behaviors. It selects cells likely to go through apoptosis, and in some cancers activate hypoxia inducible factor-1 (HIF-1). HIF-1 can be a sign for metastatic progression. Another pressure are the physical tensional ones, in which mechano-transducing integrins could accidently activate ERK, an enzyme of the MAPK pathway. MAPK is a well known signaling pathway, especially in cancer research as it stimulates growth in cells. It is a great example of how mutations are critical to the evolution of cancer. PDGF, or platelet derived growth factor, is often used to help signal cells to heal a wound. To heal, cells divide. Cancer can manipulate this signaling to proliferate and regulate growth.
To be able to detach from the tumor and locate new sites, the cells must lose their cell to cell adhesion before they can start the local invasion. For this to happen, certain changes must occur. The process in which the cells mutate is called epithelial-mesenchymal transition (EMT), in which epithelial cells biologically transform into a cell mesenchymal-type phenotype. Mesenchymal cells, compared to epithelial cells, have greater mobility and resistance to apoptosis. A part of EMT is the downregulation of E-Cadherin, an adhesive protein, which can be affected by many identifiable genes. Transcription factors including Snail, Slug, Twist, and ZEB are just examples of parts that mediate this phenomenon. These changes are important, as epithelial cells undergo anoikis, a specific type of apoptosis, after losing their adhesions.
After this transformation, the tumor cells form actin extensions. Once the cells migrate, these cells can degrade the extracellular matrix (ECM) and basement membrane with proteases like Matrix Metalloproteinases (MMP), which can degrade the ECM. Tumors sometimes might recruit allies through crosstalk, although this is a very complicated process. The level of force the tumor cells are met with during invasion depends on the environment it is in. Tumor cells spreading into the surrounding tissues and distant organs are known to reproduce the mechanisms and migration types characteristic of normal, non-tumor cells during physiological processes. Tumor cells, similar to normal cells, are capable of activating these mechanisms for changing their own shape, creating conditions for moving, as well as remodeling surrounding tissues to form migration pathways. The main problem is that tumor cells, in contrast to normal cells, do not have physiological “stop signals” to terminate these processes. Most likely, this leads to the establishment of the migration mechanisms and promotes the progression and spread of the tumor. Some cells might even grow in the lymph nodes. This can be spotted when lymph nodes get larger due to inflammation, of in this case, cancer.
During introversion, the tumor cells must find their way into the bloodstream or into lymphatic vessels, now marking the V1 stage of cancer. Tumors are estimated to have the capacity to shed millions of cells into vessels, however it is estimated that >1% of all circulating tumor cells will overcome the many challenges within the bloodstream, and only around 0.01% of all circulating tumor cells will colonize a secondary tumor. These cells are constantly targeted by immune cells, and not to mention how harsh an environment vessels can be. The ways in which vessels work can often damage and kill these cells. Tumor cells can also be caught in capillary beds because they are too large, in which they may become dominant or start colonizing. The tumor cells are not without their own defenses. Tumor cells are able to create a sort of platelet armor by secreting certain substances. Cancer cells traveling in the lymphatic system, like in the circulatory system, are also prone to the outside forces.
Extravasation is the process in which cancer cells leave the bloodstream. The tumor cells adhere with endothelial cells where it blocks the vessel. Macrophages help with this process by inhibiting the immune response through cross talk with tumor cells. It is still completely unknown why cancers will settle down in certain places. A longstanding theory is the ‘seed and soil’ theory. Similar to how a plant will scatter many seeds, leaving only the ones with the best environment to germinate, so too is how cancer cells establish a new tumor. If presented with the right microenvironment, a secondary tumor can be established. Certain cancers also are drawn to certain organs, called tissue tropism, which chemokines might explain. Tumors with certain chemokine receptors may be more drawn to certain organs who express a certain ligand more.
The metastases do not directly develop into detectable tumors. Cells may become dormant for a period of time, and cancer cells have been found in the bone marrow after many years. But before all that, the cells that have gone under EMT must undergo MET to reverse the process. Then, the metastases need to develop. Half of these micrometastases will develop, with more dormant in which cancers can reappear after 10 years the primary tumor was treated. The “soil” is not at all hospitable. To make it more hospitable, the soil has to be “primed” in a way before the cells can proliferate and create. Pre-metastatic niches might be prepared beforehand through signaling by the primary tumor. Such preparation might be growth factors, such as VEGF, a growth factor promoting angiogenesis.
Again, cancer is not meant to be underestimated. It is an utterly confusing disease, with no straightforward path. I must reiterate how important it is to understand that this model may not be perfect, and researchers are still playing with evidence supporting all kinds of theories, not to mention the holes within current ones. Like cancer, cancer research is always evolving. The nature of cancer is akin to the nature of one’s own body, the biochemical and physiological components interwoven in complex but individualized ways.
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