Players in Cancer Metastasis and Relapse

Reading time: 5 minutes

Rachel Cherney

Patients with metastatic cancer usually have a lower survival rate than patients without metastatic cancer, so it is important to understand how metastatis occurs, so we can learn how to improve patient survivability. Metastatic cancer makes up about 90% of cancer deaths. Cancer metastasis occurs when tumor cells break off and travels to different parts of the body from its original location. Metastasis (see image below) occurs through intravasation, where the broken off tumor cells enters a blood vessel or lymph vessel and circulates, or travels throughout the body. Then, through extravasation, the tumor cells exit the blood or lymph vessel into the surrounding tissue. The tumors either start growing in those organs, resulting in cancer throughout the body, or lay dormant, hiding and waiting to wake up, what happened with Walter White in Breaking Bad.

An artifact of cancer therapy is the reappearance of cancer after a patient has undergone treatment and the cancer was thought to be eradicated. This phenomenon is known as relapse and often occurs due to dormant metastatic cancer cells that were missed during a first round of cancer treatments. Dormant metastatic cancer cells are cancer cells that have traveled to a different part of the body from the original cancer site, and are “asleep,” meaning they aren’t active cancer cells but have the ability to wake up and cause tumor growth. Since relapse is a very important facet of cancer biology and patient survival, scientists are trying to understand how dormant metastatic cancer cells decide to either stay dormant or wake up. In October 2018, several studies looking at different proteins involved in the dormancy or formation of metastatic cancer cells were published. I focus on three of those studies, as all three of these studies are open access – meaning anyone can read them from anywhere.

The first study, published in Breast Cancer Research, used previous breast cancer studies to try to predict if there are any proteins or characteristics of dormant metastatic cells  that could signal if the dormant cells could wake up and cause tumors. The authors found that a protein that regulates gene expression called NR2F1 (also known as COT1), had low levels in active metastatic tumors but had higher levels in tumors that were dormant. Breast cancer patients who had a longer survival time had on average higher levels of NR2F1 than those who didn’t survive as long. Thus, high NR2F1 correlated with better survival in this Breast Cancer Study. While this is merely a correlative observation, we don’t know how this protein is related to the survival of the cancer patients. Nevertheless, it provides a lead for scientists to continue studying this protein and its involvement in cancer metastasis and dormancy in the future.

Another study, published in Nature Communications, studied medulloblastoma, an aggressive brain cancer found in children. The scientists looked for protein markers that could hint as to whether medulloblastoma will metastasize or not, and identified the protein Notch1. Notch1 is correlated with lower survival rates and increased spinal metastases, but it was unknown whether Notch1 directly caused these events or not. To provide evidence that Notch1 does have a direct effect on medulloblastoma metastasis, the scientists used mice as a model. Human medulloblastoma cells that either had Notch1 protein or did not have Notch1 protein were injected into mice cerebella (Cerebellum – brain structure image below).

Nine out of ten mice (90%) that had Notch1 medulloblastoma cells developed tumors, but tumors developed in only about one of ten mice (10%) that had medulloblastoma cells and did NOT have Notch1. The scientists noticed that when medulloblastoma cells have Notch1, the cancer is more aggressive and spreads to the spinal cord from the cerebellum. However, cells that DON’T have Notch1 did not have cancer spread past the cerebellum. They were able to determine that Notch1 is not only involved in the creation of spinal metastases, but also in the continued growth of the primary tumor (the original cancer cell mass). This means that Notch1 plays a role in the aggressive and metastatic properties of medulloblastoma, and brings scientists and doctors one step closer to understanding how medulloblastoma works and can be treated.

In the third study, also published in Nature Communications, scientists focused on identifying factors involved in prostate cancer metastasis. Current prostate cancer therapies result in poor survival rates because the they can’t control prostate cancer metastasis, since the process of prostate cancer metastasis is not known. The authors used the Cancer Genome Atlas, a collection of cancer data sets of over 33 cancer types from studies around the world, to identify common proteins that are involved in prostate metastatic cancer. They found high levels of a protein called CITED2 in a variety of cancers, one being prostate cancer, and high CITED2 levels correlated with lower patient survivability. Using cells grown in dishes, the scientists were able to determine that CITED2 interacts with a protein called NCL and that these two together promote cancer metastasis, because NCL is a metastasis promoting protein. As with the first study, scientists will need to continue to work with CITED2 and NCL to determine how they promote cancer metastasis and how to prevent it.

While all three studies provide some insight as to how different cancers metastasize, retain severity, and wake up from dormancy, it is still unclear whether the proteins identified are specific to a particular type of cancer, or if they play a role in metastases of other cancers as well. Further questions will need to be asked and answered by scientists and doctors to fully understand how cancers function, and how we can create effective therapies against them. However, the described studies above provide many leads for scientists and doctors to pursue in improving patient care.

Works Discussed:

• Borgen, E., Rypdal, M. C., Sosa, M. S., Renolen, A., Schlichting, E., Lonning, P. E., . . . Naume, B. (2018). NR2F1 stratifies dormant disseminated tumor cells in breast cancer patients. Breast Cancer Res, 20(1), 120. doi: 10.1186/s13058-018-1049-0
• Kahn, S. A., Wang, X., Nitta, R. T., Gholamin, S., Theruvath, J., Hutter, G., . . . Cheshier, S. H. (2018). Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma. Nat Commun, 9(1), 4121. doi: 10.1038/s41467-018-06564-9
• Shin, S. H., Lee, G. Y., Lee, M., Kang, J., Shin, H. W., Chun, Y. S., & Park, J. W. (2018). Aberrant expression of CITED2 promotes prostate cancer metastasis by activating the nucleolin-AKT pathway. Nat Commun, 9(1), 4113. doi: 10.1038/s41467-018-06606-2