Professor Feature — Metastatic Timing: Lessons from Human Breast Cancer Patients and Mouse Models
Dr. Lisa M. Antoszewski
When I was a graduate student, someone in my lab suggested that I sign up to receive emails with the table of contents for all three “major” scientific journals, i.e., Science, Nature, and Cell. Dutifully, I went to each website and gave them my coveted unc.edu email and waited with bated breath to receive updates on the most cutting-edge research. Let’s be honest, I was not sitting around waiting for any emails. I was a graduate student which meant I was balancing five different experiments, creating presentations, and trying to stay current with the literature relevant to my field of interest. When I did receive the table of contents for one of the aforementioned journals, I scanned it quickly and most likely deleted the email without another thought. I had to get back to the in situ hybridization or immunostaining being conducted in the other room.
Fast forward almost two decades and I still receive emails with the table of contents from Nature. At the beginning of this semester, when I still had time to read my emails thoroughly, I noticed there were several interesting articles in a particular volume of this journal. I downloaded about six different papers and printed each one of them…in color. I planned to read, annotate, and fully digest the data contained within each manuscript. It is currently 8 November 2022 and guess how many I have read. You got it…just one. But, wow, it is an incredible piece of work.
I have always been interested in cell cycle control and how it contributes to early development in multiple organisms. When cell proliferation takes place in a controlled fashion, it is magnificent. When it takes place in an uncontrolled fashion, it is magnificently terrifying. It results in one of the most insidious diseases known to man: cancer. This disease has been with us for thousands of years, but we have only recently begun to wrap our heads around the molecular modifications that define it. In a nutshell, it is a disease characterized by rampant cell division that results from mutations in a wide variety of genes including oncogenes and tumor suppressor genes. As cells divide and accumulate, a primary tumor forms. As cells within the tumor continue to divide and acquire additional mutations, they develop the ability to break away from the primary tumor and metastasize. Metastasis is what ultimately leads to the demise of the patient, yet the mechanisms underlying this cascade of events remain incompletely understood. One of the papers I came across at the beginning of the semester (the only one I read) sheds light on when individual cells, called circulating tumor cells (CTCs), make a break for it. It is not when you expect…it happens when you are sleeping.
Researchers isolated CTCs from women with either early or late-stage progressive breast cancer as well as from a variety of mouse models created to study breast cancer (Diamantopoulou, 2022). They found the highest percentage of CTCs in blood taken during the rest phase for both organisms. They attributed this abundance to increased intravasation rates, the ability of CTCs to squeeze their way into blood vessels and begin their quest through the circulatory system to a new location in the body. If you disturb the typical rest and active period in mice, i.e., give them “jet lag”, there is a decrease in the number of CTCs isolated during the rest phase suggesting that disruption of the circadian clock can limit the ability of CTCs to find their way into blood vessels. Interestingly, the CTCs isolated during the rest phase have increased metastatic burden. In other words, they are really good at establishing themselves in a new location. When mice were injected with CTCs taken from the rest phase, these cells made a bee line for the lung, a common site for breast cancer metastasis.
What underlies this drastic difference in CTC number and metastatic potential during rest? If you have taken one of my classes, your answer should be “changes in gene expression.” It always comes down to changes in gene expression. CTCs isolated during rest upregulate the expression of more than 120 genes that support mitosis and cell division (Diamantopoulou, 2022). If these cells produce more proteins that drive cell division, what do you think will result? You got it…cell division! If more cells are dividing, it makes sense that they are more likely to break away from the primary tumor and give it a go somewhere else in the body. While this paper certainly includes additional interesting data, the crux of the issue is this: how do you reconcile the apparent association between disease progression and the time during which your body is supposed to heal and repair itself? It seems counterintuitive that sleep would contribute to more advanced disease but remember, this is cancer. “It lives desperately, inventively, fiercely, territorially, cannily, and defensively — at times, as if teaching us how to survive” (Mukherjee, 2010).
References
Diamantopoulou, Z, Castro-Giner, F, Schwab FD, Foerster C, Saini M, Budinjas S, Strittmatter, K, Krol, I, Seifert B, Heinzelmann-Schwarz, V, Kurzeder C, Rochlitz, C, Vetter M, Weber, WP, and Aceto N. 2022. The metastatic spread of breast cancer accelerates during sleep. Nature. 607: 156–162.
Mukherjee, S. 2010. The Emperor of All Maladies: A Biography of Cancer. New York (NY): rScribner.
If you are interested in reading more research on this topic, you can find similar research in Breast Cancer Research and Treatment.
Grove City College students can find any of these journals by simply searching the journal name in Discover on the Henry Buhl Library’s homepage. And don’t forget — if you’d like to find more related resources, the library maintains a list of A-Z Databases with an entire tab dedicated to biology!
