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Neurobiology: Breaking into the Brain
Lake Forest College
Lake Forest, Illinois 60045
By searching for the mechanism that cancer cells use to pass through the blood brain barrier, researchers have discovered that an enzyme is responsible for promoting both invasion and growth in the brain.
On the microbial scale, the brain is as secure and heavily guarded as a bank vault, and anything trying to infect it must have as many tricks as a master criminal. In order to get into the central nervous system (CNS), pathogens first must cross the blood-brain barrier (BBB), a tightly packed wall of epithelial cells surrounding the vessels supplying nutrients to the brain (1). If they can manage that, the invaders must then somehow survive and grow within a totally new extracellular environment, while up against the immune response of reactive astrocytes (2). These defenses apply to not only pathogenic infections, but also to tumor cells from within the body. Despite all of these obstacles, breast cancer cells still metastasize (spread from one tissue to another) to the brain in up to 30% of cases (3). The specific mechanisms used by cancer cells to bypass all of these defenses in order to spread into the brain are not entirely understood. In their 2015 study, Wu et al. initially hoped to understand how the matrix metalloproteinases (MMPs) contribute to brain metastasis, but inevitably uncovered a larger pathway (4).
MMPs are a group of enzymes with a wide range of different chemical mechanisms, and the general function of degrading proteins is essential to the extracellular matrix. Because of this effect, multiple MMPs have been implicated by prior research into cancer growth and invasion, but general treatments have not been effective in significantly reducing any aspect of cancer (5, 6). In order to determine the relationship between specific MMPs and brain metastasis to better create specific therapies, Wu et al. correlated the expression of 21 different types of MMP between healthy and brain metastatic cell lines and found that only the variant MMP1 consistently increased in expression depending on brain metastasis. With the enzyme narrowed down, the researchers were able to model the BBB, and found that increased MMP1 in the system increased barrier permeability by breaking down the proteins occluding and claudin, which are critical elements in the tight junctions, allowing the passage of more cancer cells (1).
Although this finding helped to explain why MMP1 overexpression can help cancer cells into the CNS, Wu et al. still wanted to know why MMP1 expression was increased in the first place. To better understand this, they correlated MMP1 expression with a set of other genes that mark for cancer and found that it most strongly correlated with the gene encoding cyclooxegenase 2 (COX2), a protein responsible for the production of lipid-based prostaglandin compounds. This connection to brain metastasis was cemented by the discovery that COX2 overexpression was found in cancer cell lines, and in the tissue of patients suffering from brain metastasis of breast cancer. The researchers then revealed the link between COX2 and MMP1 by demonstrating that COX2’s product, PGE2, was necessary for MMP1 expression. This led to another interesting discovery. Not only does the PGE2 created from COX2 promote MMP1 expression in cancer cells, but it also promotes the expression of chemokine (C-C motif) ligand 7 (CCL7) in astrocytes. CCL7 then promotes the survival and growth of tumor-initiating cells (TICs) which can adapt to the CNS’s environment (7). COX2, therefore, contributes to brain metastasis through PGE2 in two different ways. Not only does it allow the cancer cells to produce MMP1 to break down the defensive barrier, but it also causes the astrocytes to produce CCL7, allowing the invading cells to establish themselves (Fig 1).
Figure 1: COX2 pathway promotion of brain metastasis. COX2 induced the expression of prostaglandins, including PGE1. PGE1 increases the expression of MMP1 from cancer cells, which enhances the ability for tumor cells to invade by breaking down proteins essential to the blood brain barrier, and CCL7 from astrocytes, which promotes the survival of tumor-forming cells.
With this pathway better understood, the next step for Wu et al. was to establish some form of treatment to target brain metastasis through COX2-MMP1. To test whether this works in a living system, the researchers reduced expression of both genes in mice through RNA interference (RNAi), a process in which artificial RNA molecules interact with the transcribed genes to prevent the production of protein. Both the treatments significantly improved the amount of time each group of mice went before implanted breast cancer cells invaded the brain, strongly suggesting that this pathway could act as a focus for therapies in the near future.
As promising as these findings are, there are still several steps before they can be used to help people. The RNAi method used in mice has been pursued as a method of gene therapy, but the methods of transfection carry many complex risks (8). There are many known COX2 inhibitors of various levels of specificity, so the natural next path to take is to see whether any of these drugs can effectively reduce brain metastasis (9). Another topic of future research would be to test whether these pathways apply as significantly to other forms of cancer, or if they specifically drive metastasis of breast cancer cells. Even though many questions still remain, these current findings by Wu et al. still present very valuable knowledge about how a single protein can contribute so much to the disastrous process of brain metastasis.
The assignment to create a capsule presentation helped a lot in the development of this paper. Before I had even specifically selected this paper to write about, I had read it over several times, created a summary figure and looked into related and background research. To actually create the news & views article, after selecting the paper to focus on, my first thoughts were which methods, findings and other specific details to focus on. The summary figure helped guide me with this, in order to provide evidence from the original primary article for each step in the pathway from COX2 to enhanced brain metastasis. Once I had an understanding of the basic outline, I had to put it into interesting and easy to understand language, which could be challenging for some of the details. The title and “hook” first sentence also required some serious thought. Throughout this process, I informally requested feedback from other students, both in the neuroscience department and from other fields, and also compared my writing to examples of news & views articles from Nature.
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- Gavrilovic, I. T., & Posner, J. B. (2005). Brain metastases: epidemiology and pathophysiology. Journal of neuro-oncology, 75(1), 5-14.
- Wu, K., Fukuda, K., Xing, F., Zhang, Y., Sharma, S., Liu, Y., … & Mo, Y. Y. (2015). Roles of the cyclooxygenase 2 matrix metalloproteinase 1 pathway in brain metastasis of breast cancer. Journal of Biological Chemistry, 290(15), 9842-9854.
- Ii, M., Yamamoto, H., Adachi, Y., Maruyama, Y., & Shinomura, Y. (2006). Role of matrix metalloproteinase-7 (matrilysin) in human cancer invasion, apoptosis, growth, and angiogenesis. Experimental biology and medicine, 231(1), 20-27.
- Poola, I., DeWitty, R. L., Marshalleck, J. J., Bhatnagar, R., Abraham, J., & Leffall, L. D. (2005). Identification of MMP-1 as a putative breast cancer predictive marker by global gene expression analysis. Nature medicine, 11(5), 481.
- Rajaram, M., Li, J., Egeblad, M., & Powers, R. S. (2013). System-wide analysis reveals a complex network of tumor-fibroblast interactions involved in tumorigenicity. PLoS genetics, 9(9), e1003789.
- Whitehead, K. A., Dahlman, J. E., Langer, R. S., & Anderson, D. G. (2011). Silencing or stimulation? siRNA delivery and the immune system. Annual review of chemical and biomolecular engineering, 2, 77-96.
9. Flower, R. J. (2003). The development of COX2 inhibitors. Nature Reviews Drug Discovery, 2(3), 179.
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