Blog Spotlight #1
In the United States alone, more than 200,000 people are diagnosed with brain cancer every year, a common metastasis site for patients with advanced primary lung cancer, breast cancer, or melanoma. Many of these metastases result from other primary sources and approximately 50% of lung and melanoma patients and 20% of breast cancer patients develop secondary lesions in the brain. A common feature in most brain metastases is resistance to therapy, which can be attributed to the poor penetration of therapeutics across the blood-brain barrier (BBB). This research is most impactful since there is very little understood about the mechanisms that regulate BBB permeability in normal brain tissue or brain malignancies. This prevents exploitation of the BBB for drug delivery, a method that could be useful for the treatment of many neurodegenerative or malignant brain diseases. Animal models make tumor pathophysiology comparison difficult, relying on both mouse and human cell lines for research purposes.
Major facilitator superfamily domain‐containing protein‐2a (Mfsd2a) has recently gained the spotlight for its regulatory role in the maintenance of proper functioning of the BBB (Ocak et al., n.d.). Remarkably, Mfsd2a has been implicated in the mediation of the
Loss-of-function (including familial mutations) in human MFSD2A are linked to cognitive deficits and ataxia due to deficiencies in DHA transport and metabolism. As we learned in BCM441, DHA cannot be synthesized in the brain, thus it must be transported there by other means. DHA accumulated in the brain is selectively derived from the plasma where it is bound to albumin as an unesterified fatty acid or to LPC. DHA is a crucial polyunsaturated omega‐3 fatty acid required for brain development, motor, and cognitive functioning. A previous study reported down-regulation of Mfsd2a in a pericyte-deficient mouse model, suggesting that pericytes are necessary for the induction or maintaining Mfsd2a gene expression. For this reason, the authors set out to investigate the association between pericytes and endothelial cells within the vasculature of metastatic brain tumors.
The researchers analyzed brain metastases using patient-derived xenograft (PDX) which is a tissue graft from a donor of a different species from the recipient. In this
Importantly, the results containing reduced numbers of perivascular astrocytes strongly correlated with lack of Mfsd2a expression in brain metastasis endothelial cells. The data supports the notion that endothelial cells of brain metastases are in contact or are associated with pericytes but show diminished interactions with perivascular astrocytes. As determined previously, the presence of pericytes was confirmed to be required for the expression of Mfsd2a in the brain endothelial cells. The analysis of previous microarray data of pericyte‐deficient mouse models (Armulik et al., 2010) demonstrated a significant decrease in Mfsd2a expression in pericyte‐deficient animals (Ben-Zvi et al., 2014). This data can be corroborated with reduced expression of Mfsd2a. Further, astrocytes have been known to secrete cytokines and growth factors that modulate BBB properties in the brain vascular endothelium. For this reason, the researchers examined the influence of conditioned media taken from primary mouse brain astrocytes or human astrocytes on the expression of Mfsd2a in
It is also known that Mfsd2a is a transporter for DHA when it is conjugated to lysophosphatidylcholine (LPC) in circulation, as described by the pathway in Figure 2. Thus, the effects of astrocyte conditioned media on Mfsd2a-dependent uptake of
Finally, to evaluate a direct effect of DHA on metastases, the authors treated cultured primary lung and breast brain spheroids with DHA. They observed decreased growth and survival of tumor cells treated with DHA compared to controls. Additionally, DHA treatment positively impacted the growth and survival of HBMECs. Therefore, the researchers conclude that loss of Mfsd2a in metastatic tumor endothelial cells leads to decreased uptake of essential fatty acids, specifically DHA, which promotes tumor growth and survival in the brain microenvironment.
Mediating the transport of DHA is not the only function, however. In addition, Mfsd2a suppresses caveolin-dependent transcytosis. Increased vesicles in Mfsd2a‐deficient mice have been found to be positive for caveolin‐1 (
Lipid transport pathways of Mfsd2a pay a critical role in the regulation of permeability and in the maintenance of the integrity of the BBB by acting as a suppressor on caveolae‐mediated transcytosis in the endothelial cells of the CNS vasculature. Therefore, loss of MFSD2A promotes metastatic tumor growth and survival in the brain microenvironment by altering DHA transport and metabolism. Mfsd2a is a novel LPC transporter selectively expressed in the endothelial cells of the CNS and provides impactful contributions to the formation, functioning, and maintenance of the BBB. Looking ahead to the future, this pathway can possibly be harnessed for pharmaceutical delivery across the BBB. Changes in Mfsd2a expression levels following different types of brain injury may be unique to the pathology, which will be an important factor to consider while creating specific targeted therapeutic strategies. Nonetheless, large numbers of in vivo and in vitro studies are warranted in order to corroborate the practicality and applicability of pharmacologic strategies based on the modulation of BBB permeability via Mfsd2a. Restoring DHA and or its metabolites to the tumor microenvironment may serve as a treatment option for patients with metastatic brain cancer.
1. Ocak, P.E., Ocak, U., Sherchan, P., Zhang, J.H., Tang, J., n.d. Insights into major facilitator superfamily domain-containing protein-2a (Mfsd2a) in physiology and pathophysiology. What do we know so far? J. Neurosci. Res. 0. https://doi.org/10.1002/jnr.24327
2. Pericytes regulate the blood–brain barrier | Nature [WWW Document], n.d. URL https://www.nature.com/articles/nature09522 (accessed 2.11.19).
3. Structure and function of the blood–brain barrier – ScienceDirect [WWW Document], n.d. URL https://www.sciencedirect.com/science/article/pii/S0969996109002083?via%3Dihub (accessed 2.11.19).
4. Tiwary, S., Morales, J. E., Kwiatkowski, S. C., Lang, F. F., Rao, G., & McCarty, J. H. (2018). Metastatic brain tumors disrupt the blood‐brain barrier and alter lipid metabolism by inhibiting expression of the endothelial cell fatty acid transporter Mfsd2a. Scientific Reports, 8(1), 8267. https://doi.org/10.1038/s41598-018-26636-6
5. Nguyen, L. N., Ma, D., Shui, G., Wong, P., Cazenave‐Gassiot, A., Zhang, X., … Silver, D. L. (2014). Mfsd2a is a transporter for the essential omega‐3 fatty acid docosahexaenoic acid. Nature, 509(7501), 503–506. https://doi.org/10.1038/nature13241