Cortisol promotes breast‐to‐brain metastasis through the blood‐cerebrospinal fluid barrier

Abstract

Background: Elevated basal cortisol levels are present in women with primary and metastatic breast cancer. Although cortisol's potential role in breast-to-brain metastasis has yet to be sufficiently studied, prior evidence indicates that it functions as a double-edged sword-cortisol induces breast cancer metastasis in vivo, but strengthens the bloodbrain-barrier (BBB) to protect the brain from microbes and peripheral immune cells.Aims: In this study, we provide a novel examination on whether cortisol's role in tumor invasiveness eclipses its supporting role in strengthening the CNS barriers. We expanded our study to include the blood-cerebrospinal fluid barrier (BCSFB), an underexamined site of tumor entry.Methods and Results: Utilizing in vitro BBB and BCSFB models to measure barrier strength in the presence of hydrocortisone (HC). We established that lung tumor cells migrate through both CNS barriers equally while breast tumors cells preferentially migrate through the BCSFB. Furthermore, HC treatment increased breast-to-brain metastases (BBM) but not primary breast tumor migratory capacity. When examining the transmigration of breast cancer cells across the BCSFB, we demonstrate that HC induces increased traversal of BBM but not primary breast cancer. We provide evidence that HC increases tightness of the BCSFB akin to the BBB by upregulating claudin-5, a tight junction protein formerly acknowledged as exclusive to the BBB. Conclusion:Our findings indicate, for the first time that increased cortisol levels facilitate breast-to-brain metastasis through the BCSFB-a vulnerable point of entry which has been typically overlooked in brain metastasis. Our study suggests cortisol plays a pro-metastatic role in breast-to-brain metastasis and thus caution is needed when using glucocorticoids to treat breast cancer patients.

Breast‐to‐brain metastasis is exacerbated with chemotherapy through blood–cerebrospinal fluid barrier and induces Alzheimer's‐like pathology

“…Correspondingly, we also observe enhanced tumor infiltration across the BCSFB compared to the BBB in mice treated with chemotherapy. This discovery on the impact of chemotherapy on BCSFB further supports previous reports on the preferential route of breast cancer entry into the brain via the BCSFB (Herrera et al, 2022). Therefore, given our results, the increased CTC numbers seen after chemotherapy (Ortiz‐Otero et al, 2020), and the positional proximity of the ventricles to CSF circulation in the brain (Lun et al, 2015), it is important to consider the BCSFB as a vulnerable early point of CNS‐entry for chemo‐treated breast cancer cells.…”

“…The current prevailing model is that metastatic cancer cells enter the brain by crossing the BBB. However, we recently showed breast cancer cells have a preference for crossing the BCSFB (Herrera et al, 2022). First, to determine whether systemic chemotherapy opens the entry barriers of the brain, we set up an in vivo model of acute and delayed chemotherapeutic response.…”

The microenvironment of brain metastases from solid tumors

“… 65 Recent in vitro studies show that while LC cells migrate through the BBB and BCSFB at comparable rates, breast cancer cells preferentially migrate through the BCSFB by degrading TJs in the choroid epithelium. 66 Neuroblastoma cells were able to migrate across an intact BCSFB in a paracellular fashion within 24 hours in vitro, without affecting the integrity of choroid epithelium. 67 …”

Brain metastasis: The next steps for translational research

“…Thus, the CNS must be protected from external influences at interfaces where blood and cerebral spinal fluid (CSF) come into close contact with neural elements. Intriguingly, Herrera et al describe how cortisol, a stress hormone, promotes breast to brain metastasis through the blood–CSF barrier 5 . Moreover, Remsik et al demonstrate that breast and lung tumor cells adopt a two‐phenotypic state in in leptomeningeal disease when they have spread to the CSF 6 …”

“…Intriguingly, Herrera et al describe how cortisol, a stress hormone, promotes breast to brain metastasis through the blood-CSF barrier. 5 Moreover, Remsik et al demonstrate that breast and lung tumor cells adopt a two-phenotypic state in in leptomeningeal disease when they have spread to the CSF. 6 Finally, given the global impact of COVID-19 on cancer patients, this special issue would be a remiss if it failed to address how it impacts patients with brain metastases.…”