The blood–brain barrier (BBB) is a major obstacle to the development of effective diagnostics and therapeutics for brain cancers and other central nervous system diseases. Peptide agonist analogs of kinin B1 and B2 receptors, acting as BBB permeabilizers, have been utilized to overcome this barrier. The purpose of the study was to provide new insights for the potential utility of kinin analogs as brain drug delivery adjuvants. In vivo imaging studies were conducted in various animal models (primary/secondary brain cancers, late radiation-induced brain injury) to quantify BBB permeability in response to kinin agonist administrations. Results showed that kinin B1 (B1R) and B2 receptors (B2R) agonists increase the BBB penetration of chemotherapeutic doxorubicin to glioma sites, with additive effects when applied in combination. B2R agonist also enabled extravasation of high-molecular-weight fluorescent dextrans (155 kDa and 2 MDa) in brains of normal mice. Moreover, a systemic single dose of B2R agonist did not increase the incidence of metastatic brain tumors originating from circulating breast cancer cells. Lastly, B2R agonist promoted the selective delivery of co-injected diagnostic MRI agent Magnevist in irradiated brain areas, depicting increased vascular B2R expression. Altogether, our findings suggest additional evidence for using kinin analogs to facilitate specific access of drugs to the brain.
Brain metastases are the most prevalent intracranial malignancy. Patient outcome is poor and treatment options are limited. Hence, new avenues must be explored to identify potential therapeutic targets. Inflammation is a known critical component of cancer progression. Intratumoral inflammation drives progression and leads to the release of circulating tumor cells (CTCs). Inflammation at distant sites promotes adhesion of CTCs to the activated endothelium and then initiates the formation of metastases. These interactions mostly involve cell adhesion molecules expressed by activated endothelial cells. For example, the vascular cell adhesion molecule-1 (VCAM-1) is known to promote transendothelial migration of cancer cells in different organs. However, it is unclear whether a similar mechanism occurs within the specialized environment of the brain. Our objective was therefore to use molecular imaging to assess the potential role of VCAM-1 in promoting the entry of CTCs into the brain. First, magnetic resonance imaging (MRI) and histological analyses revealed that cerebrovascular inflammation induced by intracranial injection of lipopolysaccharide significantly increased the expression of VCAM-1 in the Balb/c mouse brain. Next, intracardiac injection of 4T1 mammary carcinoma cancer cells in animals with cerebrovascular inflammation yielded a higher brain metastasis burden than in the control animals. Finally, blocking VCAM-1 prior to 4T1 cells injection prevented this increased metastatic burden. Here, we demonstrated that by contributing to CTCs adhesion to the activated cerebrovascular endothelium, VCAM-1 improves the capacity of CTCs to form metastatic foci in the brain. D.S. and L.W. contributed equally to this work Additional Supporting Information may be found in the online version of this article.
BACKGROUND: Brain metastases (BM) are the most prevalent intracranial neoplasm. Inflammation is central to the development of cancer. While an intra-tumoral inflammatory microenvironment contributes to the acquisition of malignant phenotypes and leads to the release of circulating tumor cells (CTCs), pre-existing inflammation at distant sites facilitates the adhesion of CTCs to the activated vascular endothelium and the consequent formation of metastases. Cell adhesion molecules expressed by activated endothelial cells contribute to metastatic spread outside of the brain and the vascular cell adhesion molecule-1 (VCAM-1) is a key mediator of inflammation. Herein we assessed if cancer cells entry into the brain is aided by VCAM-1 upregulation with inflammation. METHODS: Stereotaxic lipopolysaccharide (LPS, 1 µg) injection into the right hemisphere was used to induce neurovascular inflammation in Balb/c mice. The distribution of VCAM-1 was semi-quantified 24 h post LPS injection using molecular magnetic resonance imaging (MRI) with microparticles of iron oxide (MPIOs) functionalized with VCAM-1 antibody (MPIO-VCAM-1). Mice injected with saline served as control. VCAM-1 is also expressed on vessels associated with metastases, MPIO-VCAM-1 were therefore used to detect metastases. Basal level of metastases in animal brains was measured in a group of mice intracardially injected with cancer cells without LPS intra-cortical injection. To study the impact of pre-existing inflammation on tumor cell entry into the brain, mice were injected with LPS (or saline as above) 24 h prior to intracardiac injection of 4T1 breast cancer cells (105 cells in 100 µL PBS). Metastases imaging was performed 18 days post cancer cells injection. To assess if blocking VCAM-1 would affect metastases implantation, an extra LPS-injected group of mice was injected intravenously with MPIO-VCAM-1 4 hours before 4T1 cells injection. In this group, MRI was performed 3 hours after MPIO-VCAM-1 injection (VCAM-1 imaging), and on day 18 post tumor cell injection (metastases imaging). All MRI experiments were conducted on a small animal 7T scanner (Varian Inc.) with a dedicated mouse head-coil (RAPID MR International) using a T2*-weighted sequence. Following the final imaging session brains were extracted for histological analysis. RESULTS: Both MR and histological data reveal that the metastatic burden significantly increases in the LPS-injected group compared to control conditions. In inflamed animals, blocking VCAM-1 with MPIO-VCAM-1 reduces the metastatic burden back to control values. This suggests that (1) a pre-existing inflammation increases the occurrence of brain metastases and (2) blocking VCAM-1 reduces this effect. CONCLUSION: We demonstrate that inflammation-induced VCAM-1 contributes to tumor cells adhesion in the brain. Therefore, VCAM-1 may represent an attractive therapeutic target to reduce risks of metastasis. Citation Format: Dina Sikpa, Lisa Whittingstall, Jérémie P. Fouquet, Luc Tremblay, Réjean Lebel, Martin Lepage. Pre-existing neurovascular inflammation increases the occurrence of brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 86.
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