Cerebrovascular inflammation promotes the formation of brain metastases

• Published in: International journal of cancer 2020-07, Vol.147 (1), p.244-255
• Main Authors: Sikpa, Dina, Whittingstall, Lisa, Fouquet, Jérémie P., Radulska, Adrianna, Tremblay, Luc, Lebel, Réjean, Paquette, Benoit, Lepage, Martin
• Format: Article
• Language: English
• Subjects: Animals; Brain cancer; brain metastasis; Brain Neoplasms - diagnostic imaging; Brain Neoplasms - secondary; Cancer; Carcinoma; Cell adhesion & migration; Cell adhesion molecules; Cell Line, Tumor; Cell migration; Cerebrovascular Disorders - diagnostic imaging; Cerebrovascular Disorders - pathology; cerebrovascular inflammation; Endothelial cells; Endothelium; Female; Inflammation; Inflammation - diagnostic imaging; Inflammation - pathology; Injection; Lipopolysaccharides; Magnetic Resonance Imaging; Malignancy; Mammary gland; Mammary Neoplasms, Experimental - diagnostic imaging; Mammary Neoplasms, Experimental - pathology; Medical research; Metastases; Metastasis; Mice; Mice, Inbred BALB C; molecular imaging; MPIO; MRI; Neuroimaging; Receptors, Vasopressin - metabolism; Therapeutic applications; Tumor cells; VCAM‐1
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.32902

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. What's new? To date, little is known on the processes linking cerebrovascular inflammation and the formation of brain metastases. Moreover, while the vascular cell adhesion molecule‐1 (VCAM‐1) is known to promote transendothelial migration of cancer cells to different organs, it is unclear whether a similar mechanism occurs within the specialized environment of the brain. Using histological analyses and MRI images detecting VCAM‐1‐targeted microparticles of iron oxide in a brain inflammation mouse model, here the authors show that an increased level of VCAM‐1 expression contributes to the enhanced formation of brain metastases. Blocking VCAM‐1 reduces the metastatic burden down to control values.