Abstract
Brain metastases are life‐threatening complications of triple‐negative breast cancer, melanoma, and a few other tumor types. Poor outcome of cerebral secondary tumors largely depends on the microenvironment formed by cells of the neurovascular unit, among which pericytes are the least characterized. By using in vivo and in vitro techniques and human samples, here we show that pericytes play crucial role in the development of metastatic brain tumors by directly influencing key steps of the development of the disease. Brain pericytes had a prompt chemoattractant effect on breast cancer cells and established direct contacts with them. By secreting high amounts of extracellular matrix proteins, pericytes enhanced adhesion of both melanoma and triple‐negative cancer cells, which might be particularly important in the exclusive perivascular growth of these tumor cells. In addition, pericytes secreted insulin‐like growth factor 2 (IGF2), which had a very significant pro‐proliferative effect on mammary carcinoma, but not on melanoma cells. By inhibiting IGF2 signaling using silencing or picropodophyllin (PPP), we could block the proliferation‐increasing effect of pericytes on breast cancer cells. Administration of PPP (a blood–brain barrier‐permeable substance) significantly decreased the size of brain tumors in mice inoculated with triple‐negative breast cancer cells. Taken together, our results indicate that brain pericytes have significant pro‐metastatic features, especially in breast cancer. Our study underlines the importance of targeting pericytes and the IGF axis as potential strategies in brain metastatic diseases.
Highlights
Cerebral metastases are frequent and dismal complications of a few tumor cell types, including lung cancer, breast cancer, and melanoma
Since tumor co-opted endothelial cells maintained tight junctions in the absence of astrocyte end-foot coverage, we investigated whether pericytes—another cell type involved in the induction of barrier properties of cerebral endothelial cell (CEC) [9,10]—remained in contact with the vessels, as previously described in a different metastatic model [20]
We found that platelet-derived growth factor receptor b (PDGFRb)-positive pericytes were localized to capillaries inside metastatic lesions in the mouse brain (Fig. 1A)
Summary
Cerebral metastases are frequent and dismal complications of a few tumor cell types, including lung cancer, breast cancer, and melanoma. In breast cancer, which is the second most frequent cause of central nervous system (CNS) metastases, brain lesions primarily occur in triple-negative (estrogen receptor-, progesterone receptor-, and Her2-negative) and Her2/neu-overexpressing subtypes. The most important unique aspects of brain metastasis development are linked to the neurovascular unit (NVU), that is, cerebral endothelial cells (CECs), pericytes, glial cells, and neurons, with whom tumor cells form complex interactions [6]. These interactions have been extensively studied, except for pericytes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
