Pericyte‐secreted IGF2 promotes breast cancer brain metastasis formation

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.

Picturing Breast Cancer Brain Metastasis Development to Unravel Molecular Players and Cellular Crosstalk

“…Similarly, the observed expression of this growth factor may constitute a mechanism of autocrine and/or paracrine regulation of cell survival and proliferation [ 40 , 41 ], which highlights PDGF-B as a key player in the brain colonization of TNBC. Its receptor, PDGFRβ, is primarily expressed in pericytes; therefore, PDGF–PDGFR interaction might constitute another mechanism of the pro-metastatic effect of brain pericytes, in addition to the secretion of ECM proteins and insulin-like growth factor 2 [ 20 ].…”

“…Pericytes have been widely studied in the context of their capacity to stabilize BBB properties and blood vessel structure, and their role towards brain metastasis development cannot be ignored. We have shown that pericytes play a crucial role in the development of metastatic brain tumors by secreting ECM proteins, which enhanced the adhesion of TN BCCs, and by secreting insulin-like growth factor 2, which had a pro-proliferative effect [ 20 ]. Alterations in mural cells contractility indicators during BCBM formation were observed, where both α-SMA and MLCK increased over time.…”

“…Brain capillaries are ensheathed by pericytes, which are mural cells with contractile properties that play a crucial role in the regulation of microcirculation and maintenance of BBB permeability [ 19 ], but their contribution to extravasation and BCBM formation is poorly explored. We have also shown that pericytes play a crucial role in the development of metastatic brain tumors by directly influencing key steps of disease progression, including the adhesion, migration, and proliferation of TNBC cells [ 20 ]. Furthermore, the crosstalk between malignant and brain resident cells was shown to favor brain metastases formation [ 21 ].…”

Roles for growth factors and mutations in metastatic dissemination

“…• NDRG1 inhibits PSC-CM-induced migration of PaCa via inhibition of HGF/c-MET, IGF-1/IGF-1R signaling [105]. • IGF2 secreted by pericyte promotes formation of breast cancer brain metastasis [65].…”

Cerebral Metastasis of Common Cancers

“…The creation of, and interaction with, newly formed blood vessels plays a large role in the progress of invasion. The outgrowth of tumor cells in the brain is dependent on the expressional repertoire of the tumor cells and their interactions with cells in the brain micro-environment, including representatives of the local immune response [ 24 , 25 ]. The parts played by either the innate or the acquired immune response on outgrowth are topics of current explorations [ 26 ].…”