Astrocytes Directly Influence Tumor Cell Invasion and Metastasis In Vivo

Abstract

Brain metastasis is a defining component of tumor pathophysiology, and the underlying mechanisms responsible for this phenomenon are not well understood. Current dogma is that tumor cells stimulate and activate astrocytes, and this mutual relationship is critical for tumor cell sustenance in the brain. Here, we provide evidence that primary rat neonatal and adult astrocytes secrete factors that proactively induced human lung and breast tumor cell invasion and metastasis capabilities. Among which, tumor invasion factors namely matrix metalloprotease-2 (MMP-2) and MMP-9 were partly responsible for the astrocyte media-induced tumor cell invasion. Inhibiting MMPs reduced the ability of tumor cell to migrate and invade in vitro. Further, injection of astrocyte media-conditioned breast cancer cells in mice showed increased invasive activity to the brain and other distant sites. More importantly, blocking the preconditioned tumor cells with broad spectrum MMP inhibitor decreased the invasion and metastasis of the tumor cells, in particular to the brain in vivo. Collectively, our data implicate astrocyte-derived MMP-2 and MMP-9 as critical players that facilitate tumor cell migration and invasion leading to brain metastasis.

The Role of Astrocytes in Tumor Growth and Progression

“…As discussed earlier, we and others have identified astrocyte secreted MMP-2, MMP-9, and MMP-1 to promote tumor progression, and blocking them with broad spectrum MMP inhibitors does influence tumor metastasis in pre-clinical models [95,96,[165][166][167]. Interestingly, MMP-1 was one of 21 MMPs that showed clinical significance in regards to breast cancer brain metastasis, and expression analysis of brain-seeking triple negative breast cancer clonal cells confirm MMP-1 and MMP-9 as potential targets [133,168].…”

“…The expression of MMP-9 was up-regulated in reactive astrocytes, which was involved in the brain metastases of MDA-MB-435 cells [56]. Moreover, both MMP-2 and -9 secreted by astrocytes contribute to breast cancer MDA-MB-231 cell invasion and brain metastases [95]. In addition to secreting MMPs themselves, astrocytes can also induce tumor cells to secrete MMPs, as shown by Mendes et al (2007), where they found breast cancer cells to secrete significantly more MMP-2 in the presence of astrocyte conditioned media, aiding metastasis to the brain [96].…”

“…As we know, astrocytes are capable of signaling to trigger tumor cell (breast, lung, skin, and brain) migration, invasion and metastasis in vivo [88,95,127,160]. There are many targets in the brain microenvironment that provide effective intervention strategies for metastasis, and is reviewed elsewhere [164].…”

Astrocytes from the brain microenvironment alter migration and morphology of metastatic breast cancer cells

“…During metastasis, tumor cells encounter many heterogeneous microenvironments containing an array of biochemical and physical cues (2), both of which regulate the migration, mechanobiology, and signaling mechanisms used by tumor cells to navigate these environments (3). It has been shown that astrocytes in the brain microenvironment promote brain metastasis and facilitate tumor cell invasion (4)(5)(6)(7)(8). We hypothesize that astrocyte-secreted biochemical cues regulate the morphology and migration of metastatic breast tumor cells and that this effect depends on the astrocyte activation state, as well as the mechanical microenvironment of the tumor cells.…”

“…Secretion of MMPs by astrocytes does not necessarily require 2-way communication between tumor cells and astrocytes (5) and thus could be a part of the 1-way paracrine signaling of astrocytes to tumor cells that we explored in this study. MMPs are secreted by various cell types including both astrocytes and tumor cells, function to degrade the extracellular matrix, and are known to promote tumor cell splitting from a primary tumor, intravasation into the vasculature, and extravasation across capillary endothelial cells and the BBB (13).…”