**2. Brain metastasis development and the blood-brain-barrier**

A significant part of the disease burden and death of cancer is caused by the seeding of tumor cells to the brain [6]. The stages of the development of brain metastasis include the detachment of cancer cells from the primary tumors and their penetration of the BBB followed by extravasation, colonization, and macrometastatic growth [7]. The detachment of tumor cells from the primary tumor mass depends on cell adhesion molecules (CAMs) including immunoglobulins (IgCAMs), selectins, integrins, and cadherins [8–10]. The tumor cells require the loss of functional E-cadherin (CDH1) in order to increase their motility, and close relation between reduced E-cadherin expression and poor outcome due to tumor spread in NSCLC exists [11]. CDH1 regulates EGFR activity through receptor tyrosine kinases (RTKs) and provides functions in intracellular signaling. Subsequent events include the epithelial-mesenchymal transition (EMT), a crucial phenomenon in the dissemination and motility of cancer cells [12, 13]. The process of EMT relays on proteases such as secreted matrix metalloproteinases (MMPs) that degrade the extracellular matrix (ECM) components including proteoglycans, collagen, fibronectin, and laminin, and modify the structural and mechanical features of the ECM [14]. MMPs also break down cell-ECM - and cell-cell connections by cleaving CDH1 and CD44. MMP-1, MMP-2, and MMP-9 are particularly associated with metastases of lung cancer [15]. Once detached and motile, the tumor cells enter the circulation to become circulating tumor cells (CTCs). Some CTCs resist the forces of the blood flow and by using surface receptors adhere to the endothelial cells. Subsequently, the cells will migrate through the endothelial layer by the expression of selectins, integrins, and chemokines. This process is accompanied by the creation of a permissive immune microenvironment through the activation of integrins and the release of cytokines such as vascular endothelial growth factor (VEGF) [16]. VEGF is vital in the process of neovascularization and takes part in the creation of high endothelial venules, to increase lymphocyte extravasation and infiltration in the perivascular niches (PVN) at the metastatic sites [17]. The altered microenvironment promotes further migration of CTCs to the brain parenchyma by secreting site-specific chemokines such as CXCR4 and its ligand, CXCL12 [17, 18]. There is high expression of CXCR4/CXCL12 in brain metastases of NSCLC and, together with integrins, CXCR4 enhances further tumor cell invasion. The metastatic cells in the PVNs activate tumor-associated macrophages (TAMs) and microglia. TAMs play a role in the survival of CTCs and induce extravasation and colonization by expressing survival factors such as epidermal growth factor (EGF) [19]. While the TILs try to combat the tumor cells, the microglia switches from the M1 (anti-tumor) phenotype to the M2 (anti-inflammatory) phenotype by factors secreted from tumor cells [20] and display tumor-supporting activity. The M2 microglia counteracts TILs activity via the induction of immunosuppressive factors including programmed cell death protein 1(PD1) /programmed death-ligand 1 (PD-L1) [21]. Also, activated astrocytes promote the proliferation and brain invasion of the tumor cells [22]. Obviously, cell types and pathways that initially are activated to counter-act the metastatic process become collaborators in progressive colonization of the brain later on. So far, therapeutic interventions aimed at the elimination of the tumor cells growing in the brain. *Non-Small Cell Lung Cancer Brain Metastasis: The Link between Molecular Mechanisms… DOI: http://dx.doi.org/10.5772/intechopen.106385*

Future therapeutic strategies may target any of the preceding events, including CTC trafficking and penetration of the BBB.
