Tumor Metastasis to Brain: Role of Endothelial Cells, Neurotrophins, and Paracrine Growth Factors

Abstract

An important clinical endpoint in patients with cancer is formation of metastases in the brain. Understanding this phenomenon is important in several types of malignancies, including melanoma, lung and breast cancers. Metastatic tumor cells use specific adhesion molecules to home to brain, and there they must attach to microvessel endothelial cells and respond to brain endothelial cell-derived motility factors and brain invasion factors to invade the CNS. Neurotrophins are important invasion factors in this process, and the ability to invade into the brain may well depend on metastatic cell responses to neurotrophins and production of basement membrane-degradative enzymes capable of locally destroying the blood-brain barrier. Brain-metastatic human melanoma cells express low-affinity p75 receptor for neurotrophins such as nerve growth factor, but they do not express the high-affinity-type receptors for nerve growth factor encoded by the protooncogene trkA. Tumor cells can proliferate in the CNS in response to local paracrine growth factors and inhibitors, but their growth also depends on their producing and responding to autocrine growth factors. A major organ-derived (paracrine) growth factor has been isolated that differentially stimulates the growth of cells metastatic to the brain. Characterization of this mitogen demonstrated that it is a transferrin-like glycoprotein; cells that are metastatic to brain express greater numbers of transferrin receptors on their surfaces than cells that are poorly metastatic or metastatic to other sites. Transferrin-like factors are expressed in fetal brain and could represent the transferrin-like factors that stimulate growth of brain-metastatic melanoma and breast cancer cells. These and other factors are probably important in determining whether metastatic cells can successfully invade, colonize, and grow in the CNS.

Vascular Endothelial Growth Factor Up-regulates ICAM-1 Expression via the Phosphatidylinositol 3 OH-kinase/AKT/Nitric Oxide Pathway and Modulates Migration of Brain Microvascular Endothelial Cells

“…This newly identified signaling pathway in BMEC is important for BMEC function and migration as well as for maintaining the integrity of the BBB. Our findings are supported by studies in other endothelial systems such as bovine aortic endothelial cells, where VEGF is a potent inducer of bovine aortic endothelial cell proliferation and migration (3,5). Cell migration is crucial for angiogenesis, embryonic development, wound repair, tumor formation, cancer metastasis, and inflammatory immune response (6 -10).…”

“…Whereas the endothelial cell microvascular monolayer forms the barrier proper, the interaction between these various cell types seems to be necessary for the induction or maintenance of the specialized function of the BBB (1). The permeability of the BBB is important for its normal functioning, and changes in this permeability may lead to brain infection (2) and cancer metastasis to the brain (3).…”

Heparanase and a Synthetic Peptide of Heparan Sulfate-interacting Protein Recognize Common Sites on Cell Surface and Extracellular Matrix Heparan Sulfate

“…Important ECM targets for degradation by invading melanoma cells are the heparan sulfate (HS) chains found on proteoglycans (3,6,7). HS are highly negatively charged linear polysaccharides consisting of alternating residues of uronic acids and glucosamine.…”

Breast Cancer Metastasis to the Central Nervous System

“…Candidates comprise locally produced factors including receptors for neurotrophins such as nerve growth factor, transferrin, gangliosides, and other enzymes. [62][63][64][65][66][67][68][69] …”