title: 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.
authors: Department of Pediatrics, Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors: Ling
authors: L
authors: Wang
authors: Stephanie M
authors: SM
authors: Cossette
authors: Kevin R
authors: KR
authors: Rarick
authors: Jill
authors: J
authors: Gershan
authors: Michael B
authors: MB
authors: Dwinell
authors: David R
authors: DR
authors: Harder
authors: Ramani
authors: R
authors: Ramchandran
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D001685:Biological Factors / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000737:chemistry; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control; D009368:Neoplasm Transplantation; D061251:Primary Cell Culture; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured
chemical_list: D001685:Biological Factors; D017077:Culture Media, Conditioned; D011480:Protease Inhibitors; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9