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Am J Pathol. 2013 Oct;183(4):1293-1305. doi: 10.1016/j.ajpath.2013.06.026. Epub 2013 Aug 5.

Role of collagen matrix in tumor angiogenesis and glioblastoma multiforme progression.

Author information

1
Vascular Biology Program, Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
2
Vascular Biology Program, Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; Division of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
3
Vascular Biology Program, Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: akiko.mammoto@childrens.harvard.edu.

Abstract

Glioblastoma is a highly vascularized brain tumor, and antiangiogenic therapy improves its progression-free survival. However, current antiangiogenic therapy induces serious adverse effects including neuronal cytotoxicity and tumor invasiveness and resistance to therapy. Although it has been suggested that the physical microenvironment has a key role in tumor angiogenesis and progression, the mechanism by which physical properties of extracellular matrix control tumor angiogenesis and glioblastoma progression is not completely understood. Herein we show that physical compaction (the process in which cells gather and pack together and cause associated changes in cell shape and size) of human glioblastoma cell lines U87MG, U251, and LN229 induces expression of collagen types IV and VI and the collagen crosslinking enzyme lysyl oxidase and up-regulates in vitro expression of the angiogenic factor vascular endothelial growth factor. The lysyl oxidase inhibitor β-aminopropionitrile disrupts collagen structure in the tumor and inhibits tumor angiogenesis and glioblastoma multiforme growth in a mouse orthotopic brain tumor model. Similarly, d-penicillamine, which inhibits lysyl oxidase enzymatic activity by depleting intracerebral copper, also exhibits antiangiogenic effects on brain tumor growth in mice. These findings suggest that tumor microenvironment controlled by collagen structure is important in tumor angiogenesis and brain tumor progression.

PMID:
23928381
PMCID:
PMC3791684
DOI:
10.1016/j.ajpath.2013.06.026
[Indexed for MEDLINE]
Free PMC Article

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