Abstract
The goal of this work was to determine the molecular basis for the induction of tumour vascularization and progression by injury. Magnetic resonance imaging (MRI) studies demonstrated that administration of wound fluid derived from cutaneous injuries in pigs reduced the lag for vascularization and initiation of growth of C6 glioma spheroids, implanted in nude mice, and accelerated tumour doubling time. The former effect can be attributed to the angiogenic capacity of wound fluid as detected in vivo by MRI, and in vitro in promoting endothelial cell proliferation. The latter effect, namely the induced rate of tumour growth, is consistent with the angiogenic activity of wound fluid as well as with the finding that wound fluid was directly mitogenic to the tumour cells, and accelerated growth of C6 glioma in spheroid culture. Of the multiple growth factors present in wound fluid, two key factors, heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) and platelet-derived growth factor (PDGF), were identified as the dominant mitogens for C6 glioma, and inhibition of their activity using specific neutralizing antibodies suppressed the mitogenic effect of wound fluid on DNA synthesis in C6 glioma. This study suggests that the stimulatory effect of injury on tumour progression can possibly be attenuated by therapeutic targeting directed against a limited number of specific growth factors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inducing Agents / administration & dosage
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Angiogenesis Inducing Agents / antagonists & inhibitors
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Angiogenesis Inducing Agents / metabolism
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Angiogenesis Inducing Agents / physiology*
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Animals
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Becaplermin
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Cell Division
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DNA, Neoplasm / biosynthesis
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Epidermal Growth Factor / administration & dosage
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Epidermal Growth Factor / antagonists & inhibitors
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Epidermal Growth Factor / metabolism
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Epidermal Growth Factor / physiology*
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Female
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Fibroblast Growth Factor 2 / administration & dosage
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Fibroblast Growth Factor 2 / antagonists & inhibitors
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Fibroblast Growth Factor 2 / metabolism
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Fibroblast Growth Factor 2 / physiology
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Glioma / blood supply
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Glioma / pathology
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Heparin-binding EGF-like Growth Factor
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Humans
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Intercellular Signaling Peptides and Proteins
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Magnetic Resonance Imaging
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Mice
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Mice, Nude
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Neovascularization, Pathologic / etiology*
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Platelet-Derived Growth Factor / administration & dosage
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Platelet-Derived Growth Factor / antagonists & inhibitors
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Platelet-Derived Growth Factor / metabolism
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Platelet-Derived Growth Factor / physiology*
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Proto-Oncogene Proteins c-sis
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Rats
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Spheroids, Cellular / pathology*
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Swine
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Wounds and Injuries / metabolism*
Substances
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Angiogenesis Inducing Agents
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DNA, Neoplasm
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HBEGF protein, human
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Hbegf protein, mouse
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Hbegf protein, rat
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Heparin-binding EGF-like Growth Factor
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Intercellular Signaling Peptides and Proteins
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Platelet-Derived Growth Factor
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Proto-Oncogene Proteins c-sis
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Fibroblast Growth Factor 2
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Becaplermin
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Epidermal Growth Factor