Macrophage Inflammatory Protein-2 Promotes Angiogenesis, Cell Migration, and Tumor Growth in Hepatic Metastasis
- 20 January 2006
- journal article
- Published by Springer Science and Business Media LLC in Annals of Surgical Oncology
- Vol. 13 (2), 263-275
- https://doi.org/10.1245/aso.2006.03.096
Abstract
In a mouse model of hepatic metastasis, we herein analyzed whether the CXC chemokine macrophage inflammatory protein (MIP)-2, a functional analogue of the human interleukin 8, stimulates tumor cell migration in vitro and angiogenesis and tumor growth in vivo. By using chemotaxis chambers, CT26.WT colorectal tumor cell adhesion and migration were studied under stimulation with different concentrations of MIP-2. To evaluate angiogenesis and tumor growth in vivo, 1 × 105 CT26.WT cells were implanted into the left liver lobe of syngeneic BALB/c mice, and 10, 100, and 1000 nM of MIP-2 or phosphate-buffered saline (controls) was injected into the peritumoral area. After 7 days, angiogenesis, proliferation, tumor growth, apoptosis, cleaved caspase 3, and CXCR-2 expression were analyzed by using intravital fluorescence microscopy, histology, immunohistochemistry, and fluorescence-activated cell sorting. In vitro, 98.8% of unstimulated CT26.WT cells showed CXCR-2 receptor expression. In the chemotaxis assays, MIP-2 provoked a dose-dependent increase of cell migration and a most pronounced cell adhesion at a dose of 100 nM. In vivo, MIP-2, in particular in a dose of 100 or 1000 nM, induced a significant increase of tumor capillary density and a marked widening of the angiogenic front at the tumor margin. Capillaries of the angiogenic front, but not of the tumor center, showed significant dilation, thus indicating a pronounced action of vascular endothelial growth factor. Tumor volume was significantly increased, in particular after 100 nM of MIP-2 stimulation, when compared with phosphate-buffered saline–treated controls, whereas only 1000 nM of MIP-2–treated animals additionally showed a higher frequency of apoptotic cell death within the tumor margin. Our study indicates for the first time that the CXC chemokine MIP-2 promotes angiogenesis and growth of colorectal CT26.WT hepatic metastasis.Keywords
This publication has 44 references indexed in Scilit:
- Critical role of CXC chemokines in endotoxemic liver injury in miceJournal of Leukocyte Biology, 2003
- Mitogenic Properties of Endogenous and Pharmacological Doses of Macrophage Inflammatory Protein-2 after 70% Hepatectomy in the MouseThe American Journal of Pathology, 2003
- Molecular regulation of vessel maturationNature Medicine, 2003
- Staphylococcal Enterotoxin B-Induced Acute Inflammation Is Inhibited by Dexamethasone: Important Role of CXC Chemokines KC and Macrophage Inflammatory Protein 2Infection and Immunity, 2003
- Inflammation and cancerNature, 2002
- Dissecting tumour pathophysiology using intravital microscopyNature Reviews Cancer, 2002
- Chemokines: agents for the immunotherapy of cancer?Nature Reviews Immunology, 2002
- Expression and function of MIP‐2 are reduced by dexamethasone treatment in vivoBritish Journal of Pharmacology, 2000
- An intravital fluorescence microscopic study of hepatic microvascular and cellular derangements in developing cirrhosis in ratsHepatology, 1998
- Properties of the Novel Proinflammatory Supergene "Intercrine" Cytokine FamilyAnnual Review of Immunology, 1991