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Review
. 2015 May-Jul:44-46:94-112.
doi: 10.1016/j.matbio.2015.04.004. Epub 2015 Apr 22.

Tumor angiogenesis: MMP-mediated induction of intravasation- and metastasis-sustaining neovasculature

Elena I Deryugina  1 , James P Quigley  2
Affiliations
Review

Tumor angiogenesis: MMP-mediated induction of intravasation- and metastasis-sustaining neovasculature

Elena I Deryugina et al. Matrix Biol. 2015 May-Jul.

Abstract

Metastasis is a distinct stage of cancer progression that requires the development of angiogenic blood vessels serving as conduits for tumor cell dissemination. An accumulated body of evidence indicates that metastasis-supporting neovasculature should possess certain structural characteristics allowing for the process of tumor cell intravasation, an active entry of cancer cells into the vessel interior. It appears that the development of tumor vessels with lumens of a distinctive size and support of these vessels by a discontinuous pericyte coverage constitute critical microarchitectural requirements to: (a) provide accessible points for vessel wall penetration by primary tumor cells; (b) provide enough lumen space for a tumor cell or cell aggregate upon intravasation; and (c) allow for sufficient rate of blood flow to carry away intravasated cells from the primary tumor to the next, proximal or distal site. This review will primarily focus on the functional roles of matrix metalloproteinases (MMPs), which catalytically trigger the development of an intravasation-sustaining neovasculature at the early stages of tumor growth and are also required for the maintenance of a metastasis-supporting state of blood vessels at later stages of cancer progression.

Keywords: Epidermal growth factor receptor; Matrix metalloproteinase; Tissue inhibitor of metalloproteinases; Tumor angiogenesis; Tumor cell intravasation and metastasis; Tumor-associated macrophages; Tumor-associated neutrophils; Vascular endothelial growth factor.

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Figures

Figure 1
Figure 1. TANs constitute the major cellular source of angiogenic proMMP-9
(A) LLC tumor was stained for MMP-9 (red) and either macrophage-specific antigen F4/80 or neutrophil-specific antigen Ly6G (green). Note the MMP-9-positive fibrillar matrix surrounding the MMP-9/Ly6G–positive neutrophils that appear yellow due to the overlap of red and green immunofluorescent signals. Bars, 20 µm. (B) Isolated TAMs and TANs were stained for common cell myeloid marker CD11b (green) and MMP-9 (red). Only isolated TANs are positively stained for MMP-9, producing yellow signal indicating the overlap of MMP-9 (red) and lineage-specific (green) signals. Bars, 10 µm. (C) Western blot analysis of MMP-9 and TIMP-1 produced by isolated TAMs and TANs. Whereas both cell types do not produce detectable TIMP-1, only TANs release substantial quantities of proMMP-9. (D) Angiogenic potential of isolated TAMs and TANs and their respective products, TAMs’ conditioned medium and TANs’ releasate, as measured in the in vivo angiogenesis assay in live chick embryos. Note that TANs and TANs releasate induce higher levels of angiogenesis compared to low angiogenic TAMs and their conditioned medium.
Figure 2
Figure 2. Development of intratumoral lumen-containing angiogenic vessels and their partial coverage with pericytes depend on the host MMP-9
(A) LLC tumors grown in wild-type (WT) or MMP-9 knockout (KO) mice were immunostained for the endothelial cell marker CD31 (green) and pericyte marker NG2 (red). Blood vessels in WT tumors exhibit enlarged lumens (outlined) associated with more pericytes than the vessels in MMP-9-deficient tumors. Bars, 20 µm. (B) Lumen-containing vessels (Y axis on the left) and average number of lumen-associated pericytes (Y axis on the right) were quantified in WT tumors versus MMP-9-deficient LLC tumors. Note a 4-fold differential in both parameters in favor of angiogenic vessels in MMP-9-competent tumors.
Figure 3
Figure 3. Tumor cell EGFR regulates the development of angiogenic vessels in the HT-hi/diss microtumors in a neutrophil MMP-9/VEGF-dependent manner
(A) GFP-tagged HT-hi/diss cells were treated with control siRNA (siCtrl) or EGFR siRNA (siEGFR) and grafted on the CAM of live chick embryos. After 5 days, intratumoral blood vessels within developed microtumors were highlighted in vivo with red-fluorescent lectin. Despite the similar size of HT-hi/diss microtumors (upper panels; bars, 100 µm), EGFR silencing resulted in the development of thin and collapsed blood vessels with reduced size lumens compared to control (lower panels; bars, 50 µm). Note that treatment of siEGFR tumors with purified neutrophil proMMP-9 restored the appearance of intratumoral blood vessels. (B) Quantification of intratumoral angiogenic vessels with 15–30 µm-lumens, the density of intratumoral MMP-9-positive TANs, the levels of intravasation and the levels of bioavailable VEGF in tumors. Downregulation of EGFR resulted in a significant underrepresentation of angiogenic vessels with the lumens of specific 15–30 µm size, concomitant with the reduction of neutrophil influx and tumor cell intravasation. Both blood vessel development and intravasation rates were restored by supplementation of siEGFR-silenced tumors with purified neutrophil MMP-9 (nMMP-9), which also fully restored the levels of bioavailable VEGF.
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