Stromal regulation of vessel stability by MMP14 and TGFβ

Sounni, Nor Eddine; Dehne, Kerstin; Kempen, Léon C van; Egeblad, Mikala; Affara, Nesrine I.; Cuevas, Ileana; Wiesen, Jane; Junankar, Simon; Korets, Lidiya; Lee, Jake; Shen, Juqun; Morrison, Chet A.; Overall, Christopher M.; Krane, Stephen M.; Werb, Zena; Boudreau, Nancy; Coussens, Lisa M.

doi:10.1242/dmm.003863

Cited by 85 publications

(89 citation statements)

References 79 publications

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“…29 -34 Strategies that promote vascular dilatation, constriction, leakiness, or normalization also are being tried to promote delivery of chemotherapeutics. 20,[35][36][37][38][39][40][41][42] Our studies extend previous work indicating that the delivery and efficacy of CTX can be improved by inhibition of PDGF-B signaling. 20 …”

Section: Strategies To Improve Drug Delivery To Tumorssupporting

confidence: 86%

Increased Vascular Delivery and Efficacy of Chemotherapy after Inhibition of Platelet-Derived Growth Factor-B

Falcón

Pietras

Chou

et al. 2011

The American Journal of Pathology

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Inhibition of platelet-derived growth factor-B (PDGF-B)has multiple effects on tumors, including loss of pericytes, regression of some vessels, normalization of other vessels, and reduction of interstitial pressure. PDGF-B inhibition also increases the efficacy of cancer therapeutics, but the role on tumor vessel efficiency and drug delivery is unclear. We sought to determine whether inhibition of PDGF-B signaling can increase delivery and efficacy of cyclophosphamide in Lewis lung carcinomas or RIP-Tag2 tumors. PDGF-B blockade in Lewis lung carcinoma tumors by the DNA aptamer AX102 for 14 days increased the number of perfused tumor vessels marked by lectin in the bloodstream by 50%. AX102 also increased the width of sleeves of viable tumor cells around blood vessels by 66%, increased tumor cell proliferation by 90%, and increased intratumoral delivery of Hoechst 33342 by 78%. A low dose of cyclophosphamide (20 mg/kg) reduced tumor cell proliferation by 31% when combined with AX102 but not when given alone. Synergy of cyclophosphamide and AX102 on tumor cell proliferation also was found in RIP-Tag2 tumors. Similarly, the PDGF receptor signaling inhibitor imatinib increased delivery of cyclophosphamide and reduced tumor burden in RIP-Tag2 mice, without evidence of tumor cell sensitization to chemotherapy. Together, these findings indicate that inhibition of PDGF-B signaling promotes the delivery and efficacy of chemotherapeutic agents by increasing the efficiency of tumor blood vessels.

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Section: Strategies To Improve Drug Delivery To Tumorssupporting

confidence: 86%

Increased Vascular Delivery and Efficacy of Chemotherapy after Inhibition of Platelet-Derived Growth Factor-B

Falcón

Pietras

Chou

et al. 2011

The American Journal of Pathology

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“…Substrate conversion assay and application of MMPI 1,10 phenanthroline (Sigma) was carried out as described. 69 Fluorescence measurements were performed using a microplate spectrofluorometer (SpectraMax Gemini EM, Molecular Devices, Sunnyvale, CA, USA) operated by SoftMax Pro 4.1 software. Values shown represent the mean ± s.e.m.…”

Section: Substrate Conversion Assay and Zymographymentioning

confidence: 99%

Increased invasiveness of MMP-9-deficient tumors in two mouse models of neuroendocrine tumorigenesis

Shchors

Nozawa

et al. 2012

Oncogene

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Despite their apparent success in pre-clinical trials, metalloproteinase (MMP) inhibitors proved to be inefficacious in clinical settings. In an effort to understand the underlying causes of this unanticipated outcome, we modeled the consequences of long-term MMP inhibition by removing one of the major players in tumorigenesis, MMP9, in two complimentary mouse models of pancreatic neuroendocrine carcinogenesis: Myc;BclXl and RIP1-Tag2. By employing gel zymography and a fluoregenic solution assay, we first established that MMP9 is expressed and activated in Myc;BclXl tumors in an interleukin-1b-dependent manner. The genetic deletion of MMP9 in Myc;BclXl mice impairs tumor angiogenesis and growth analogous to its absence in the RIP1-Tag2 model. Notably, tumors that developed in the context of MMP9-deficient backgrounds in both models were markedly more invasive than their typical wild-type counterparts, and expressed elevated levels of pro-invasive cysteine cathepsin B. The increased invasion of MMP9-deficient tumors was associated with a switch in the spectrum of inflammatory cells at the tumor margins, involving homing of previously undetected, cathepsin-B expressing CD11b;Gr1-positive cells to the invasive fronts. Thus, plasticity in the tumor inflammatory compartment is partially responsible for changes in the expression pattern of tumorassociated proteases, and may contribute to the compensatory effects observed on MMP inhibition, hence accounting for the heightened tumor progression described in late stage clinical trials.Oncogene advance online publication, 5 March 2012; doi:10.1038/onc.2012.60Keywords: tumor; metalloproteinase; invasion; cathepsin; Myc; interleukin-1b INTRODUCTIONMatrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases that contribute to development and tissue homeostasis, and modulate cancer progression by digesting a variety of substrates. Owing to the role of MMP in extracellular matrix (ECM) re-arrangement (also referred to as remodeling or degradation), and in the promotion of neoangiogenesis, it was anticipated that MMP inhibition in vivo would have an anti-tumorigenic effect. However, phase III clinical trials with an MMP inhibitor (MMPI), combined with standard-of-care chemotherapy, failed to demonstrate clinical benefit for late stage cancer patients and, remarkably, was in some cases worse than the chemotherapyonly control arm. For instance, the use of Bay 12-9566 in treating patients with pancreatic cancer reduced both median progressionfree survival and quality-of-life when compared with standard care gemcitabine.1 In another case, treatment of glioblastoma patients rendered no statistically significant survival benefits.2 Additionally, the clinical trials in small-cell lung carcinomas had to be terminated prematurely.3 This failure led to the early cessation of ongoing trials, and to reconsideration of the merit of a variety of MMPIs in clinical development by a number of pharmaceutical companies. 4 --6 The molecular mechanism behind this disappointing outc...

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“…Meanwhile, MT1‐MMP plays a critical role in stabling the vessels, reducing leakage, and promoting regeneration after vascular ischemia (Sounni et al., 2010). There are many evidences showing that MT1‐MMP promotes the regeneration of the peripheral vessels (Kwak et al., 2012) but seldom research on the regeneration of cerebral blood vessels.…”

Section: Introductionmentioning

confidence: 99%

Effects of treadmill exercise on cerebral angiogenesis and MT1‐MMP expression after cerebral ischemia in rats

et al. 2018

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IntroductionDespite the increased understanding of treadmill training on angiogenesis of stroke patients, its mechanism is not clearly known. The metalloproteinase membrane type 1‐metalloprotease (MT1‐MMP) promotes the regeneration of the peripheral vessels but seldom research on the regeneration of cerebral blood vessels. This study was designed to investigate the effects of treadmill exercise on angiogenesis and MT1‐MMP expression after cerebral ischemia in rats.MethodsThe adult male Sprague Dawley(SD) rats were randomly divided into three groups: sham operation group, the middle cerebral artery occlusion group(MCAO) and middle cerebral artery occlusion group(MCAO)+exercise group. In 4d, 7d or 14d after MCAO, respectively, the rats’ neurological function was evaluated by the modified neurologic severity scores (mNSS); the microvessel numbers in areas surrounding cerebral ischemia were counted with Microvessel Density(MVD)analysis; the levels of MT1‐MMP and reversion‐inducing cysteine‐rich protein with Kazalmotifs (RECK) were detected by Western‐blot and immunohistochemical method.ResultsCompared with MCAO group, the number of capillaries and the level of MT1‐MMP expression around the area of cerebral ischemia were significantly increased in each exercise group (p < 0.05), while the level of RECK expression and the scores of mNSS in each exercise group were significantly decreased (p < 0.05).ConclusionThis study suggested that treadmill exercise training can significantly promote angiogenesis and improve neurological function after cerebral ischemia. Its mechanism may be related to the upgraduation of the MT1‐MMP expression in brain microvessels surrounding area of the ischemic rat.

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Stromal regulation of vessel stability by MMP14 and TGFβ

Abstract: /MMP2 -/-mice (four mice/experimental group) in response to mustard oil (black bars), as compared with mineral oil (white bars). Data reflect mean ± S.E.M. *P<0.005.

Cited by 85 publications

References 79 publications

Increased Vascular Delivery and Efficacy of Chemotherapy after Inhibition of Platelet-Derived Growth Factor-B

Increased Vascular Delivery and Efficacy of Chemotherapy after Inhibition of Platelet-Derived Growth Factor-B

Increased invasiveness of MMP-9-deficient tumors in two mouse models of neuroendocrine tumorigenesis

Effects of treadmill exercise on cerebral angiogenesis and MT1‐MMP expression after cerebral ischemia in rats

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