vascular leakage; TGFbeta; MMP14/MT1-MMP; extracellular matrix; type I collagen
Abstract :
[en] Innate regulatory networks within organs maintain tissue homeostasis and facilitate rapid responses to damage. We identified a novel pathway regulating vessel stability in tissues involving matrix metalloproteinase 14 (MMP14) and transforming growth factor beta (TGFbeta)1. Whereas plasma proteins rapidly extravasate out of vasculature in wildtype mice following acute damage, short-term treatment of mice in vivo with a broad-spectrum metalloproteinase inhibitor, neutralizing antibodies to TGFbeta1 or an ALK5 inhibitor significantly enhanced vessel leakage. In contrast, in a mouse model of age-related dermal fibrosis where MMP14 activity and TGFbeta bioavailability are chronically elevated, or in mice that ectopically express TGFbeta in epidermis, cutaneous vessels are resistant to acute leakage. Characteristic responses to tissue damage are reinstated if fibrotic mice are pre-treated with metalloproteinase inhibitors or TGFbeta signaling antagonists. Neoplastic tissues on the other hand are in a constant state of tissue damage and exhibit altered hemodynamics due to hyperleaky angiogenic vasculature. In two distinct transgenic mouse tumor models, inhibition of ALK5 further enhanced vascular leakage into interstitium and facilitated increased delivery of high molecular weight compounds into premalignant tissue and tumors. Taken together, these data define a central pathway involving MMP14 and TGFbeta that mediate vessel stability and vascular response to tissue injury. Antagonists of this pathway could be therapeutically exploited to improve delivery of therapeutics or molecular contrast agents into tissues where chronic damage or neoplastic disease limits their efficient delivery.
Disciplines :
Biotechnology
Author, co-author :
Sounni, Nor Eddine ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Stromal regulation of vessel stability by MMP14 and TGFbeta.
Publication date :
May 2010
Journal title :
Disease Models and Mechanisms
ISSN :
1754-8411
eISSN :
1754-8403
Publisher :
The Company of Biologists Ltd, Cambridge, United Kingdom
Volume :
3
Pages :
317-332
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
CAC - Centre anticancéreux près l'Université de Liège asbl NIH grants CA72006, AI053194 and CA105379 (ZW and ME), CA72006, CA98075, CA94168 National Technology Center for Networks and Pathways (U54 RR020843) Department of Defense Breast Cancer Research Program Era of Hope Scholar Award (W81XWH-06-1-0416)
Commentary :
TRANSLATIONAL IMPACT
Clinical issue
In patients with locally advanced solid tumors, the first-line treatment is often neo-adjuvant or pre-operative chemotherapy, which helps shrink tumors before surgery, allowing for more conservative surgical approaches and reducing the potential for developing systemic disease. However, despite aggressive chemotherapy, long-term survival for many patients remains poor, in part owing to limitations with the targeting and accumulation of cytotoxic drugs in tumor tissue.
The vasculature of solid tumors is abnormal, both in terms of vessel architecture and the dynamics of blood flow. Permeable heterogeneous vessel walls allow the leakage of proteins and fluid that, coupled with the inefficiency of lymphatic drainage, could be exploited to develop novel, enhanced drug delivery strategies that are therapeutically selective and improve clinical outcome.
Results
This work describes a previously unappreciated role for transforming growth factor beta (TGFbeta) in regulating vascular stability and vessel permeability in solid tumors. Using mouse models, the authors demonstrate an endogenous pathway that regulates normal vascular permeability, which is controlled by perivascular collagen, the metalloproteinase enzyme MMP14, and TGFbeta. In wild-type mice, inhibitors of either MMP14 or TGFbeta signaling induce blood vessel permeability. Conversely, enhanced MMP14 or TGFbeta activity in the mouse epidermis decreases leakage across cutaneous vessels. This pathway remains functional during tumor progression, as acute blockade of either MMP14 or TGFbeta signaling transiently alters vessel stability, ‘opening’ vascular beds and promoting intravenous delivery of high molecular weight compounds to the tumor.
Implications and future directions
The delivery of standard therapeutic agents or diagnostic molecular imaging
agents to tumor tissue may be enhanced by transient blockade of the TGFbeta
pathway. If so, this could advance disease therapy and/or diagnostic imaging,
not only in cancer medicine, but also in fibrotic disorders such as scleroderma
and kidney failure.
Press releases related to this work:
Drug delivery to solid tumors can be enhanced by transient breakdown of blood vessel walls
Genetic Engineering and Biotechnology news: Mar 10, 2010
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Public release date: 10-Mar-2010
http://www.eurekalert.org/pub_releases/2010-03/tcob-eta030410.php
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http://www.firstscience.com/home/news/breaking-news-all-topics/exploiting-the-architecture-of-cancers-may-lead-to-their-destruction-page-2-1_80558.html
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http://www.btsurvivor.com/bb/viewtopic.php?p=4391&sid=d04fc97e24aed5f1f6b3480472c0b348
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