Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Accepted manuscripts
    • Issue in progress
    • Latest complete issue
    • Issue archive
    • Archive by article type
    • Subject collections
    • Interviews
    • Sign up for alerts
  • About us
    • About DMM
    • Editors and Board
    • Editor biographies
    • Travelling Fellowships
    • Grants and funding
    • Journal Meetings
    • Workshops
    • The Company of Biologists
    • Journal news
  • For authors
    • Submit a manuscript
    • Aims and scope
    • Presubmission enquiries
    • Article types
    • Manuscript preparation
    • Cover suggestions
    • Editorial process
    • Promoting your paper
    • Open Access
    • Outstanding paper prize
    • Biology Open transfer
  • Journal info
    • Journal policies
    • Rights and permissions
    • Media policies
    • Reviewer guide
    • Sign up for alerts
  • Contact
    • Contact DMM
    • Advertising
    • Feedback
  • COB
    • About The Company of Biologists
    • Development
    • Journal of Cell Science
    • Journal of Experimental Biology
    • Disease Models & Mechanisms
    • Biology Open

User menu

  • Log in

Search

  • Advanced search
Disease Models & Mechanisms
  • COB
    • About The Company of Biologists
    • Development
    • Journal of Cell Science
    • Journal of Experimental Biology
    • Disease Models & Mechanisms
    • Biology Open

supporting biologistsinspiring biology

Disease Models & Mechanisms

Advanced search

RSS   Twitter   Facebook   YouTube

  • Home
  • Articles
    • Accepted manuscripts
    • Issue in progress
    • Latest complete issue
    • Issue archive
    • Archive by article type
    • Subject collections
    • Interviews
    • Sign up for alerts
  • About us
    • About DMM
    • Editors and Board
    • Editor biographies
    • Travelling Fellowships
    • Grants and funding
    • Journal Meetings
    • Workshops
    • The Company of Biologists
    • Journal news
  • For authors
    • Submit a manuscript
    • Aims and scope
    • Presubmission enquiries
    • Article types
    • Manuscript preparation
    • Cover suggestions
    • Editorial process
    • Promoting your paper
    • Open Access
    • Outstanding paper prize
    • Biology Open transfer
  • Journal info
    • Journal policies
    • Rights and permissions
    • Media policies
    • Reviewer guide
    • Sign up for alerts
  • Contact
    • Contact DMM
    • Advertising
    • Feedback
Journal Club
Vascular homeostasis: insights from a fibrotic mouse
Stephen P. Santoro, Nancy L. Maas
Disease Models & Mechanisms 2011 4: 5-6; doi: 10.1242/dmm.006726
Stephen P. Santoro
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: ssantoro@upenn.edu nmaas@upenn.edu
Nancy L. Maas
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: ssantoro@upenn.edu nmaas@upenn.edu
  • Article
  • Figures & tables
  • Info & metrics
  • PDF
Loading

Efficient delivery of cancer chemotherapeutic agents depends on the permeability of the tumor vasculature. The natural hyperpermeability of tumor vessels increases absorption of macromolecular drugs into tumor tissue, suggesting that further enhancement of this process could be beneficial to the treatment of cancer (Baban and Seymour, 1998). Numerous studies have demonstrated that collagen, the most abundant protein of the extracellular matrix, plays an important role in regulating vessel permeability (Brown et al., 2003; Loeffler et al., 2006). The mechanism by which this occurs, however, had not been shown. A recent study by Sounni et al. in Disease Models & Mechanisms identifies a pathway by which collagen maintains vascular integrity in the Colα1(I)r/r mouse model (Sounni et al., 2010). In these mice, the collagenase cleavage site within type I collagen is mutated (Liu et al., 1995), causing a compensatory increase in collagenolytic activity and hemodynamic perturbation (Sounni et al., 2010). The proposed model suggests that type I collagen is a crucial component of a regulatory loop that links protease breakdown of extracellular matrix components with vascular permeability.

Sounni et al. identified matrix metalloproteinase-14 (MMP14) as the crucial protease that is activated downstream of type I collagen. This supports the earlier observation that MMPs are involved in vascular permeability (Gade et al., 2009). To determine which MMP is required for vessel stability, Sounni et al. conducted a series of in vivo assays to assess vascular leakage in MMP-knockout mice (see figure 1B in Sounni et al., 2010). The enhanced steady-state leakage in MMP14-null mice implicated MMP14 as the metalloproteinase that is crucial for maintaining vascular stability in this model (see figure 1D in Sounni et al., 2010). In addition, Sounni et al. employed the Colα1(I)r/r mouse model to demonstrate the influence of increased collagen levels on MMP activity and vessel stability. As expected, the Colα1(I)r/r mouse displayed increased MMP activity and decreased vascular permeability (see figure 2A,B in Sounni et al., 2010). The broad-spectrum metalloproteinase inhibitor GM6001 rescued this phenotype. Although the authors interrogated the influence of the related metalloproteinase MMP2 on their proposed mechanism, the potential off-target effects of GM6001 on other MMPs should also be considered. Use of MMP14-specific antibodies, which have recently become available (Devy et al., 2009), would serve to strengthen these data. However, the results strongly suggest that the overabundance of uncleaved collagen in the Colα1(I)r/r mouse induces hyperactivation of MMP14, which in turn decreases vascular permeability.

The observation that MMP14 can activate latent transforming growth factor-β (TGFβ) (Mu et al., 2002; Werb, 1997) led Sounni et al. to hypothesize that TGFβ might be the downstream mediator of vascular permeability. The authors supported this assertion through additional work in the Colα1(I)r/r mouse. TGFβ levels were found to be elevated in the Colα1(I)r/r mouse when compared with the wild-type control (see figure 4B in Sounni et al., 2010). In addition, MMP14-knockout mice showed reduced levels of TGFβ. The authors validated the direct effect of collagen and MMP14 on TGFβ bioavailability through in vitro studies in a cell line overexpressing MMP14 and grown on collagen isolated from Colα1(I)r/r mice (see figure 4H in Sounni et al., 2010). These cell lines exhibited increased TGFβ activity, as measured by a luciferase reporter assay. To demonstrate that TGFβ directly mediates vascular permeability, Sounni et al. injected TGFβ-neutralizing antibodies into the Colα1(I)r/r mice before challenging them with mustard oil, and observed rescue of vascular permeability (see figure 4I in Sounni et al., 2010). Inhibition of the TGFβ receptor, ALK5, also restored the vascular response in these mice. As a final verification that this phenomenon was not restricted to Colα1(I)r/r mice, the authors used an inducible TGFβ bigenic mouse model. As predicted, overexpression of TGFβ resulted in decreased vessel permeability (see figure 5B in Sounni et al., 2010). Taken together, these data strongly support a mechanism of collagen-induced MMP14 activation, leading to the release of active TGFβ and a subsequent decrease in vascular permeability.

Finally, Sounni et al. showed that inhibition of this pathway results in increased uptake of high-molecular-weight compounds into tumor tissue. TGFβ blockade with an ALK5 inhibitor increased dextran delivery to tumor tissue in an MMTV-PyMT mouse model of breast cancer (see figure 6E in Sounni et al., 2010). Although suggestive, the ability of TGFβ blockade to enhance the effectiveness of chemotherapy was not assessed. Furthermore, this study did not consider that TGFβ acts as a tumor suppressor early in neoplastic growth and promotes tumor progression later in the disease (Pardali and ten Dijke, 2009). Therefore, inhibiting TGFβ early in primary or secondary tumor development might actually promote tumor growth. Last, the influence of TGFβ seems to be dependent upon the cellular microenvironment. In contrast to the stabilizing effect of TGFβ on the vasculature observed by Sounni et al., TGFβ has also been shown to increase the permeability of endothelial cells in culture (Birukova et al., 2005). These data suggest that TGFβ inhibition elicits differential responses depending on both tumor stage and tumor microenvironment. Careful consideration must therefore be taken when extrapolating the potential advantages of manipulating the pathway described by Sounni et al. (Sounni et al., 2010).

Regardless of the therapeutic implications, the data presented by Sounni et al. (summarized in Table 1) uniquely address the role of the collagen-MMP14-TGFβ pathway in vascular homeostasis, as demonstrated through use of the Colα1(I)r/r mouse. Their work provides mechanistic evidence for the role of TGFβ in stabilizing vessels after acute insult, and for the role of type I collagen in regulating vascular permeability (see figure 7 in Sounni et al., 2010). In conclusion, these data provide a platform for further investigation and a rationale for testing the effects of manipulating vascular permeability during chemotherapeutic intervention.

View this table:
  • View inline
  • View popup
  • Download powerpoint
Table 1.

Summary of results presented by Sounni et al., 2010

  • © 2011. Published by The Company of Biologists Ltd

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0), which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms

REFERENCES

  1. ↵
    1. Baban, D.F. and
    2. Seymour, L.W.
    (1998). Control of tumour vascular permeability. Adv. Drug. Deliv. Rev. 34, 109–119.
    OpenUrlCrossRefPubMedWeb of Science
  2. ↵
    1. Birukova, A.A.,
    2. Adyshev, D.,
    3. Gorshkov, B.,
    4. Birukov, K.G. and
    5. Verin, A.D.
    (2005). ALK5 and Smad4 are involved in TGF-beta1-induced pulmonary endothelial permeability. FEBS Lett. 579, 4031–4037.
    OpenUrlCrossRefPubMedWeb of Science
  3. ↵
    1. Brown, E.,
    2. McKee, T.,
    3. diTomaso, E.,
    4. Pluen, A.,
    5. Seed, B.,
    6. Boucher, Y. and
    7. Jain, RK.
    (2003). Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation. Nat. Med. 9, 796–800.
    OpenUrlCrossRefPubMedWeb of Science
  4. ↵
    1. Devy, L.,
    2. Huang, L.,
    3. Naa, L.,
    4. Yanamandra, N.,
    5. Pieters, H.,
    6. Frans, N.,
    7. Chang, E.,
    8. Tao, Q.,
    9. Vanhove, M.,
    10. Lejeune, A.,
    11. et al.
    (2009). Selective inhibition of matrix metalloproteinase-14 blocks tumor growth, invasion, and angiogenesis. Cancer Res. 69, 1517–1526.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Gade, T.P.,
    2. Buchanan, I.M.,
    3. Motley, M.W.,
    4. Mazaheri, Y.,
    5. Spees, W.M. and
    6. Koutcher, J.A.
    (2009). Imaging intratumoral convection: pressure-dependent enhancement in chemotherapeutic delivery to solid tumors. Clin. Cancer Res. 15, 247–255.
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Liu, X.,
    2. Wu, H.,
    3. Byrne, M.,
    4. Jeffrey, J.,
    5. Krane, S. and
    6. Jaenisch, R.
    (1995). A targeted mutation at the known collagenase cleavage site in mouse type I collagen impairs tissue remodeling. J. Cell Biol. 130, 227–237.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Loeffler, M.,
    2. Kruger, J.A.,
    3. Niethammer, A.G. and
    4. Reisfeld, R.A.
    (2006). Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J. Clin. Invest. 116, 1955–1962.
    OpenUrlCrossRefPubMedWeb of Science
  8. ↵
    1. Mu, D.,
    2. Cambier, S.,
    3. Fjellbirkeland, L.,
    4. Baron, J.L.,
    5. Munger, J.S.,
    6. Kawakatsu, H.,
    7. Sheppard, D.,
    8. Broaddus, V.C. and
    9. Nishimura, S.L.
    (2002). The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1. J. Cell Biol. 157, 493–507.
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Pardali, E. and
    2. ten Dijke, P.
    (2009). Transforming growth factor-beta signaling and tumor angiogenesis. Front. Biosci. 14, 4848–4861.
    OpenUrlPubMed
  10. ↵
    1. Sounni, N.E.,
    2. Dehne, K.,
    3. van Kempen, L.,
    4. Egeblad, M.,
    5. Affara, N.I.,
    6. Cuevas, I.,
    7. Wiesen, J.,
    8. Junankar, S.,
    9. Korets, L.,
    10. Lee, J.,
    11. et al.
    (2010). Stromal regulation of vessel stability by MMP14 and TGFβ. Dis. Model. Mech. 3, 317–332.
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Werb, Z.
    (1997). ECM and cell surface proteolysis: regulating cellular ecology. Cell 91, 439–442.
    OpenUrlCrossRefPubMedWeb of Science
Previous ArticleNext Article
Back to top
Previous ArticleNext Article

This Issue

RSSRSS

 Download PDF

Email

Thank you for your interest in spreading the word on Disease Models & Mechanisms.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Vascular homeostasis: insights from a fibrotic mouse
(Your Name) has sent you a message from Disease Models & Mechanisms
(Your Name) thought you would like to see the Disease Models & Mechanisms web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Journal Club
Vascular homeostasis: insights from a fibrotic mouse
Stephen P. Santoro, Nancy L. Maas
Disease Models & Mechanisms 2011 4: 5-6; doi: 10.1242/dmm.006726
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Citation Tools
Journal Club
Vascular homeostasis: insights from a fibrotic mouse
Stephen P. Santoro, Nancy L. Maas
Disease Models & Mechanisms 2011 4: 5-6; doi: 10.1242/dmm.006726

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Alerts

Please log in to add an alert for this article.

Sign in to email alerts with your email address

Article navigation

  • Top
  • Article
    • REFERENCES
  • Figures & tables
  • Info & metrics
  • PDF

Related articles

Cited by...

More in this TOC section

  • Modelling how initiating and transforming oncogenes cooperate to produce a leukaemic cell state
  • Finding NECA: zebrafish screen identifies key signalling pathway in β-cell regeneration
  • Lactate-starved neurons in ALS
Show more Journal Club

Similar articles

Other journals from The Company of Biologists

Development

Journal of Cell Science

Journal of Experimental Biology

Biology Open

Advertisement

DMM and COVID-19

We are aware that the COVID-19 pandemic is having an unprecedented impact on researchers worldwide. The Editors of all The Company of Biologists’ journals have been considering ways in which we can alleviate concerns that members of our community may have around publishing activities during this time. Read about the actions we are taking at this time.

Please don’t hesitate to contact the Editorial Office if you have any questions or concerns.


Professor Elizabeth Patton appointed as DMM’s next Editor-in-Chief

We are pleased to announce that The Company of Biologists directors have appointed Professor Elizabeth Patton as DMM's new Editor-in-Chief. As Paresh Vyas writes in his Editorial, Liz ‘brings vitality and a passion for the remit of DMM, and is deeply embedded in the community.’


Did you know DMM Conference Travel Grants can be used for online meetings?

With travel restrictions still in place, we want to continue supporting early-career researchers in their careers. DMM’s Conference Travel Grants can now be used to attend virtual and online scientific meetings, workshops, conferences and training courses.

The current application round closes on 8 February 2021 – find out more.


Identification of MYOM2 as a candidate gene in hypertrophic cardiomyopathy and Tetralogy of Fallot, and its functional evaluation in the Drosophila heart

Research from Silke Sperling and colleagues uses Drosophila to identify MYOM2 as a candidate gene in congenital heart malformations in this issue’s Editor’s choice.


C. elegans as a disease model

A new Research article from Doyle et al., models spinal muscular atrophy in C. elegans to show that that targeting therapies to muscle cells is more effective than neuronal delivery. Find more research using C. elegans as a disease model in our latest subject collection.


Call for papers – The RAS Pathway: Diseases, Therapeutics and Beyond

Our upcoming special issue is now welcoming submissions until 1 April 2021. Guest-edited by Donita Brady (Perelman School of Medicine at the University of Pennsylvania, USA) and Arvin Dar (Icahn School of Medicine at Mount Sinai, USA), the issue will focus on the targeting the RAS pathway. Find out more about the issue and how to submit your manuscript.


Interview – Kim Landry-Truchon and Nicolas Houde

In an interview, first authors Kim Landry-Truchon and Nicolas Houde discuss their mouse model of the early stages of pleuropulmonary blastoma, reflecting on the implications of their work and the future of their field.

Articles

  • Accepted manuscripts
  • Issue in progress
  • Latest complete issue
  • Issue archive
  • Archive by article type
  • Subject collections
  • Interviews
  • Sign up for alerts

About us

  • About DMM
  • Editors and Board
  • Editor biographies
  • Travelling Fellowships
  • Grants and funding
  • Journal Meetings
  • Workshops
  • The Company of Biologists

For Authors

  • Submit a manuscript
  • Aims and scope
  • Presubmission enquiries
  • Article types
  • Manuscript preparation
  • Cover suggestions
  • Editorial process
  • Promoting your paper
  • Open Access
  • Biology Open transfer

Journal Info

  • Journal policies
  • Rights and permissions
  • Media policies
  • Reviewer guide
  • Sign up for alerts

Contact

  • Contact DMM
  • Advertising
  • Feedback

Twitter   YouTube   LinkedIn

© 2021   The Company of Biologists Ltd   Registered Charity 277992