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Matrix metalloproteinases: regulators of the tumor microenvironment. ​

Literature Information ​

DOI10.1016/j.cell.2010.03.015
PMID20371345
JournalCell
Impact Factor42.5
JCR QuartileQ1
Publication Year2010
Times Cited2373
KeywordsMatrix metalloproteinases, tumor microenvironment, cell signaling pathways, cancer therapy
Literature TypeJournal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review
ISSN0092-8674
Pages52-67
Issue141(1)
AuthorsKai Kessenbrock, Vicki Plaks, Zena Werb

TL;DR ​

This research highlights the critical role of matrix metalloproteinases (MMPs) in cancer, revealing how their altered proteolytic activity contributes to tumor growth, metastasis, and modulation of the tumor microenvironment. By understanding MMPs not only as proteases but also as regulators of key signaling pathways, the study suggests new avenues for developing effective cancer therapies.

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Matrix metalloproteinases · tumor microenvironment · cell signaling pathways · cancer therapy

Abstract ​

Extracellular proteolysis mediates tissue homeostasis. In cancer, altered proteolysis leads to unregulated tumor growth, tissue remodeling, inflammation, tissue invasion, and metastasis. The matrix metalloproteinases (MMPs) represent the most prominent family of proteinases associated with tumorigenesis. Recent technological developments have markedly advanced our understanding of MMPs as modulators of the tumor microenvironment. In addition to their role in extracellular matrix turnover and cancer cell migration, MMPs regulate signaling pathways that control cell growth, inflammation, or angiogenesis and may even work in a nonproteolytic manner. These aspects of MMP function are reorienting our approaches to cancer therapy.

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Primary Questions Addressed ​

  1. How do matrix metalloproteinases influence the immune response within the tumor microenvironment?
  2. What specific signaling pathways are modulated by matrix metalloproteinases in cancer progression?
  3. In what ways can targeting matrix metalloproteinases enhance the efficacy of existing cancer therapies?
  4. What are the potential nonproteolytic functions of matrix metalloproteinases in tumor biology?
  5. How does the expression of matrix metalloproteinases vary across different cancer types and stages?

Key Findings ​

Research Background and Purpose ​

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that play crucial roles in tissue remodeling, inflammation, and cancer progression. This review discusses the regulatory functions of MMPs within the tumor microenvironment, highlighting their complex roles in tumor growth, metastasis, and interactions with nonmalignant stromal cells. The authors aim to elucidate the dual roles of MMPs as both promoters and suppressors of tumorigenesis and to address the challenges faced in targeting MMPs for cancer therapy.

Main Methods/Materials/Experimental Design ​

The review synthesizes recent advancements in the understanding of MMP functions in cancer, drawing on various studies and technologies. Key methodologies include:

  • Imaging Techniques: Use of non-invasive imaging modalities (e.g., PET, MRI) to assess MMP activity in vivo.
  • Cell Culture and Animal Models: Experiments using xenograft models and cell cultures to investigate MMP activity and its effects on tumor behavior.
  • Biochemical Assays: Analyzing MMP expression and activity in tumor and stromal cells to understand their regulatory mechanisms.

The following flowchart illustrates the key processes involving MMPs in the tumor microenvironment:

Mermaid diagram

Key Results and Findings ​

  1. MMP Functions: MMPs are involved in ECM remodeling, activation of growth factors (e.g., TGF-β), and regulation of signaling pathways that influence cell proliferation and apoptosis.
  2. Dual Roles: MMPs can promote or suppress tumorigenesis depending on the context and the specific MMP involved.
  3. Stromal Interactions: The cellular source of MMPs, primarily from stromal cells like macrophages and fibroblasts, significantly impacts their functional outcomes in the tumor microenvironment.
  4. Imaging Advancements: New imaging techniques have enhanced the ability to visualize MMP activity in tumors, aiding in the assessment of therapeutic efficacy.

Main Conclusions/Significance/Innovation ​

The review emphasizes that MMPs are not merely degradative enzymes but are pivotal regulators of the tumor microenvironment. Their roles in modulating inflammation, cell signaling, and the ECM underscore the complexity of cancer biology. The findings advocate for a nuanced approach to targeting MMPs in cancer therapy, suggesting that specific inhibitors may be more effective than broad-spectrum MMP inhibitors, which have shown limited success in clinical trials.

Research Limitations and Future Directions ​

  • Complexity of MMP Roles: The multifunctional nature of MMPs complicates therapeutic targeting, as they can exhibit both pro- and anti-tumor effects.
  • Clinical Trials: Previous clinical trials with MMP inhibitors have often failed, necessitating better design and timing of interventions.
  • Future Research: Further studies are needed to explore the specific contexts in which MMPs promote or inhibit tumor progression, and to develop targeted therapies that can effectively modulate their activity without adverse effects. Additionally, enhancing imaging techniques to better understand MMP dynamics in vivo could lead to more effective therapeutic strategies.

References ​

  1. Visualizing stromal cell dynamics in different tumor microenvironments by spinning disk confocal microscopy. - Mikala Egeblad;Andrew J Ewald;Hanne A Askautrud;Morgan L Truitt;Bryan E Welm;Emma Bainbridge;George Peeters;Matthew F Krummel;Zena Werb - Disease models & mechanisms (2008)
  2. Matrix crosslinking forces tumor progression by enhancing integrin signaling. - Kandice R Levental;Hongmei Yu;Laura Kass;Johnathon N Lakins;Mikala Egeblad;Janine T Erler;Sheri F T Fong;Katalin Csiszar;Amato Giaccia;Wolfgang Weninger;Mitsuo Yamauchi;David L Gasser;Valerie M Weaver - Cell (2009)
  3. The ADAM metalloproteinases. - Dylan R Edwards;Madeleine M Handsley;Caroline J Pennington - Molecular aspects of medicine (2008)
  4. Tissue resident stem cells produce CCL5 under the influence of cancer cells and thereby promote breast cancer cell invasion. - Severin Pinilla;Eckhard Alt;F J Abdul Khalek;Constantin Jotzu;Fabian Muehlberg;Christoph Beckmann;Yao-Hua Song - Cancer letters (2009)
  5. ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death. - M Schulte;K Reiss;M Lettau;T Maretzky;A Ludwig;D Hartmann;B de Strooper;O Janssen;P Saftig - Cell death and differentiation (2007)
  6. Loss of collagenase-2 confers increased skin tumor susceptibility to male mice. - Milagros Balbín;Antonio Fueyo;Angus M Tester;Alberto M Pendás;Ana S Pitiot;Aurora Astudillo;Christopher M Overall;Steven D Shapiro;Carlos López-Otín - Nature genetics (2003)
  7. Lymphatic metastasis in the absence of functional intratumor lymphatics. - Timothy P Padera;Ananth Kadambi;Emmanuelle di Tomaso;Carla Mouta Carreira;Edward B Brown;Yves Boucher;Noah C Choi;Douglas Mathisen;John Wain;Eugene J Mark;Lance L Munn;Rakesh K Jain - Science (New York, N.Y.) (2002)
  8. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. - Jennifer M Burns;Bretton C Summers;Yu Wang;Anita Melikian;Rob Berahovich;Zhenhua Miao;Mark E T Penfold;Mary Jean Sunshine;Dan R Littman;Calvin J Kuo;Kevin Wei;Brian E McMaster;Kim Wright;Maureen C Howard;Thomas J Schall - The Journal of experimental medicine (2006)
  9. Direct visualization of protease activity on cells migrating in three-dimensions. - Beverly Z Packard;Vira V Artym;Akira Komoriya;Kenneth M Yamada - Matrix biology : journal of the International Society for Matrix Biology (2009)
  10. Modeling lymphangiogenesis in a three-dimensional culture system. - Françoise Bruyère;Laurence Melen-Lamalle;Silvia Blacher;Guy Roland;Marc Thiry;Lieve Moons;Francis Frankenne;Peter Carmeliet;Kari Alitalo;Claude Libert;Jonathan P Sleeman;Jean-Michel Foidart;Agnès Noël - Nature methods (2008)

Literatures Citing This Work ​

  1. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion. - Dimitra Bourboulia;William G Stetler-Stevenson - Seminars in cancer biology (2010)
  2. Internal cleavages of the autoinhibitory prodomain are required for membrane type 1 matrix metalloproteinase activation, although furin cleavage alone generates inactive proteinase. - Vladislav S Golubkov;Piotr Cieplak;Alexei V Chekanov;Boris I Ratnikov;Alexander E Aleshin;Natalya V Golubkova;Tatiana I Postnova;Ilian A Radichev;Dmitri V Rozanov;Wenhong Zhu;Khatereh Motamedchaboki;Alex Y Strongin - The Journal of biological chemistry (2010)
  3. Cholesterol sulfate alters substrate preference of matrix metalloproteinase-7 and promotes degradations of pericellular laminin-332 and fibronectin. - Kazuhiro Yamamoto;Kaoru Miyazaki;Shouichi Higashi - The Journal of biological chemistry (2010)
  4. Tumorigenic and adhesive properties of heparanase. - Flonia Levy-Adam;Neta Ilan;Israel Vlodavsky - Seminars in cancer biology (2010)
  5. Tumors as organs: complex tissues that interface with the entire organism. - Mikala Egeblad;Elizabeth S Nakasone;Zena Werb - Developmental cell (2010)
  6. [EMMPRIN (CD147). A prognostic and potentially therapeutic marker in urothelial cancer]. - R Nawroth;A Hartmann;P Wild;J Lehmann;R Stöhr;J E Gschwend;M Retz - Der Pathologe (2010)
  7. Activity-based protein profiling for biochemical pathway discovery in cancer. - Daniel K Nomura;Melissa M Dix;Benjamin F Cravatt - Nature reviews. Cancer (2010)
  8. TLR2-mediated expansion of MDSCs is dependent on the source of tumor exosomes. - Xiaoyu Xiang;Yuelong Liu;Xiaoyin Zhuang;Shuangqin Zhang;Sue Michalek;Douglas D Taylor;William Grizzle;Huang-Ge Zhang - The American journal of pathology (2010)
  9. The Wnt/planar cell polarity protein-tyrosine kinase-7 (PTK7) is a highly efficient proteolytic target of membrane type-1 matrix metalloproteinase: implications in cancer and embryogenesis. - Vladislav S Golubkov;Alexei V Chekanov;Piotr Cieplak;Alexander E Aleshin;Andrei V Chernov;Wenhong Zhu;Ilian A Radichev;Danhua Zhang;P Duc Dong;Alex Y Strongin - The Journal of biological chemistry (2010)
  10. Inhibition of matrix metalloproteinases in Siberian hamsters impedes photostimulated recrudescence of ovaries. - Julie Whited;Asha Shahed;Carling F McMichael;Kelly A Young - Reproduction (Cambridge, England) (2010)

... (2363 more literatures)

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