Trends in Cell Biology
ReviewFeature ReviewBreaching the basement membrane: who, when and how?
Introduction
Early in development, animals ranging from flies to humans direct the embryonic epithelium to orchestrate the organization of an extracellular, supramolecular network of proteins, glycoproteins and proteoglycans, termed the basement membrane (BM) 1, 2, 3. This conglomerate of structural macromolecules coalesces to form a dense, 100–300 nm-thick lamina that underlies all epithelia and, in higher organisms, ensheaths endothelial cells, nerves, smooth muscle cells and adipocytes 1, 4, 5. The assembled BM provides adherent cells with structural support and functional cues by virtue of its biomechanical properties, display of adhesion receptor ligands and repertoire of matrix-bound growth factors 4, 6. With a pore size in the order of 50 nm, only small molecules are able to passively diffuse across this thin, but structurally rugged, barrier 6, 7, 8. Nonetheless, normal cells are able to traffic freely and rapidly across BMs by activating tissue-invasive programs during morphogenesis and immune surveillance 9, 10, 11, 12, 13. Furthermore, in a repetitive theme familiar to biologists, cell populations participating in pathologic events such as cancer can inappropriately co-opt ‘normal’ BM-transmigration programs to dire and, most often, lethal consequences by driving the metastatic process [14].
The transmigration of cells across the BM has an unquestionably important role in normal and neoplastic events and has been the subject of thousands of reports – not to mention innumerable reviews – in the literature 1, 2, 3, 6, 14. Nevertheless, it probably comes as a surprise that the mechanisms that enable cells to cross this structural barrier remain largely unknown and the subject of considerable debate. Whereas the ability of a migrating cell to perforate the BM has been almost uniformly ascribed to proteolytic events, >500 proteinases are encoded within the mammalian genome, thus complicating efforts to identify a subset of crucial, matrix-degrading enzymes [15]. As such, using various model constructs designed to recapitulate BM structure in vitro, most investigators have, over the past 20 years, accepted a largely circumstantial premise that secreted proteinases directly regulate transmigration in both physiologic and pathologic states 16, 17, 18. Very recently, however, evidence has begun to accumulate indicating that accepted dogma might now be ripe for revisiting 1, 19, 20, 21. New insights into BM assembly and structure have raised serious concerns regarding the use of most of the in vitro models used for analyzing invasion 22, 23, 24. Furthermore, in vivo studies of mice harboring inactivating mutations of proteinases commonly implicated as the ‘usual suspects’ in BM transmigration seldom seem to exhibit frank defects in BM invasion-associated events 25, 26, 27, 28. Instead, recent studies support the contention that a small subset of membrane-anchored metalloproteases assumes a previously unrecognized role in this process [21]. Although we would be pleased to inform readers that solutions to all queries regarding BM invasion programs lie within this perspective, this is far from the case and continued efforts are required to build a definitive model of BM transmigration. Rather, it is our intent to highlight existing conundrums and caveats in the field, to pose possible solutions as to the means by which normal and neoplastic cells traverse BM barriers and to outline experimental systems in which these hypotheses might be evaluated and tested in rigorous fashion.
Section snippets
BM structure
Comprising >50 distinct macromolecules, the predominant components of BMs are intertwined meshworks of polymeric laminin and type IV collagen (see Glossary) 2, 3, 4, 6. Distinct from all other BM constituents, only laminin and type IV collagen are able to self-assemble into polymers [4]. Until recently, most models of BM organization assumed that type IV collagen serves as the major scaffolding upon which the laminin network is deposited. Newer studies indicate, however, that laminin polymers
When do cells cross BMs?
Multiple cell types traverse BM barriers in the course of developmental, inflammatory, fibrotic and neoplastic processes (Figure 2). During mammalian development, the early embryo consists of two apposed layers of epithelial cells. With the inception of gastrulation, genesis of the third germ layer (the mesoderm) occurs when epithelial cells at the primitive streak adopt mesenchymal (i.e. fibroblast-like) characteristics and penetrate the underlying BM to populate the intervening space 11, 12,
Mechanisms of BM transmigration: an introduction
To probe the mechanisms underlying BM transmigration, it must first be asked: what are the properties of BMs and the associated invasive cell populations that influence the transmigration process? From a structural perspective, the migrating cell will be confronted with a semi-permeable, type-IV-collagen-rich barrier, the pore size of which is dictated by both extracellular matrix (ECM) density and crosslinking 5, 21, 43. In turn, the degree to which the cell can deform its cytoplasm and
Breaking down the door: protease-dependent BM transmigration
Evidence for proteolytic BM destruction during transmigration is supported by the observation that tissue-invasive events associated with developmental and disease states are characterized frequently by irreversible changes in BM structure 1, 12, 13, 21, 38, 39. During development in worms, flies and mammals, BM effacement is commonly observed at sites of invasion (e.g. within the vulva in C. elegans and the primitive streak in mammals) 1, 19, 20. Similarly, BM discontinuities have been
Opening the door: non-proteolytic BM transmigration
Clearly, proteinases, especially MT-MMPs, can function as crucial regulators of transmigration by degrading BM-associated structural barriers and generating a conduit through which normal and malignant epithelial cells can pass. By contrast, are there any BM-transmigration events wherein proteolysis is dispensable?
Recently, non-proteolytic means of cell invasion have been reported using Matrigel as a BM surrogate 103, 130, 131. Carcinoma cells are capable of invading Matrigel matrices using a
Concluding remarks and future perspectives
Despite the obvious strengths of in vitro models, the full repertoire of proteolytic and non-proteolytic systems available to normal or neoplastic cells might only be accessible in vivo. As such, additional insights into the role of MT-MMPs in BM transmigration will be gleaned from further analyses of gene-targeted mice. Whereas many developmental BM-invasive events are intact in both Mmp14 and Mmp16 (MT3-MMP) mutant mice 165, 166, current studies indicate that the expression of either MT1-MMP,
Glossary
- Anchor cell
- a specialized cell in C. elegans that invades the vulval epithelium and crosses the underlying BM during normal worm development.
- Basement membrane
- a specialized form of extracellular matrix comprised of an interwoven mixture of type IV collagen, laminins, nidogen and sulfated proteoglycans that lies beneath epithelial and endothelial cells and surrounds muscles, nerves, adipocytes and smooth muscle cells.
- Branching morphogenesis
- during development and angiogenesis, the formation of a
References (173)
Cell invasion through basement membranes: an anchor of understanding
Trends Cell Biol.
(2006)Basement membrane assembly, stability and activities observed through a developmental lens
Matrix Biol.
(2004)Regulation of mesodermal differentiation of mouse embryonic stem cells by basement membranes
J. Biol. Chem.
(2007)Tumor invasion through the human amniotic membrane: requirement for a proteinase cascade
Cell
(1986)Basement membrane pores in human bronchial epithelium: a conduit for infiltrating cells?
Am. J. Pathol.
(2001)Identification of S-hydroxylysyl-methionine as the covalent cross-link of the noncollagenous (NC1) hexamer of the α1α1α2 collagen IV network: a role for the post-translational modification of lysine 211 to hydroxylysine 211 in hexamer assembly
J. Biol. Chem.
(2005)Physiological levels of tumstatin, a fragment of collagen IV α3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via αV β3 integrin
Cancer Cell
(2003)Role of laminin terminal globular domains in basement membrane assembly
J. Biol. Chem.
(2007)A role for collagen IV cross-links in conferring immune privilege to the goodpasture autoantigen: structural basis for the crypticity of b cell epitopes
J. Biol. Chem.
(2008)A transient, EMT-linked loss of basement membranes indicates metastasis and poor survival in colorectal cancer
Gastroenterology
(2006)
Wnt signaling induces matrix metalloproteinase expression and regulates T cell transmigration
Immunity
Neutrophil motility in extracellular matrix gels: mesh size and adhesion affect speed of migration
Biophys. J.
The urokinase plasminogen activator receptor as a gene therapy target for cancer
Trends Biotechnol.
Tales from the crypt[ic] sites of the extracellular matrix
Trends Cell Biol.
Activation and silencing of matrix metalloproteinases
Semin. Cell Dev. Biol.
The recognition sites of the integrins α1β1 and α2β1 within collagen IV are protected against gelatinase A attack in the native protein
J. Biol. Chem.
Evidence of in situ stability of the type IV collagen triple helix in human inflammatory bowel disease using a denaturation specific epitope antibody
Matrix Biol.
Studies on the ability of 65-kDa and 92-kDa tumor cell gelatinases to degrade type IV collagen
J. Biol. Chem.
Nonenzymatic glycation of type IV collagen and matrix metalloproteinase susceptibility
Kidney Int.
Non-helical type IV collagen polypeptides in human placenta
Biochem. Biophys. Res. Commun.
MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes
Cell
A crucial role for matrix metalloproteinase 2 in osteocytic canalicular formation and bone metabolism
J. Biol. Chem.
Proteomics discovery of metalloproteinase substrates in the cellular context by iTRAQ labeling reveals a diverse MMP-2 substrate degradome
Mol. Cell. Proteomics
Amniotic basement membrane: a barrier to neutrophil invasion
Am. J. Obstet. Gynecol.
Matrigel: basement membrane matrix with biological activity
Semin. Cancer Biol.
Laminin α1-chain shows a restricted distribution in epithelial basement membranes of fetal and adult human tissues
Exp. Cell Res.
Cell migration in 3D matrix
Curr. Opin. Cell Biol.
Membrane-type matrix metalloproteinase-1 (MT1-MMP) is a processing enzyme for human laminin γ 2 chain
J. Biol. Chem.
Mammalian collagen IV
Microsc. Res. Tech.
Alport’s syndrome, Goodpasture’s syndrome, and type IV collagen
N. Engl. J. Med.
Biomechanical properties of native basement membranes
FEBS J.
Basement membranes: structure, assembly and role in tumour angiogenesis
Nat. Rev. Cancer
Nanoscale topography of the corneal epithelial basement membrane and Descemet’s membrane of the human
Cornea
Nanoscale topography of the basement membrane underlying the corneal epithelium of the rhesus macaque
Cell Tissue Res.
Disruption of the subendothelial basement membrane during neutrophil diapedesis in an in vitro construct of a blood vessel wall
J. Clin. Invest.
Getting to the site of inflammation: the leukocyte adhesion cascade updated
Nat. Rev. Immunol.
Morphology of incipient mesoderm formation in the rabbit embryo: a light- and retrospective electron-microscopic study
Acta Anat. (Basel)
Epithelio-mesenchymal transformation during formation of the mesoderm in the mammalian embryo
Acta Anat. (Basel)
New signals from the invasive front
Nature
Human and mouse proteases: a comparative genomic approach
Nat. Rev. Genet.
Metastatic potential correlates with enzymatic degradation of basement membrane collagen
Nature
Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases
Nat. Rev. Drug Discov.
Matrix metalloproteinases and the regulation of tissue remodelling
Nat. Rev. Mol. Cell Biol.
Basement membrane remodeling is essential for Drosophila disc eversion and tumor invasion
Proc. Natl. Acad. Sci. U. S. A.
A cancer cell metalloprotease triad regulates the basement membrane transmigration program
Genes Dev.
The 1.9-A crystal structure of the noncollagenous (NC1) domain of human placenta collagen IV shows stabilization via a novel type of covalent Met-Lys cross-link
Proc. Natl. Acad. Sci. U. S. A.
Matrix metalloproteinases 2 and 9 are dispensable for pancreatic islet formation and function in vivo
Diabetes
Matrix metalloproteinase-2 and -9 expression increases in Mycoplasma-infected airways but is not required for microvascular remodeling
Am. J. Physiol. Lung Cell. Mol. Physiol.
The role of matrix metalloproteinase-2 and matrix metalloproteinase-9 in antibody-induced arthritis
J. Immunol.
Laminin-sulfatide binding initiates basement membrane assembly and enables receptor signaling in Schwann cells and fibroblasts
J. Cell Biol.
Cited by (366)
Correlation between hypoxia and HGF/c-MET expression in the management of pancreatic cancer
2023, Biochimica et Biophysica Acta - Reviews on CancerMimicking the Natural Basement Membrane for Advanced Tissue Engineering
2022, Biomacromolecules