The Laminin Receptor and Basement Membrane Dissolution: Role in Tumour Metastasis

Liotta, Lance A.; Rao, N C; Barsky, Sanford H.; Bryant, G.

doi:10.1002/9780470720899.ch10

Cited by 19 publications

(11 citation statements)

References 28 publications

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“…Based in part on these observations, inhibitors of matrix metalloproteinases have been used in clinical trials for patients with advanced cancer, though patient survival was not increased 18 . Reduced BM synthesis and changes in composition have also been postulated to underlie localized loss 11,14,23 . To resolve the mechanisms that cells use to overcome BM barriers it is crucial to follow the fate of breached BM in vivo and experimentally examine the removal mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Basement membrane sliding and targeted adhesion remodels tissue boundaries during uterine–vulval attachment in Caenorhabditis elegans

et al. 2011

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Large gaps in basement membrane (BM) occur at sites of cell invasion and tissue remodelling in development and cancer. Though never followed directly in vivo, BM dissolution or reduced synthesis have been postulated to create these gaps. Using landmark photobleaching and optical highlighting of laminin and type IV collagen, we find that a new mechanism, BM sliding, underlies BM gap enlargement during uterine-vulval attachment in C. elegans. Laser ablation and mutant analysis reveal that the invaginating vulval cells promote BM movement. Further, an RNA interference and expression screen identify the integrin INA-1/PAT-3 and VAB-19, homolog of the tumour suppressor Kank, as regulators of BM opening. Both concentrate within vulval cells at the BM gap boundary and halt expansion of the shifting BM. BM sliding followed by targeted adhesion represents a new mechanism for creating precise BM breaches that can be used by cells to break down compartment boundaries.

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Section: Introductionmentioning

confidence: 99%

Basement membrane sliding and targeted adhesion remodels tissue boundaries during uterine–vulval attachment in Caenorhabditis elegans

et al. 2011

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“…The interaction between LamR and laminin mediates changes in the cell environment that affect cell adhesion and tumor growth and metastasis5;6;22;42. We utilized sequence and structure analyses to guide LamR mutagenesis to map a laminin binding site on LamR.…”

Section: Discussionmentioning

confidence: 99%

“…The specific inhibition of LamR interactions with laminin has been shown to elicit anti-tumor effects32;42;47;48. Targeting LamR in the tumor environment may be possible due to a larger percentage of unoccupied LamR sites compared to normal cells, on which laminin binding is saturated22;23;24. Mapping the LamR binding site for laminin may contribute to the development of therapeutics that inhibit LamR interactions with laminin and aid in the prevention of tumor growth and metastasis.…”

Section: Discussionmentioning

confidence: 99%

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Structure-Guided Identification of a Laminin Binding Site on the Laminin Receptor Precursor

Jamieson

Hubbard

Meruelo

2011

Journal of Molecular Biology

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The 37/67 kDa human laminin receptor (LamR) is a cell surface receptor for laminin, prion protein, and a variety of viruses. Because of its wide range of ligands, LamR plays a role in numerous pathologies. LamR overexpression correlates with a highly invasive cell phenotype and increased metastatic ability, mediated by interactions between LamR and laminin. In addition, the specific targeting of LamR with small-interfering RNAs (siRNAs), blocking antibodies, and Sindbis viral vectors confers anti-tumor effects. We adopted a structure-based approach to map a laminin binding site on human LamR, by comparing the sequences and crystal structures of LamR and A. fulgidus S2p, a non-laminin binding ortholog. Here, we identify a laminin binding site on LamR, comprising residues Phe32, Glu35, and Arg155, which are conserved among mammalian species. Mutation of these residues results in a significant loss of laminin binding. Further, recombinant wild-type LamR is able to act as a soluble decoy to inhibit cellular migration toward laminin. Mutation of this laminin binding site results in loss of migration inhibition, which demonstrates the physiological role of Phe32, Glu35, and Arg155 for laminin binding activity. Mapping of the LamR binding site should contribute to the development of therapeutics that inhibit LamR interactions with laminin, and may aid in the prevention of tumor growth and metastasis.

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“…Earlier works determined that these pre-invasive lesions are present and undetected in a percentage of the population as much as ~34–39% for human prostrate and breast lesions respectively [4–6]. These lesions remain quiescent for several decades and in some cases never progress to its fully invasive potential The CIS remains a local aberration as long as the basement membrane (BM) remains intact (Figure 1) [7, 8]. In a review, Bissell et al suggest that “We get more cancer” when the normal tissue architecture can no longer suppress the local malignancy[9].…”

Section: Introductionmentioning

confidence: 99%

Regulation of the basement membrane by epithelia generated forces

Tanner

2012

Phys. Biol.

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Tumor metastasis involves a progressive loss of tissue architecture and dissolution of structural boundaries between the epithelium and connective tissue. The basement membrane (BM), a specialized network of extracellular matrix proteins forms a barrier that physically restricts pre- invasive lesions such that they remain as local insults. The BM is not a static structure, but one that is constantly regenerated and remodeled in the adult organism. Matrix organization also regulates cell function. Thus alterations in the balance of synthesis, remodeling and proteolytic degradation of the extracellular matrix proteins may contribute to a loss of structural integrity. However, the de novo assembly and maintenance of the complex structural properties of in vivo basement membranes remain elusive. Here, this paper highlights the current understanding on the structural properties and the establishment of the BM, and discusses the potential role of self-generated forces in adult tissue remodeling and the maintenance of the BM as a malignancy suppressor.

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The Laminin Receptor and Basement Membrane Dissolution: Role in Tumour Metastasis

Cited by 19 publications

References 28 publications

Basement membrane sliding and targeted adhesion remodels tissue boundaries during uterine–vulval attachment in Caenorhabditis elegans

Basement membrane sliding and targeted adhesion remodels tissue boundaries during uterine–vulval attachment in Caenorhabditis elegans

Structure-Guided Identification of a Laminin Binding Site on the Laminin Receptor Precursor

Regulation of the basement membrane by epithelia generated forces

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