Biology of tumor cell invasion: Interplay of cell adhesion and matrix degradation

Tumor cell migration and the concomitant degradation of extracellular matrix (ECM) are two essential steps in the metastatic process. It is well established that focal adhesions (FAs) play an important role in regulating migration; however, whether these structures contribute to matrix degradation is not clear. In this study, we report that multiple cancer cell lines display degradation of ECM at FA sites that requires the targeted action of MT1-MMP. Importantly, we have found that this MT1-MMP targeting is dependent on an association with a FAK–p130Cas complex situated at FAs and is regulated by Src-mediated phosphorylation of Tyr 573 at the cytoplasmic tail of MT1. Disrupting the FAK–p130Cas–MT1 complex significantly impairs FA-mediated degradation and tumor cell invasion yet does not appear to affect invadopodia formation or function. These findings demonstrate a novel function for FAs and also provide molecular insights into MT1-MMP targeting and function.

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Characterization of a synthetic peptide from type IV collagen that promotes melanoma cell adhesion, spreading, and motility.

The Journal of Cell Biology ◽

10.1083/jcb.111.1.261 ◽

1990 ◽

Vol 111 (1) ◽

pp. 261-270 ◽

Cited By ~ 76

Author(s):

M K Chelberg ◽

J B McCarthy ◽

A P Skubitz ◽

L T Furcht ◽

E C Tsilibary

Keyword(s):

Cell Adhesion ◽

Tumor Cell ◽

Melanoma Cell ◽

Cell Invasion ◽

Synthetic Peptide ◽

Type Iv Collagen ◽

Cell Types ◽

Tumor Cell Invasion ◽

Type Iv

The adhesion and motility of tumor cells on basement membranes is a central consideration in tumor cell invasion and metastasis. Basement membrane type IV collagen directly promotes the adhesion and migration of various tumor cell types in vitro. Our previous studies demonstrated that tumor cells adhered and spread on surfaces coated with intact type IV collagen or either of the two major enzymatically purified domains of this protein. Only one of these major domains, the pepsin-generated major triple helical fragment, also supported tumor cell motility in vitro, implicating the involvement of the major triple helical region in type IV collagen-mediated tumor cell invasion in vivo. The present studies extend our previous observations using a synthetic peptide approach. A peptide, designated IV-H1, was derived from a continuous collagenous region of the major triple helical domain of the human alpha 1(IV) chain. This peptide, which has the sequence GVKGDKGNPGWPGAP, directly supported the adhesion, spreading, and motility of the highly metastatic K1735 M4 murine melanoma cell line, as well as the adhesion and spreading of other cell types, in a concentration-dependent manner in vitro. Furthermore, excess soluble peptide IV-H1, or polyclonal antibodies directed against peptide IV-H1, inhibited type IV collagen-mediated melanoma cell adhesion, spreading, and motility, but had no effect on these cellular responses to type I collagen. The full complement of cell adhesion, spreading, and motility promoting activities was dependent upon the preservation of the three prolyl residues in the peptide IV-H1 sequence. These studies indicate that peptide IV-H1 represents a cell-specific adhesion, spreading, and motility promoting domain that is active within the type IV collagen molecule.

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Inhibition of Tumor Cell Invasion and Matrix Degradation by Aminopeptidase Inhibitors.

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.19.6 ◽

1996 ◽

Vol 19 (1) ◽

pp. 6-10 ◽

Cited By ~ 27

Author(s):

Hideji FUJII ◽

Motowo NAKAJIMA ◽

Takaaki AOYAGI ◽

Takashi TSURUO

Keyword(s):

Tumor Cell ◽

Cell Invasion ◽

Tumor Cell Invasion ◽

Matrix Degradation ◽

Aminopeptidase Inhibitors

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Disruption of STAT3 signaling leads to tumor cell invasion through alterations of homotypic cell–cell adhesion complexes

Oncogene ◽

10.1038/sj.onc.1207437 ◽

2004 ◽

Vol 23 (19) ◽

pp. 3317-3327 ◽

Cited By ~ 32

Author(s):

Christine Rivat ◽

Olivier De Wever ◽

Erik Bruyneel ◽

Marc Mareel ◽

Christian Gespach ◽

...

Keyword(s):

Cell Adhesion ◽

Tumor Cell ◽

Cell Invasion ◽

Tumor Cell Invasion ◽

Stat3 Signaling ◽

Cell Cell

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α1 and α2 Integrins Mediate Invasive Activity of Mouse Mammary Carcinoma Cells through Regulation of Stromelysin-1 Expression

Molecular Biology of the Cell ◽

10.1091/mbc.10.2.271 ◽

1999 ◽

Vol 10 (2) ◽

pp. 271-282 ◽

Cited By ~ 60

Author(s):

André Lochter ◽

Marc Navre ◽

Zena Werb ◽

Mina J. Bissell

Keyword(s):

Cell Migration ◽

Cell Adhesion ◽

Basement Membrane ◽

Tumor Cell ◽

Cell Invasion ◽

Mammary Carcinoma ◽

Carcinoma Cells ◽

Tumor Cell Invasion ◽

Mouse Mammary Carcinoma ◽

Mammary Carcinoma Cells

Tumor cell invasion relies on cell migration and extracellular matrix proteolysis. We investigated the contribution of different integrins to the invasive activity of mouse mammary carcinoma cells. Antibodies against integrin subunits α6 and β1, but not against α1 and α2, inhibited cell locomotion on a reconstituted basement membrane in two-dimensional cell migration assays, whereas antibodies against β1, but not against α6 or α2, interfered with cell adhesion to basement membrane constituents. Blocking antibodies against α1 integrins impaired only cell adhesion to type IV collagen. Antibodies against α1, α2, α6, and β1, but not α5, integrin subunits reduced invasion of a reconstituted basement membrane. Integrins α1 and α2, which contributed only marginally to motility and adhesion, regulated proteinase production. Antibodies against α1 and α2, but not α6 and β1, integrin subunits inhibited both transcription and protein expression of the matrix metalloproteinase stromelysin-1. Inhibition of tumor cell invasion by antibodies against α1 and α2 was reversed by addition of recombinant stromelysin-1. In contrast, stromelysin-1 could not rescue invasion inhibited by anti-α6 antibodies. Our data indicate that α1 and α2 integrins confer invasive behavior by regulating stromelysin-1 expression, whereas α6 integrins regulate cell motility. These results provide new insights into the specific functions of integrins during tumor cell invasion.

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LIMK Regulates Tumor-Cell Invasion and Matrix Degradation Through Tyrosine Phosphorylation of MT1-MMP

Scientific Reports ◽

10.1038/srep24925 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 34

Author(s):

Emilie Lagoutte ◽

Clémentine Villeneuve ◽

Laurence Lafanechère ◽

Claire M. Wells ◽

Gareth E. Jones ◽

...

Keyword(s):

Tumor Cell ◽

Tyrosine Phosphorylation ◽

Cell Invasion ◽

Tumor Cell Invasion ◽

Matrix Degradation

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Actin-associated protein palladin promotes tumor cell invasion by linking extracellular matrix degradation to cell cytoskeleton

Molecular Biology of the Cell ◽

10.1091/mbc.e13-11-0667 ◽

2014 ◽

Vol 25 (17) ◽

pp. 2556-2570 ◽

Cited By ~ 33

Author(s):

Pernilla von Nandelstadh ◽

Erika Gucciardo ◽

Jouko Lohi ◽

Rui Li ◽

Nami Sugiyama ◽

...

Keyword(s):

Extracellular Matrix ◽

Tumor Cell ◽

Protein Interaction ◽

Cell Invasion ◽

Dominant Negative ◽

Tumor Cell Invasion ◽

Matrix Degradation ◽

Breast Carcinomas ◽

Mesenchymal Transition ◽

Extracellular Matrix Degradation

Basal-like breast carcinomas, characterized by unfavorable prognosis and frequent metastases, are associated with epithelial-to-mesenchymal transition. During this process, cancer cells undergo cytoskeletal reorganization and up-regulate membrane-type 1 matrix metalloproteinase (MT1-MMP; MMP14), which functions in actin-based pseudopods to drive invasion by extracellular matrix degradation. However, the mechanisms that couple matrix proteolysis to the actin cytoskeleton in cell invasion have remained unclear. On the basis of a yeast two-hybrid screen for the MT1-MMP cytoplasmic tail-binding proteins, we identify here a novel Src-regulated protein interaction between the dynamic cytoskeletal scaffold protein palladin and MT1-MMP. These proteins were coexpressed in invasive human basal-like breast carcinomas and corresponding cell lines, where they were associated in the same matrix contacting and degrading membrane complexes. The silencing and overexpression of the 90-kDa palladin isoform revealed the functional importance of the interaction with MT1-MMP in pericellular matrix degradation and mesenchymal tumor cell invasion, whereas in MT1-MMP–negative cells, palladin overexpression was insufficient for invasion. Moreover, this invasion was inhibited in a dominant-negative manner by an immunoglobulin domain–containing palladin fragment lacking the dynamic scaffold and Src-binding domains. These results identify a novel protein interaction that links matrix degradation to cytoskeletal dynamics and migration signaling in mesenchymal cell invasion.

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