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Monoclonal antibody and synthetic peptide inhibitors of human tumor cell migration
K M Yamada1, D W Kennedy, S S Yamada
1Membrane Biochemistry Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Abstract:
The processes of migration and invasion by human tumor cells are likely to involve specific cell surface receptors, such as receptors for the extracellular matrix molecules fibronectin, laminin, and collagen. We have examined the roles of several of these receptors using a set of monoclonal antibodies directed against the beta 1 integrin family, as well as a series of synthetic peptides reported to inhibit various interactions of each of these proteins with the cell surface. The most general inhibitor of tumor cell migration was found to be the anti-beta 1 monoclonal antibody 13, which inhibited the migration of human HT-1080 fibrosarcoma cells, 5637 bladder carcinoma cells, VA13 viral transformants, and HCT 116 colon carcinoma cells when fibronectin was the migration substrate. Moreover, this antibody was particularly effective in blocking cell migration on laminin, as well as migration within 3-dimensional collagen gels. It also inhibited in vitro invasiveness in a reconstituted basement membrane invasion assay (Matrigel assay) at concentrations as low as 1 microgram/ml. Integrins of the beta 1 class thus appear to play a central role in several types of migration by a variety of human tumor cell lines. Anti-alpha 5 fibronectin receptor monoclonal antibody 16 also significantly inhibited migration on fibronectin, but not on other substrates, in 3 of the 4 cell lines. Conversely, anti-alpha 2 monoclonal antibody F17 strikingly inhibited migration in 3-dimensional collagen gels, but not on other substrates, implicating the alpha 2 beta 1 integrin system in migration of tumor cells within collagenous matrices. A series of synthetic peptides previously reported to inhibit interactions of normal cells with fibronectin, laminin, and collagen were also tested as inhibitors of tumor cell migration. Peptides containing the Arg-Gly-Asp adhesive recognition signal were partially inhibitory, but with occasional exceptions, most other peptides had no effects on migration. Our results indicate the central importance of several specific beta 1 integrins in human tumor cell migration and show the effectiveness of monoclonal antibody treatment in blocking this process in vitro.
Insights
Beta 1 integrins are crucial for human tumor cell migration and invasion. Monoclonal antibodies targeting these integrins effectively block tumor cell movement and invasion in vitro.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Tumor cell migration and invasion are complex processes.
- Cell surface receptors, particularly integrins, mediate interactions with the extracellular matrix (ECM).
- Understanding these interactions is key to developing anti-cancer therapies.
Purpose of the Study:
- To investigate the role of beta 1 integrins in human tumor cell migration and invasion.
- To evaluate the efficacy of monoclonal antibodies and synthetic peptides in inhibiting these processes.
Main Methods:
- Utilized a panel of monoclonal antibodies against beta 1 integrin family members.
- Employed synthetic peptides known to inhibit integrin-ECM interactions.
- Assessed tumor cell migration on fibronectin, laminin, and collagen substrates.
- Evaluated in vitro invasiveness using a Matrigel invasion assay.
Main Results:
- Anti-beta 1 monoclonal antibody 13 broadly inhibited migration across various cell lines and ECM substrates.
- This antibody also effectively blocked in vitro invasiveness.
- Anti-alpha 5 and anti-alpha 2 antibodies showed substrate-specific inhibition.
- Synthetic peptides with Arg-Gly-Asp motif offered partial inhibition.
Conclusions:
- Beta 1 integrins play a central role in the migration and invasion of diverse human tumor cell lines.
- Monoclonal antibody-based therapies show promise for blocking tumor cell motility and invasiveness.