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Autocrine epidermal growth factor signaling stimulates directionally persistent mammary epithelial cell migration.

Maheshwari G, Wiley HS, Lauffenburger DA - J. Cell Biol. (2001)

Bottom Line: The possibly diverse effect of presenting a growth factor in autocrine as opposed to exogenous (or paracrine) mode is an especially important issue in cell biology.Addition of exogenous EGF to these cells abrogates their enhanced directional persistence, reducing their directionality to a level similar to wild-type cells.These findings emphasize the functional importance of spatial restriction of EGFR signaling, and suggest critical implications for growth factor-based therapeutic treatments.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

ABSTRACT
Cell responses to soluble regulatory factors may be strongly influenced by the mode of presentation of the factor, as in matrix-bound versus diffusible modes. The possibly diverse effect of presenting a growth factor in autocrine as opposed to exogenous (or paracrine) mode is an especially important issue in cell biology. We demonstrate here that migration behavior of human mammary epithelial cells in response to stimulation by epidermal growth factor (EGF) is qualitatively different for EGF presented in exogenous (paracrine), autocrine, and intracrine modes. When EGF is added as an exogenous factor to the medium of cells that express EGF receptor (EGFR) but not EGF, cell migration speed increases while directional persistence decreases. When these EGFR-expressing cells are made to also express via retroviral transfection EGF in protease-cleaveable transmembrane form on the plasma membrane, migration speed similarly increases, but directional persistence increases as well. Addition of exogenous EGF to these cells abrogates their enhanced directional persistence, reducing their directionality to a level similar to wild-type cells. If the EGFR-expressing cells are instead transduced with a gene encoding EGF in a soluble form, migration speed and directional persistence were unaffected. Thus, autocrine presentation of EGF at the plasma membrane in a protease-cleavable form provides these cells with an enhanced ability to migrate persistently in a given direction, consistent with their increased capability for organizing into gland-like structures. In contrast, an exogenous/paracrine mode of EGF presentation generates a "scattering" response by the cells. These findings emphasize the functional importance of spatial restriction of EGFR signaling, and suggest critical implications for growth factor-based therapeutic treatments.

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Effect of ligand presentation on cell tracks of EGF-Ct expressing cells. (A) Typical cell paths of cells expressing EGF-Ct in the absence of exogenously added EGF. Paths are of cells tracked over a period of 4–5 h and are replotted such that all paths start from the origin. (B) Cell paths of EGF-Ct–expressing cells in the presence of 2 nM exogenously added EGF. Cells shown in A and B have the same average cell speed, but have significantly different patterns of motion.
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fig3: Effect of ligand presentation on cell tracks of EGF-Ct expressing cells. (A) Typical cell paths of cells expressing EGF-Ct in the absence of exogenously added EGF. Paths are of cells tracked over a period of 4–5 h and are replotted such that all paths start from the origin. (B) Cell paths of EGF-Ct–expressing cells in the presence of 2 nM exogenously added EGF. Cells shown in A and B have the same average cell speed, but have significantly different patterns of motion.

Mentions: In addition to effects on cell migration speed, EGF can strongly affect persistence of directionality (Ware et al., 1998). Such effects can be visualized qualitatively by reproducing sample cell movement paths on windrose plots (see Fig. 3). Fig. 3 A shows that EGF-Ct–expressing cells appear to travel in significantly more persistent paths in comparison to their paths in the presence of exogenous added EGF in Fig. 3 B. However, the mean speed of migration for the cells under these two conditions are not significantly different (Fig. 2).


Autocrine epidermal growth factor signaling stimulates directionally persistent mammary epithelial cell migration.

Maheshwari G, Wiley HS, Lauffenburger DA - J. Cell Biol. (2001)

Effect of ligand presentation on cell tracks of EGF-Ct expressing cells. (A) Typical cell paths of cells expressing EGF-Ct in the absence of exogenously added EGF. Paths are of cells tracked over a period of 4–5 h and are replotted such that all paths start from the origin. (B) Cell paths of EGF-Ct–expressing cells in the presence of 2 nM exogenously added EGF. Cells shown in A and B have the same average cell speed, but have significantly different patterns of motion.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199328&req=5

fig3: Effect of ligand presentation on cell tracks of EGF-Ct expressing cells. (A) Typical cell paths of cells expressing EGF-Ct in the absence of exogenously added EGF. Paths are of cells tracked over a period of 4–5 h and are replotted such that all paths start from the origin. (B) Cell paths of EGF-Ct–expressing cells in the presence of 2 nM exogenously added EGF. Cells shown in A and B have the same average cell speed, but have significantly different patterns of motion.
Mentions: In addition to effects on cell migration speed, EGF can strongly affect persistence of directionality (Ware et al., 1998). Such effects can be visualized qualitatively by reproducing sample cell movement paths on windrose plots (see Fig. 3). Fig. 3 A shows that EGF-Ct–expressing cells appear to travel in significantly more persistent paths in comparison to their paths in the presence of exogenous added EGF in Fig. 3 B. However, the mean speed of migration for the cells under these two conditions are not significantly different (Fig. 2).

Bottom Line: The possibly diverse effect of presenting a growth factor in autocrine as opposed to exogenous (or paracrine) mode is an especially important issue in cell biology.Addition of exogenous EGF to these cells abrogates their enhanced directional persistence, reducing their directionality to a level similar to wild-type cells.These findings emphasize the functional importance of spatial restriction of EGFR signaling, and suggest critical implications for growth factor-based therapeutic treatments.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

ABSTRACT
Cell responses to soluble regulatory factors may be strongly influenced by the mode of presentation of the factor, as in matrix-bound versus diffusible modes. The possibly diverse effect of presenting a growth factor in autocrine as opposed to exogenous (or paracrine) mode is an especially important issue in cell biology. We demonstrate here that migration behavior of human mammary epithelial cells in response to stimulation by epidermal growth factor (EGF) is qualitatively different for EGF presented in exogenous (paracrine), autocrine, and intracrine modes. When EGF is added as an exogenous factor to the medium of cells that express EGF receptor (EGFR) but not EGF, cell migration speed increases while directional persistence decreases. When these EGFR-expressing cells are made to also express via retroviral transfection EGF in protease-cleaveable transmembrane form on the plasma membrane, migration speed similarly increases, but directional persistence increases as well. Addition of exogenous EGF to these cells abrogates their enhanced directional persistence, reducing their directionality to a level similar to wild-type cells. If the EGFR-expressing cells are instead transduced with a gene encoding EGF in a soluble form, migration speed and directional persistence were unaffected. Thus, autocrine presentation of EGF at the plasma membrane in a protease-cleavable form provides these cells with an enhanced ability to migrate persistently in a given direction, consistent with their increased capability for organizing into gland-like structures. In contrast, an exogenous/paracrine mode of EGF presentation generates a "scattering" response by the cells. These findings emphasize the functional importance of spatial restriction of EGFR signaling, and suggest critical implications for growth factor-based therapeutic treatments.

Show MeSH
Related in: MedlinePlus