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Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis.

Hazan RB, Phillips GR, Qiao RF, Norton L, Aaronson SA - J. Cell Biol. (2000)

Bottom Line: To determine whether N-cadherin promotes invasion and metastasis, we transfected a weakly metastatic and E-cadherin-expressing breast cancer cell line, MCF-7, with N-cadherin and analyzed the effects on cell migration, invasion, and metastasis.These results demonstrate that N-cadherin promotes motility, invasion, and metastasis even in the presence of the normally suppressive E-cadherin.The increase in MMP-9 production by N-cadherin-expressing cells in response to a growth factor may endow them with a greater ability to penetrate matrix protein barriers, while the increase in their adherence to endothelium may improve their ability to enter and exit the vasculature, two properties that may be responsible for metastasis of N-cadherin-expressing cells.

View Article: PubMed Central - PubMed

Affiliation: The Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine of New York University, New York, New York 10029, USA. rhazan@smtplink.mssm.edu

ABSTRACT
E- and N-cadherin are calcium-dependent cell adhesion molecules that mediate cell-cell adhesion and also modulate cell migration and tumor invasiveness. The loss of E-cadherin-mediated adhesion has been shown to play an important role in the transition of epithelial tumors from a benign to an invasive state. However, recent evidence indicates that another member of the cadherin family, N-cadherin, is expressed in highly invasive tumor cell lines that lacked E-cadherin expression. These findings have raised the possibility that N-cadherin contributes to the invasive phenotype. To determine whether N-cadherin promotes invasion and metastasis, we transfected a weakly metastatic and E-cadherin-expressing breast cancer cell line, MCF-7, with N-cadherin and analyzed the effects on cell migration, invasion, and metastasis. Transfected cells expressed both E- and N-cadherin and exhibited homotypic cell adhesion from both molecules. In vitro, N-cadherin-expressing cells migrated more efficiently, showed an increased invasion of Matrigel, and adhered more efficiently to monolayers of endothelial cells. All cells produced low levels of the matrix metalloproteinase MMP-9, which was dramatically upregulated by treatment with FGF-2 only in N-cadherin-expressing cells. Migration and invasion of Matrigel were also greatly enhanced by this treatment. When injected into the mammary fat pad of nude mice, N-cadherin-expressing cells, but not control MCF-7 cells, metastasized widely to the liver, pancreas, salivary gland, omentum, lung, lymph nodes, and lumbar spinal muscle. The expression of both E- and N-cadherin was maintained both in the primary tumors and metastatic lesions. These results demonstrate that N-cadherin promotes motility, invasion, and metastasis even in the presence of the normally suppressive E-cadherin. The increase in MMP-9 production by N-cadherin-expressing cells in response to a growth factor may endow them with a greater ability to penetrate matrix protein barriers, while the increase in their adherence to endothelium may improve their ability to enter and exit the vasculature, two properties that may be responsible for metastasis of N-cadherin-expressing cells.

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N-cadherin promotes coaggregation of N-cadherin–transfected MCF-7 cells with N-cadherin–transfected L-cells. L-cells and L-E-cadherin and L-N-cadherin cells, labeled with the fluorescent dye diO (green) were coaggregated with diI-labeled (red) MCF-7 cells (A, B, and C, respectively) or N-cad-5 cells (D, E, and F respectively). Yellow appears when green and red are superimposed, indicating coaggregation.
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Figure 2: N-cadherin promotes coaggregation of N-cadherin–transfected MCF-7 cells with N-cadherin–transfected L-cells. L-cells and L-E-cadherin and L-N-cadherin cells, labeled with the fluorescent dye diO (green) were coaggregated with diI-labeled (red) MCF-7 cells (A, B, and C, respectively) or N-cad-5 cells (D, E, and F respectively). Yellow appears when green and red are superimposed, indicating coaggregation.

Mentions: To determine whether the transfected N-cadherin was functionally active in adhesion and whether it interfered with the adhesive function of E-cadherin, parental MCF-7 cells or the N-cad-5 clone, labeled with Fast diO, were mixed and coaggregated either with parental L-cells or with L-cells transfected with either mouse E- (L-E cells) or N-cadherin (L-N cells), which were labeled with Fast diI (Fig. 2). N-Cad-5 cells formed large coaggregates with both L-E and L-N cells (Fig. 2E and Fig. F). In contrast, MCF-7 cells aggregated with L-E but not with L-N cells (Fig. 2B and Fig. C, respectively). Neither N-cad-5 nor MCF-7 cells aggregated with untransfected L-cells (Fig. 2A and Fig. D), and no aggregation occurred in calcium-free conditions (data not shown). These data demonstrate that both endogenous E- and transfected N-cadherin present on the surface of MCF-7 cells are capable of mediating calcium-dependent, homotypic cellular interactions.


Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis.

Hazan RB, Phillips GR, Qiao RF, Norton L, Aaronson SA - J. Cell Biol. (2000)

N-cadherin promotes coaggregation of N-cadherin–transfected MCF-7 cells with N-cadherin–transfected L-cells. L-cells and L-E-cadherin and L-N-cadherin cells, labeled with the fluorescent dye diO (green) were coaggregated with diI-labeled (red) MCF-7 cells (A, B, and C, respectively) or N-cad-5 cells (D, E, and F respectively). Yellow appears when green and red are superimposed, indicating coaggregation.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2169367&req=5

Figure 2: N-cadherin promotes coaggregation of N-cadherin–transfected MCF-7 cells with N-cadherin–transfected L-cells. L-cells and L-E-cadherin and L-N-cadherin cells, labeled with the fluorescent dye diO (green) were coaggregated with diI-labeled (red) MCF-7 cells (A, B, and C, respectively) or N-cad-5 cells (D, E, and F respectively). Yellow appears when green and red are superimposed, indicating coaggregation.
Mentions: To determine whether the transfected N-cadherin was functionally active in adhesion and whether it interfered with the adhesive function of E-cadherin, parental MCF-7 cells or the N-cad-5 clone, labeled with Fast diO, were mixed and coaggregated either with parental L-cells or with L-cells transfected with either mouse E- (L-E cells) or N-cadherin (L-N cells), which were labeled with Fast diI (Fig. 2). N-Cad-5 cells formed large coaggregates with both L-E and L-N cells (Fig. 2E and Fig. F). In contrast, MCF-7 cells aggregated with L-E but not with L-N cells (Fig. 2B and Fig. C, respectively). Neither N-cad-5 nor MCF-7 cells aggregated with untransfected L-cells (Fig. 2A and Fig. D), and no aggregation occurred in calcium-free conditions (data not shown). These data demonstrate that both endogenous E- and transfected N-cadherin present on the surface of MCF-7 cells are capable of mediating calcium-dependent, homotypic cellular interactions.

Bottom Line: To determine whether N-cadherin promotes invasion and metastasis, we transfected a weakly metastatic and E-cadherin-expressing breast cancer cell line, MCF-7, with N-cadherin and analyzed the effects on cell migration, invasion, and metastasis.These results demonstrate that N-cadherin promotes motility, invasion, and metastasis even in the presence of the normally suppressive E-cadherin.The increase in MMP-9 production by N-cadherin-expressing cells in response to a growth factor may endow them with a greater ability to penetrate matrix protein barriers, while the increase in their adherence to endothelium may improve their ability to enter and exit the vasculature, two properties that may be responsible for metastasis of N-cadherin-expressing cells.

View Article: PubMed Central - PubMed

Affiliation: The Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine of New York University, New York, New York 10029, USA. rhazan@smtplink.mssm.edu

ABSTRACT
E- and N-cadherin are calcium-dependent cell adhesion molecules that mediate cell-cell adhesion and also modulate cell migration and tumor invasiveness. The loss of E-cadherin-mediated adhesion has been shown to play an important role in the transition of epithelial tumors from a benign to an invasive state. However, recent evidence indicates that another member of the cadherin family, N-cadherin, is expressed in highly invasive tumor cell lines that lacked E-cadherin expression. These findings have raised the possibility that N-cadherin contributes to the invasive phenotype. To determine whether N-cadherin promotes invasion and metastasis, we transfected a weakly metastatic and E-cadherin-expressing breast cancer cell line, MCF-7, with N-cadherin and analyzed the effects on cell migration, invasion, and metastasis. Transfected cells expressed both E- and N-cadherin and exhibited homotypic cell adhesion from both molecules. In vitro, N-cadherin-expressing cells migrated more efficiently, showed an increased invasion of Matrigel, and adhered more efficiently to monolayers of endothelial cells. All cells produced low levels of the matrix metalloproteinase MMP-9, which was dramatically upregulated by treatment with FGF-2 only in N-cadherin-expressing cells. Migration and invasion of Matrigel were also greatly enhanced by this treatment. When injected into the mammary fat pad of nude mice, N-cadherin-expressing cells, but not control MCF-7 cells, metastasized widely to the liver, pancreas, salivary gland, omentum, lung, lymph nodes, and lumbar spinal muscle. The expression of both E- and N-cadherin was maintained both in the primary tumors and metastatic lesions. These results demonstrate that N-cadherin promotes motility, invasion, and metastasis even in the presence of the normally suppressive E-cadherin. The increase in MMP-9 production by N-cadherin-expressing cells in response to a growth factor may endow them with a greater ability to penetrate matrix protein barriers, while the increase in their adherence to endothelium may improve their ability to enter and exit the vasculature, two properties that may be responsible for metastasis of N-cadherin-expressing cells.

Show MeSH
Related in: MedlinePlus