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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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E- and N-cadherin expression in metastatic lesions. Sections of salivary glands (Sal, top left), pancreas (top right); axillary lymph nodes (LN, bottom right), from mice injected with N-cad-5 and N-cad-17 (Table ) were stained with N- and E-cadherin antibodies using a secondary DAB detection. The metastatic cells (mets) express high levels of both N- and E-cadherin. Staining of primary tumors from MCF-7–injected mice (bottom left) shows a positive reaction with E-cadherin but not with N-cadherin antibodies. Bar, 20 μm.
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Figure 7: E- and N-cadherin expression in metastatic lesions. Sections of salivary glands (Sal, top left), pancreas (top right); axillary lymph nodes (LN, bottom right), from mice injected with N-cad-5 and N-cad-17 (Table ) were stained with N- and E-cadherin antibodies using a secondary DAB detection. The metastatic cells (mets) express high levels of both N- and E-cadherin. Staining of primary tumors from MCF-7–injected mice (bottom left) shows a positive reaction with E-cadherin but not with N-cadherin antibodies. Bar, 20 μm.

Mentions: The preceding data show that N-cadherin transfection has a striking effect on the metastasis of MCF-7 breast tumor cells. It remained to be determined whether metastatic cells in vivo retained N- and E-cadherin expression. Staining of metastatic lesions in the salivary gland, pancreas (Fig. 7, top) and axillary lymph nodes (bottom right panels) as well as in the lumbar muscle (data not shown), with anti-human E- or N-cadherin antibodies revealed that both cadherins were present in areas of contact between tumor cells. Note the massive infiltration of tumor cells into the salivary gland and pancreas but only marginal invasion of the lymph nodes. In contrast, N-cadherin staining was not detected in primary tumors produced by the nonmetastatic, non–N-cadherin–expressing MCF-7 cells, which continued to express E-cadherin (Fig. 7, bottom left). Since N-cadherin expression was conserved during the metastatic progression of transfected MCF-7 tumor cells, it must play a dominant role over E-cadherin in inducing this phenotype.


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)

E- and N-cadherin expression in metastatic lesions. Sections of salivary glands (Sal, top left), pancreas (top right); axillary lymph nodes (LN, bottom right), from mice injected with N-cad-5 and N-cad-17 (Table ) were stained with N- and E-cadherin antibodies using a secondary DAB detection. The metastatic cells (mets) express high levels of both N- and E-cadherin. Staining of primary tumors from MCF-7–injected mice (bottom left) shows a positive reaction with E-cadherin but not with N-cadherin antibodies. Bar, 20 μm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2169367&req=5

Figure 7: E- and N-cadherin expression in metastatic lesions. Sections of salivary glands (Sal, top left), pancreas (top right); axillary lymph nodes (LN, bottom right), from mice injected with N-cad-5 and N-cad-17 (Table ) were stained with N- and E-cadherin antibodies using a secondary DAB detection. The metastatic cells (mets) express high levels of both N- and E-cadherin. Staining of primary tumors from MCF-7–injected mice (bottom left) shows a positive reaction with E-cadherin but not with N-cadherin antibodies. Bar, 20 μm.
Mentions: The preceding data show that N-cadherin transfection has a striking effect on the metastasis of MCF-7 breast tumor cells. It remained to be determined whether metastatic cells in vivo retained N- and E-cadherin expression. Staining of metastatic lesions in the salivary gland, pancreas (Fig. 7, top) and axillary lymph nodes (bottom right panels) as well as in the lumbar muscle (data not shown), with anti-human E- or N-cadherin antibodies revealed that both cadherins were present in areas of contact between tumor cells. Note the massive infiltration of tumor cells into the salivary gland and pancreas but only marginal invasion of the lymph nodes. In contrast, N-cadherin staining was not detected in primary tumors produced by the nonmetastatic, non–N-cadherin–expressing MCF-7 cells, which continued to express E-cadherin (Fig. 7, bottom left). Since N-cadherin expression was conserved during the metastatic progression of transfected MCF-7 tumor cells, it must play a dominant role over E-cadherin in inducing this phenotype.

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