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ADAM8 expression in invasive breast cancer promotes tumor dissemination and metastasis.

Romagnoli M, Mineva ND, Polmear M, Conrad C, Srinivasan S, Loussouarn D, Barillé-Nion S, Georgakoudi I, Dagg Á, McDermott EW, Duffy MJ, McGowan PM, Schlomann U, Parsons M, Bartsch JW, Sonenshein GE - EMBO Mol Med (2013)

Bottom Line: Circulating tumor cells and brain metastases were also significantly reduced.Furthermore, antibody treatment of established tumors profoundly decreased metastases in a resection model.As a non-essential protein under physiological conditions, ADAM8 represents a promising novel target for treatment of TNBCs, which currently lack targeted therapies and frequently progress with fatal dissemination.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA.

ABSTRACT
The transmembrane metalloprotease-disintegrin ADAM8 mediates cell adhesion and shedding of ligands, receptors and extracellular matrix components. Here, we report that ADAM8 is abundantly expressed in breast tumors and derived metastases compared to normal tissue, especially in triple-negative breast cancers (TNBCs). Furthermore, high ADAM8 levels predicted poor patient outcome. Consistently, ADAM8 promoted an aggressive phenotype of TNBC cells in culture. In a mouse orthotopic model, tumors derived from TNBC cells with ADAM8 knockdown failed to grow beyond a palpable size and displayed poor vascularization. Circulating tumor cells and brain metastases were also significantly reduced. Mechanistically, ADAM8 stimulated both angiogenesis through release of VEGF-A and transendothelial cell migration via β1-integrin activation. In vivo, treatment with an anti-ADAM8 antibody from the time of cell inoculation reduced primary tumor burden and metastases. Furthermore, antibody treatment of established tumors profoundly decreased metastases in a resection model. As a non-essential protein under physiological conditions, ADAM8 represents a promising novel target for treatment of TNBCs, which currently lack targeted therapies and frequently progress with fatal dissemination.

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Related in: MedlinePlus

When solid tumors reach a few millimeters in diameter, hypoxic stress is induced, which leads to ADAM8 induction resulting in strong pro-angiogenic signaling, in part via VEGF-A release into the extracellular compartment, and endothelial cell recruitment. ADAM8 also promotes β1-integrin activation on tumor cells needed for their adhesion onto and transmigration through the blood vessel wall, which supports dissemination of CTCs and development of metastases. Importantly, here we demonstrate that if the induction of ADAM8 is blocked or its activity inhibited with antibody, there is an insufficient angiogenic response, leading to tumor mass dormancy or slowing of growth, as well as to a striking reduction of CTCs and metastases.
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fig08: When solid tumors reach a few millimeters in diameter, hypoxic stress is induced, which leads to ADAM8 induction resulting in strong pro-angiogenic signaling, in part via VEGF-A release into the extracellular compartment, and endothelial cell recruitment. ADAM8 also promotes β1-integrin activation on tumor cells needed for their adhesion onto and transmigration through the blood vessel wall, which supports dissemination of CTCs and development of metastases. Importantly, here we demonstrate that if the induction of ADAM8 is blocked or its activity inhibited with antibody, there is an insufficient angiogenic response, leading to tumor mass dormancy or slowing of growth, as well as to a striking reduction of CTCs and metastases.

Mentions: Overall, our findings validate ADAM8 as a therapeutic target for TNBC. ADAM8, which is abundantly expressed in aggressive human breast tumors and their metastases, was shown to be essential for tumor growth and dissemination in orthotopic mouse models using knockdown and antibody strategies. Notably, treatment of pre-existing tumors with an antibody targeting ADAM8 profoundly reduced their ability to metastasize in a resection model. Two essential novel roles for ADAM8 in tumor progression were identified (Fig 8). ADAM8 facilitates the release of pro-angiogenic factors, including VEGF-A, into the tumor microenvironment, leading to neovascularization and continued tumor growth. ADAM8 also activates β1-integrin on the tumor cells permitting their attachment to the vascular endothelium and entry into the blood circulation. Increased numbers of CTCs raise the risk of developing metastases in distant organs such as brain and lungs. While TNBCs are highly aggressive and more likely to spread compared to other breast tumors, no targeted treatment options are currently available. Given the importance of ADAM8 in growth and dissemination of TNBC, and its advantageous localization on the tumor cell surface, our studies identify ADAM8 as a promising novel druggable target for the treatment of these breast cancers.


ADAM8 expression in invasive breast cancer promotes tumor dissemination and metastasis.

Romagnoli M, Mineva ND, Polmear M, Conrad C, Srinivasan S, Loussouarn D, Barillé-Nion S, Georgakoudi I, Dagg Á, McDermott EW, Duffy MJ, McGowan PM, Schlomann U, Parsons M, Bartsch JW, Sonenshein GE - EMBO Mol Med (2013)

When solid tumors reach a few millimeters in diameter, hypoxic stress is induced, which leads to ADAM8 induction resulting in strong pro-angiogenic signaling, in part via VEGF-A release into the extracellular compartment, and endothelial cell recruitment. ADAM8 also promotes β1-integrin activation on tumor cells needed for their adhesion onto and transmigration through the blood vessel wall, which supports dissemination of CTCs and development of metastases. Importantly, here we demonstrate that if the induction of ADAM8 is blocked or its activity inhibited with antibody, there is an insufficient angiogenic response, leading to tumor mass dormancy or slowing of growth, as well as to a striking reduction of CTCs and metastases.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927960&req=5

fig08: When solid tumors reach a few millimeters in diameter, hypoxic stress is induced, which leads to ADAM8 induction resulting in strong pro-angiogenic signaling, in part via VEGF-A release into the extracellular compartment, and endothelial cell recruitment. ADAM8 also promotes β1-integrin activation on tumor cells needed for their adhesion onto and transmigration through the blood vessel wall, which supports dissemination of CTCs and development of metastases. Importantly, here we demonstrate that if the induction of ADAM8 is blocked or its activity inhibited with antibody, there is an insufficient angiogenic response, leading to tumor mass dormancy or slowing of growth, as well as to a striking reduction of CTCs and metastases.
Mentions: Overall, our findings validate ADAM8 as a therapeutic target for TNBC. ADAM8, which is abundantly expressed in aggressive human breast tumors and their metastases, was shown to be essential for tumor growth and dissemination in orthotopic mouse models using knockdown and antibody strategies. Notably, treatment of pre-existing tumors with an antibody targeting ADAM8 profoundly reduced their ability to metastasize in a resection model. Two essential novel roles for ADAM8 in tumor progression were identified (Fig 8). ADAM8 facilitates the release of pro-angiogenic factors, including VEGF-A, into the tumor microenvironment, leading to neovascularization and continued tumor growth. ADAM8 also activates β1-integrin on the tumor cells permitting their attachment to the vascular endothelium and entry into the blood circulation. Increased numbers of CTCs raise the risk of developing metastases in distant organs such as brain and lungs. While TNBCs are highly aggressive and more likely to spread compared to other breast tumors, no targeted treatment options are currently available. Given the importance of ADAM8 in growth and dissemination of TNBC, and its advantageous localization on the tumor cell surface, our studies identify ADAM8 as a promising novel druggable target for the treatment of these breast cancers.

Bottom Line: Circulating tumor cells and brain metastases were also significantly reduced.Furthermore, antibody treatment of established tumors profoundly decreased metastases in a resection model.As a non-essential protein under physiological conditions, ADAM8 represents a promising novel target for treatment of TNBCs, which currently lack targeted therapies and frequently progress with fatal dissemination.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA.

ABSTRACT
The transmembrane metalloprotease-disintegrin ADAM8 mediates cell adhesion and shedding of ligands, receptors and extracellular matrix components. Here, we report that ADAM8 is abundantly expressed in breast tumors and derived metastases compared to normal tissue, especially in triple-negative breast cancers (TNBCs). Furthermore, high ADAM8 levels predicted poor patient outcome. Consistently, ADAM8 promoted an aggressive phenotype of TNBC cells in culture. In a mouse orthotopic model, tumors derived from TNBC cells with ADAM8 knockdown failed to grow beyond a palpable size and displayed poor vascularization. Circulating tumor cells and brain metastases were also significantly reduced. Mechanistically, ADAM8 stimulated both angiogenesis through release of VEGF-A and transendothelial cell migration via β1-integrin activation. In vivo, treatment with an anti-ADAM8 antibody from the time of cell inoculation reduced primary tumor burden and metastases. Furthermore, antibody treatment of established tumors profoundly decreased metastases in a resection model. As a non-essential protein under physiological conditions, ADAM8 represents a promising novel target for treatment of TNBCs, which currently lack targeted therapies and frequently progress with fatal dissemination.

Show MeSH
Related in: MedlinePlus