Activated integrin αvβ3 cooperates with metalloproteinase MMP-9 in regulating migration of metastatic breast cancer cells

Abstract

Expression of adhesion receptor integrin ␣v␤3 in an activated functional form strongly promotes metastasis in human breast cancer cells. Here, we report that ␣v␤3 cooperates with matrix metalloproteinase type 9 (MMP-9) in breast cancer cell migration. This cooperation is regulated by the activation state of the integrin. Expression of activated ␣v␤3 in metastatic variants of MDA-MB 435 human breast cancer cells and primary metastatic cells from breast cancer patients strongly enhanced migration toward vitronectin and fibrinogen. This enhancement was mediated by a soluble factor produced by breast cancer cells expressing activated ␣v␤3. When transferred, this factor also up-regulated ␣v␤3-dependent migration of breast cancer cells that express the nonactivated integrin. The factor was identified as metalloproteinase MMP-9. Whereas all tested breast cancer cell variants produced latent MMP-9, only those with activated ␣v␤3 produced the mature form of this metalloproteinase. Recombinant mature MMP-9, but not latent MMP-9 or either form of MMP-2, enhanced ␣v␤3-dependent breast cancer cell migration. The migratory response was inhibited by tissue inhibitors of metalloproteinase or when MMP-9 was depleted from the inducing supernatants. The results indicate a causal relationship between the expression of activated integrin ␣v␤3 and production of enzymatically active MMP-9 in metastatic breast cancer cells. These molecules cooperate to enhance breast cancer cell migration toward specific matrix proteins, and this may contribute to the strongly enhanced metastatic capacity of breast cancer cells that express activated ␣v␤3.M etastasis is the primary cause of death in breast cancer patients. Metastatic dissemination depends on tumor cell adhesion, migration, and invasion. These steps involve integrins, a family of transmembrane adhesion receptors, composed of noncovalently linked ␣ and ␤ subunits (1). Integrins are known to exist in distinct states of activation, and these determine integrin functionality and affinity for ligands (2). For example, integrin activation controls which ligands are recognized, whether an integrin can support cell arrest under dynamic flow conditions or only stationary adhesion, and whether cells can migrate on or toward specific substrates (3). The importance of integrin activation has long been appreciated in leukocytes and platelets, where it controls inflammatory responses and thrombus formation (4, 5). Recent findings indicate that other cell types, such as endothelial cells and tumor cells, can also regulate their interaction with extracellular matrix proteins by integrin activation (6-9). This regulation may help to control angiogenesis and tumor metastasis.In breast and ovarian cancer, as well as in melanoma and glioma, malignant progression is associated with expression of tumor cell integrin ␣v␤3 (10-14). We recently found that ␣v␤3 can exist in human breast cancer cells in an activated or a nonactivated functional state. Only the activated state supports breast cancer cell arrest du...

Matrine suppresses breast cancer cell proliferation and invasion via VEGF-Akt-NF-κB signaling

“…Many reports indicated that in Akt signaling, pAkt, NF-jB, EGF, VEGF, VEGFR1, MMP-9 and MMP-2 play important roles in promoting proliferation, migration, invasion, angiogenesis, and metastasis of cancer cells (Price et al 1999;Helbig et al 2003;Rolli et al 2003;Koivunen et al1999;Kletsas et al 2000;John and Tuszynski 2001;Shibata et al 2002;Gibson et al 2002;Lee et al 2007). Thus, we next investigated if the suppression of the cancer cell shown as mean ± SD is relative to that of 0 lg/mL (0.1% DMSO vehicle) or 0 h as the control (designated as 100%).…”

“…MMP-9 is a NF-jB-regulated gene. MMP-9 and MMP-2 are not only associated with invasion and metastasis but also MMP-9 and VEGF have been implicated in angiogenesis, and hence they are considered to be the therapeutic targets of high priority (Rolli et al 2003;Koivunen et al 1999;Mitropoulou et al 2003).…”

“…Activation of p-Akt and the NF-jB/bcl-2 pathway leads to inhibition of chemotherapy-induced apoptosis, which results in treatment resistance (Wang et al 1996). Therefore, the p-Akt, NF-jB, Bcl-2/Bax, EGF, MMP-9, MMP-2, VEGF and VEGFR1 in the Akt signaling have become the important targets of action by anticancer agents against the proliferation, invasion, angiogenesis and metastasis in cancer cells (Price et al 1999;Helbig et al 2003;Rolli et al 2003;Koivunen et al 1999;John and Tuszynski 2001;Gibson et al 2002;Mitropoulou et al 2003;Wang et al 1996;Emi et al 2005). Our present results have demonstrated that matrine significantly inhibits these important targets in the Akt signaling that is associated with the proliferation and invasion of MDA-MB-231 cells.…”

IFN‐γ withdrawal after immunotherapy potentiates B16 melanoma invasion and metastasis by intensifying tumor integrin αvβ3 signaling

“…20,21 The expression of av and b3 subunits in B16 cells was reduced in the presence of IFN-g, whereas they were increased 24 h after the removal of IFN-g (Fig. 5a).…”

No association of breast cancer risk with integrin beta3 (ITGB3) Leu33Pro genotype

“…Although two later case -control studies did not confirm an increased risk of invasive breast cancer among Leu33Pro homozygotes (Ayala et al, 2003;Jin et al, 2004), certain considerations nevertheless favour the possibility that the ITGB3 Leu33Pro polymorphism may influence risk of invasive breast cancer. First, beta 3 integrins are ectopically expressed on breast carcinoma cells where they enhance invasive and metastasiogenic properties of these cells (Murthy et al, 1996;Wewer et al, 1997;Chen et al, 2001Chen et al, , 2004Rolli et al, 2003). Second, the Pro33 vs Leu33 allele enhances integrin-mediated activation of MAPK pathways (Vijayan et al, 2003), crucial for the malignant potential of cancer cells (Johnson and Lapadat, 2002).…”