Background: CD147 induces invadopodia activity and invasiveness in breast epithelial cells. Results: CD147 forms complexes with CD44 and EGFR in lipid raftlike membrane domains and induces hyaluronan-CD44-dependent EGFR-Ras-ERK signaling that promotes invadopodia activity and invasiveness. Conclusion: CD147 induces signaling complexes critical to invasiveness in breast epithelial cells. Significance: CD147 is a potential therapeutic target and disease marker in breast cancer.
The chick embryo has long been a favorite model system for morphologic and physiologic studies of the developing heart, largely because of its easy visualization and amenability to experimental manipulations. However, this advantage is diminished after 5 days of incubation, when rapidly growing chorioallantoic membranes reduce visibility of the embryo. Using high-frequency ultrasound, we show that chick embryonic cardiovascular structures can be readily visualized throughout the period of Stages 9 -39. At most stages of development, a simple ex ovo culture technique provided the best imaging opportunities. We have measured cardiac and vascular structures, blood flow velocities, and calculated ventricular volumes as early as Stage 11 with values comparable to those previously obtained using video microscopy. The endocardial and myocardial layers of the pre-septated heart are readily seen as well as the acellular layer of the cardiac jelly. Ventricular inflow in the pre-septated heart is biphasic, just as in the mature heart, and is converted to a monophasic
The Kaposi’s sarcoma-associated herpesvirus is the causative agent of primary effusion lymphoma (PEL), for which cytotoxic chemotherapy represents the standard of care. The high mortality associated with PEL may be explained in part by resistance of these tumors to chemotherapy. The membrane-bound glycoprotein emmprin (CD147) enhances chemoresistance in tumors through effects on transporter expression, trafficking and interactions. Interactions between hyaluronan and hyaluronan receptors on the cell surface also facilitate emmprin-mediated chemoresistance. Whether emmprin or hyaluronan-receptor interactions regulate chemotherapeutic resistance for virus-associated malignancies is unknown. Using human PEL tumor cells, we found that PEL sensitivity to chemotherapy is directly proportional to expression of emmprin, the lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and a drug transporter known as the breast cancer resistance protein/ABCG2 (BCRP), and that emmprin, LYVE-1 and BCRP interact with each other and colocalize on the PEL cell surface. In addition, we found that emmprin induces chemoresistance in PEL cells through upregulation of BCRP expression, and RNA interference targeting of emmprin, LYVE-1 or BCRP enhances PEL cell apoptosis induced by chemotherapy. Finally, disruption of hyaluronan-receptor interactions using small hyaluronan oligosaccharides reduces expression of emmprin and BCRP while sensitizing PEL cells to chemotherapy. Collectively, these data support interdependent roles for emmprin, LYVE-1 and BCRP in chemotherapeutic resistance for PEL.
SummaryA defining feature of malignant tumor progression is cellular penetration through the basement membrane and interstitial matrices that separate various cellular compartments. Accumulating evidence supports the notion that invasive cells employ specialized structures termed invadopodia to breach these structural barriers. Invadopodia are actin-based, lipid-raft-enriched membrane protrusions containing membrane-type-1 matrix metalloproteinase (MT1-MMP; also known as matrix metalloproteinase 14; MMP14) and several signaling proteins. CD147 (emmprin, basigin), an immunoglobulin superfamily protein that is associated with tumor invasion and metastasis, induces the synthesis of various matrix metalloproteinases in many systems. In this study we show that upregulation of CD147 is sufficient to induce MT1-MMP expression, invasiveness and formation of invadopodia-like structures in non-transformed, non-invasive, breast epithelial cells. We also demonstrate that CD147 and MT1-MMP are in close proximity within these invadopodialike structures and co-fractionate in membrane compartments with the properties of lipid rafts. Moreover, manipulation of CD147 levels in invasive breast carcinoma cells causes corresponding changes in MT1-MMP expression, invasiveness and invadopodia formation and activity. These findings indicate that CD147 regulates invadopodia formation and activity, probably through assembly of MT1-MMPcontaining complexes within lipid-raft domains of the invadopodia.
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