The prognostic value of CD147 expression was also shown in bone cancer. a key component of the tumor microenvironment. MMP expression induced by CD147 in both tumor and stromal compartments in turn releases biologically active angiogenic growth factors from matrix-bound complexes. In 2005, Tang et al. showed that CD147 stimulates tumor angiogenesis by increasing VEGF and MMP expression levels in both tumor and stromal compartments [85]. Our studies have shown that tumoral CD147 increased the production by endothelial cells of VEGF soluble isoforms (particularly the most angiogenic isoforms) and of its main receptor VEGFR-2 through the transcription factor HIF-2, both in vitro and in experimental tumor models in vivo. Moreover, Octreotide CD147 promotes capillary-like formation, migration and cell survival through VEGFR-2 and its ligand VEGF [10]. We have also shown that Rabbit Polyclonal to SLC39A7 this regulation of VEGF/VEGFR-2 by CD147 is not limited to endothelial cells and can be also observed in melanoma tumor cells leading to an increase of their malignant properties [86]. Further studies allowed us to identify a unique mechanism of action of CD147, showing that its direct conversation with VEGFR-2 around the plasma membrane is required for VEGF induced VEGFR-2 activation. This VEGFR-2 co-receptor role of CD147 has been analyzed using computational docking analyses and mutagenesis and led to the identification of a molecular binding site in the extracellular domain name of CD147 located close to the cell membrane and made up of the amino acids 195/199. The overexpression of CD147 in malignancy is able to further potentiate VEGFR-2 activation, suggesting that a combinatory therapy of an antiangiogenic drug together with an inhibitor of CD147/VEGFR-2 conversation may have a greater impact on inhibiting angiogenesis and malignancy [87]. CD147 is also implicated in lactate efflux, via its cotransporter monocarboxylate transporter 4. Indeed, MCT4 regulates CD147 maturation and trafficking to the plasma membrane in breast malignancy cells [88]. Accumulation of lactic acid Octreotide in the ECM is also known to promote angiogenesis via the increase of VEGF/VEGFR-2 synthesis by tumor and endothelial cells, which reinforce the role of CD147 in the regulation of tumor angiogenesis. 6. CD147 Therapeutic Targeting Strategies Drug resistance is a major issue in malignancy therapy that promotes treatment failure and patients relapse. A big challenge is the identification of those patients who will develop a therapy resistance and the setup of more effective alternative therapeutic strategies. A number of studies brought several Octreotide levels of evidence that converge to a role of CD147 in drug resistance. CD147/CD98hc complex (a high glycosylated chain linked with a low glycosylated chain highly expressed on human tumor cells) is found overexpressed in cisplatin-resistant malignancy cell lines [89]. CD147 expression increased chemotherapeutic drug resistance (Doxorubicin, BCNU, Taxol and Vincristine) via hyaluronan [90] and CD44 conversation, including receptor tyrosine kinase, Abdominal muscles transporter and MCTs activities facilitating drug efflux with resistance to cisplatin and methotrexate in head and neck malignancy [91], to cisplatin in lung malignancy [92], and to vincristine in lymphoma [93]. Cooperation between CD147 and the lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) was also explained in the regulation of chemoresistance in lymphoma through upregulation of the drug transporter/ABCG2 (BCRP, the breast cancer resistance protein) [94]. Another conversation between CD147 and ABCG2 has been involved in breast malignancy chemoresistance. Indeed, CD147 can bind to ABCG2 to form a complex that maintains it stability [51]. In the light of these works, CD147-targeted therapy could be a potential approach to bypass such drug resistance. An antibody (MEM-M6/1) directed against CD147 and MCT-1 conversation was shown to induce necrosis-like cell death in colon cancer cells and melanoma cells. Moreover, MEM-M6/1 inhibited the lactate release [95]. More recently, a drug-screening assay recognized Acriflavine (ACF), a small molecule responsible for the inhibition of CD147 and MCT-4 conversation and as a result of glioblastoma tumor growth and angiogenesis [96]. CD147 blockade with a specific antibody strategy inhibited secretion of Octreotide MMP-9 and VEGF in a dose-dependent manner. Indeed, the antibody (161-Ab) reduced tumor growth even when used in well-established tumors and.
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