The situation of the COVID-19 pandemic reminds us that we permanently need high-value flexible solutions to urgent clinical needs including simplified diagnostic technologies suitable for use in the field and for delivering targeted therapeutics. From our perspective nanotechnology is revealed as a vital resource for this, as a generic platform of technical solutions to tackle complex medical challenges. It is towards this perspective and focusing on nanomedicine that we take issue with Prof Park's recent editorial published in the Journal of Controlled Release. Prof. Park argued that in the last 15 years nanomedicine failed to deliver the promised innovative clinical solutions to the patients (Park, K. The beginning of the end of the nanomedicine hype. Journal of Controlled Release, 2019; 305, 221–222 [1]. We, the ETPN (European Technology Platform on Nanomedicine) [ 2 ], respectfully disagree. In fact, the more than 50 formulations currently in the market, and the recent approval of 3 key nanomedicine products (e. g. Onpattro, Hensify and Vyxeos), have demonstrated that the nanomedicine field is concretely able to design products that overcome critical barriers in conventional medicine in a unique manner, but also to deliver within the cells new drug-free therapeutic effects by using pure physical modes of action, and therefore make a difference in patients lives. Furthermore, the >400 nanomedicine formulations currently in clinical trials are expecting to bring novel clinical solutions (e.g. platforms for nucleic acid delivery), alone or in combination with other key enabling technologies to the market, including biotechnologies, microfluidics, advanced materials, biomaterials, smart systems, photonics, robotics, textiles, Big Data and ICT (information & communication technologies) more generally. However, we agree with Prof. Park that “ it is time to examine the sources of difficulty in clinical translation of nanomedicine and move forward “. But for reaching this goal, the investments to support clinical translation of promising nanomedicine formulations should increase, not decrease. As recently encouraged by EMA in its roadmap to 2025, we should create more unity through a common knowledge hub linking academia, industry, healthcare providers and hopefully policy makers to reduce the current fragmentation of the standardization and regulatory body landscape. We should also promote a strategy of cross-technology innovation, support nanomedicine development as a high value and low-cost solution to answer unmet medical needs and help the most promising innovative projects of the field to get better and faster to the clinic. This global vision is the one that the ETPN chose to encourage for the last fifteen years. All actions should be taken with a clear clinical view in mind, “ without any fanfare ”, to focus “ on what matters in real life ”, which is the patient and his/her quality of life....
The cell surface nucleotidase CD73 is an immunosuppressive enzyme involved in tumor progression and metastasis. Although preclinical studies suggest that CD73 can be targeted for cancer treatment, the clinical impact of CD73 in ovarian cancer remains unclear. In this study, we investigated the prognostic value of CD73 in high-grade serous (HGS) ovarian cancer using gene and protein expression analyses. Our results demonstrate that high levels of CD73 are significantly associated with shorter diseasefree survival and overall survival in patients with HGS ovarian cancer. Furthermore, high levels of CD73 expression in ovarian tumor cells abolished the good prognosis associated with intraepithelial CD8 þ cells. Notably, CD73 gene expression was highest in the C1/stromal molecular subtype of HGS ovarian cancer and positively correlated with an epithelial-to-mesenchymal transition gene signature. Moreover, in vitro studies revealed that CD73 and extracellular adenosine enhance ovarian tumor cell growth as well as expression of antiapoptotic BCL-2 family members. Finally, in vivo coinjection of ID8 mouse ovarian tumor cells with mouse embryonic fibroblasts showed that CD73 expression in fibroblasts promotes tumor immune escape and thereby tumor growth. In conclusion, our study highlights a role for CD73 as a prognostic marker of patient survival and also as a candidate therapeutic target in HGS ovarian cancers.Cancer Res; 75(21); 4494-503. Ó2015 AACR.
Functional inactivation of the protein tyrosine phosphatase DEP-1 leads to increased endothelial cell proliferation and failure of vessels to remodel and branch. DEP-1 has also been proposed to contribute to the contact inhibition of endothelial cell growth via dephosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), a mediator of vascular development. However, how DEP-1 regulates VEGF-dependent signaling and biological responses remains ill-defined. We show here that DEP-1 targets tyrosine residues in the VEGFR2 kinase activation loop. Consequently, depletion of DEP-1 results in the increased phosphorylation of all major VEGFR2 autophosphorylation sites, but surprisingly, not in the overall stimulation of VEGFdependent signaling. The increased phosphorylation of Src on Y529 under these conditions results in impaired Src and Akt activation. This inhibition is similarly observed upon expression of catalytically inactive DEP-1, and coexpression of an active Src-Y529F mutant rescues Akt activation. Reduced Src activity correlates with decreased phosphorylation of Gab1, an adapter protein involved in VEGF-dependent Akt activation. Hypophosphorylated Gab1 is unable to fully associate with phosphatidylinositol 3-kinase, VEGFR2, and VEcadherin complexes, leading to suboptimal Akt activation and increased cell death. Overall, our results reveal that despite its negative role on global VEGFR2 phosphorylation, DEP-1 is a positive regulator of VEGFmediated Src and Akt activation and endothelial cell survival.
CD73 is an ecto-nucleotidase overexpressed in various types of tumors that catabolizes the generation of extracellular adenosine, a potent immunosuppressor. We and others have shown that targeted blockade of CD73 can rescue anti-tumor T cells from the immunosuppressive effects of extracellular adenosine. Another important function of extracellular adenosine is to regulate adaptive responses to hypoxia. However, the importance of CD73 for tumor angiogenesis and the effect of anti-CD73 therapy on tumor angiogenesis remain unknown. In this study, we demonstrated that CD73 expression on tumor cells and host cells contribute to tumor angiogenesis. Our data revealed that tumor-derived CD73 enhances the production of vascular endothelial growth factor (VEGF) by tumor cells that host-derived CD73 is required for in vivo angiogenic responses and that endothelial cells require CD73 expression for tube formation and migration. Notably, the pro-angiogeneic effects of CD73 relied on both enzymatic and non-enzymatic functions. Using a mouse model of breast cancer, we demonstrated that targeted blockade of CD73 with a monoclonal antibody significantly decreased tumor VEGF levels and suppressed tumor angiogenesis in vivo. Taken together, our study strongly suggests that targeted blockade of CD73 can significantly block tumor angiogenesis, and further supports its clinical development for cancer treatment.CD73 is a glycosyl-phosphatidylinositol (GPI)-anchored nucleotidase that catalyzes the hydrolysis of extracellular adenosine monophosphates (AMP) into adenosine. CD73 is found overexpressed in several types of cancer, including bladder cancer, leukemia, glioma, glioblastoma, melanoma, ovarian cancer, colon cancer and breast cancer. 1,2 CD73 overexpression in tumors is at least in part a consequence of the hypoxic nature of the tumor microenvironment. Accordingly, CD73 transcription is induced by hypoxia-inducible factor (HIF)21. 3,4 CD73 expression is also upregulated following loss of estrogen receptor (ER) signaling in breast cancer 5 and epigenetically regulated in melanoma 6 and breast cancer cells. 7 Landmark studies by Sitkovsky et al. demonstrated that extracellular adenosine accumulates in tumors and potently suppresses the function of tumor-infiltrating T cells via A2A adenosine receptors. [8][9][10][11] Inspired by this body of work, studies from our laboratory and others have underscored the therapeutic potential of blocking CD73 for cancer therapy. 12-16 Using CD73-deficient mice and targeted CD73 blockade with a monoclonal antibody (mAb), we demonstrated that anti-CD73 therapy can effectively rescue endogenous and treatment-induced anti-tumor immune responses from the suppressive effects of extracellular adenosine. [12][13][14]
DEP-1/CD148 is a receptor-like protein tyrosine phosphatase with antiproliferative and tumor-suppressive functions. Interestingly, it also positively regulates Src family kinases in hematopoietic and endothelial cells, where we showed it promotes VE-cadherin-associated Src activation and endothelial cell survival upon VEGF stimulation. However, the molecular mechanism involved and its biologic functions in endothelial cells remain illdefined. We demonstrate here that DEP-1 is phosphorylated in a Src-and Fyndependent manner on Y1311 and Y1320, IntroductionDEP-1/CD148 (also called PTP or PTPRJ) is a receptor-like protein tyrosine phosphatase (PTP) expressed in several cell types including epithelial, endothelial, and hematopoietic cells. 1 It encompasses an extracellular domain containing 8 fibronectin-type IIIlike motifs, a transmembrane domain, a single intracellular catalytic domain, and a short C-terminal tail. 2 Initial studies demonstrated that its expression increases with cell density and suggested a function in cell contact-mediated growth inhibition. 2,3 Overexpression of DEP-1 in cancer cells was also reported to inhibit their growth, while thyroid cell transformation was associated with its decreased expression, indicative of a role for DEP-1 as a tumor suppressor. 4-8 DEP-1 was further identified as the gene associated with the mouse colon cancer susceptibility locus (Scc1), and was found to be frequently deleted and mutated in human cancers. 9 These growth inhibitory functions of DEP-1 are consistent with the nature of some of its reported substrates, which include the PDGF-, HGF (Met), and VEGF (VEGFR2) receptors as well as Src family kinases (SFKs), ERK1/2, and the p85 subunit of PI3K. 10-18 DEP-1 also dephosphorylates proteins from the cell-cell junctional complexes including p120catenin, occludin, and ZO-1, which might impact biologic functions dependent on the loosening/strengthening of intercellular contacts. 11,14,19 VEGFR2 is a potent activator of the angiogenic response and is the main mediator of the mitogenic, chemotactic, permeability, and survival effects of VEGF in normal and tumor-associated vessels. 20 VE-cadherin adhesion complexes are important sites of VEGFdependent signaling in confluent cells, as activated VEGFR2 associates to these complexes to mediate Akt activation and cell survival. 21 DEP-1 was shown to colocalize to these sites and to attenuate the phosphorylation of VEGFR2, resulting in the impaired activation of ERK1/2 and the contact inhibition of endothelial cell proliferation. 13,22 However, DEP-1 was also reported to positively regulate VE-cadherin-associated Src and Akt and to promote VEGF-dependent endothelial cell survival. 15 Consistent with these distinct in vitro functions, inactivation of DEP-1 in mice via the swapping of its catalytic domain and C-terminal tail with GFP revealed both positive and negative regulatory effects in vascular development, and resulted in defective vessel remodeling and branching in addition to increased endothelial cell proliferati...
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