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Dll4 inhibition regulates cancer stem cells frequency and suspends tumor growth. Dll4 overexpression has proven to be implicated in cancer development by promoting tumor growth.
- endometrial cancer
- notch signaling pathway
- Dll 4
- prognostic role
1. Dll4 in Cancer Development
Dll4 inhibition regulates cancer stem cells frequency and suspends tumor growth. Dll4 overexpression has proven to be implicated in cancer development by promoting tumor growth. Another study involving 383 patients suffering from human gastric cancer (GC) were analyzed with their tissue samples immersed in immunohistochemical discoloration the appearance of Dll4 to determine the distinguished and undistinguishable gastric tumor stem cells. Fascinatingly, positive Dll4 appearance was meaningly related to improved lymph node metastasis and distal metastasis danger as likened with patients presenting adverse Dll4 appearance. The connection between Dll4 appearance level and the cancer stem cell associated protein Nestin (an angiogenesis indicator of multiplying endothelial cells in colorectal tumor vessels) was also analyzed. Positive appearance of Dll4 was proven to be related to Nestin. The authors concluded that Dll4 is associated with gastric cancer progenitor cells, and its expression influences features linked to the Notch-1 pathway involving tumor formation, growth and development [1].
Hu et al., examined the clinical significance of Dll4 in ovarian carcinoma utilizing immunohistochemical peroxidase discoloration in eighty-four patients. Eighty-three percent of cancers had severe histology and ninety one percent had extreme level of histology. 88% of participants had progressive phase ailment and fifty nine percent related ascites. Dll4 was administered endothelial and cancer sections of ovarian cancers and its appearance was not linked to grade and extent of cytoreduction. The authors reported that Dll4 overexpression and suboptimal cytoreduction were self-regulating forecasters of poor survival. Moreover, muzzling Dll4 reaction with Dll4 siRNA repressed explosion of ovarian tumor cells by 2.1-fold associated with the regulation. Moreover, the authors examined the impacts of intervention with restrained Dll4 for 48 h on cell relocation. Immobilized Dll4 bigger the relocation of (murine ovarian endothelial cells) MOECs by 2.7-fold compared to interfered cells (p < 0.05) although it showed no impact on VEGF-initiated relocation. The major results of the current research show that Dll4 overexpression was significantly connected with reducing health outcome and survival. Moreover, it predicted the Dll4 reaction to anti-VEGF intervention. The suppression of Dll4 in cancer cells caused by reserve of ovarian tumor development and control of angiogenesis, escorted by initiation of hypoxia in the tumor microenvironment, revealing that Dll4 has a key role in ovarian cancer development and that focusing on Dll4 could improve the effectiveness of ovarian tumor intervention n [2]. In addition to the previous study, Yen et al., reported the use of anti-Dll4 treatment for ovarian cancer by regulating cancer stem cell function and tumor angiogenesis. The authors utilized anti-human Dll4 (OMP-21M18) and anti-murine Dll4 to block Notch signaling and found that anti-Dll4 treatment was broadly efficacious in these ovarian cancer models, significantly inhibiting tumor growth [3].
Hoey et al. investigated the results of Dll4 inhibition in cancer stem cells by creating antibodies (anti-hDll4 21M18) selectively aiming at Dll4 in the cancer or in the host vasculature and stroma in xenograft models derived from primary human tumors. Each antibody was proven to inhibit cancer development and that the grouping of two antibodies was even more effective. Administration of anti-human Dll4 reserved the administration of Notch target genes reducing proliferation of cancer cells, reduced cancer stem cell frequency, and deregulated angiogenesis by aiming at Dll4 in the vasculature [4]. The effect of monoclonal antibody (MEDI0639) that selectively binds to Dll4 was also examined in small-cell lung tumor. Tumor stem cells are responsible for the high metastatic profile and rapid frequency of many cancer types. In half of the patients that MEDI0639 was administered, the tumor stem cells frequency was suppressed while 25% of the patients demonstrated >50% reduction of the tumor [5]. In a more recent study, tumor metastasis was also reported to be altered by deregulation of Dll4. Lewis Lung Carcinoma (LLC) cells were used to study tumor metastasis in vivo, by endothelial-specific Dll4 loss-of-function. Cancer stem cells were apparently reduced and hypoxia was increased in the tumor that led to an increase in tumoral blood vessel density, but with neo-vessels poorly perfused, with increased leakage and reduced perivascular maturation. Number and burden of macro-metastasis was significantly reduced and the tumor growth was suspended [6].
Yen et al., studied the activity of targeting DLL4 in tumor cells with an anti-human Dll4 antibody and in the host stroma/vasculature with an anti-mouse Dll4 antibody. The combination of these antibodies was efficacious in a broad spectrum of pancreatic tumor xenografts and showed additive antitumor activity together with gemcitabine. Treatment with either human or mouse anti-Dll4 delayed pancreatic tumor recurrence following termination of gemcitabine treatment, and the two together produced an additive effect, suggesting a novel therapeutic approach for pancreatic cancer treatment through antagonism of DLL4/Notch signaling [7].
Zohny et al. have reviewed the oncogenic function of Notch ligands and receptors in different breast cancer subtypes. Notch 1 has an oncogenic function in estrogen receptors (ER) luminal cell lines, tumor negative breast cancer (TNBC) and in invasive ductal carcinoma. Even though the role of Notch 2 remains ambiguous, similarly to Notch 1, represents an oncogenic factor in HER2 and basal subtype invasive ductal carcinoma (IDC) breast cancer, while it is a tumor-suppressor in ER+ luminal and TNBC cell lines. Moreover, Notch 3 is an oncogenic factor for ER+ and HER2+ human patients, but a tumor suppressor for TNBC cell lines and ERBB2 basal tumor cells. Furthermore, Notch 4 is an oncogenic factor for TNBC human breast cancer. Jag1,2 and Dll1 all act as oncogenic factors in Luminal and TBC cell lines, while Dll4 has a wide oncogenic function in different breast cancer subtypes [8].
2. Cancer Stem Cells and Dll4 Expression in Endometrial Cancer
Adult stem cells are identified in various types of mature tissue including normal endometrium and endometrial tumor. Menstrual blood-derived stem cells are called endometrial regenerative cells while gene mutations of these stem cells proven to be able to create cancer stem cells. More specific, Kato et al., presented the function of stem cells in endometrial tumor where stem cells identified in the cancerous tissues revealed specific characteristics including reduced expression of differentiation markers, extended repopulating specifications, self-renewal abilities, enhanced metastatic tendency and increased tumorigenicity revealing their key function in endometrial tumor development [9]. Fasoulakis et al. reported that Dll4 is overexpressed in endometrial cancer cells and vasculature and is also elevated in the plasma of a fraction of patients before surgery [10].
The Notch signaling pathway and especially the Delta gene have been found to exist in uterine endometrium. Mazella et al. revealed that the human endometrial cells articulated Dll4 in a design known as spatiotemporal. Immunohistochemistry educations demonstrated the cytoplasm and membrane discoloration with apical localization in the luminal and glandular epithelium and modest diffuse discoloration in the cytoplasm present in the stromal cells while Western spot examination displayed a common scope of the endometrial Dll4 to that in the human umbilical endothelial cells. The placement of Dll4 mRNA in human endometrial cells was determined to be administered in large variations in the glandular epithelium, raised in the proliferative and early productory endometrium. However, the authors found that the Dll4 and mRNA was less in endometrial had no relation with the menstrual cycle. The author failed to study the effect of hormones. In glandular cells, estradiol had little effect, and medroxyprogesterone acetate decreased mRANs. Relaxin induced the Dll4 mRNA. In stromal cells, both estradiol and medroxyprogesterone acetate decreased the Dll4 mRNA [11].
During the past decade, studies have proven that Dll4 happens to encourage explosion and sustain the stem cells through angiogenic, but also non-angiogenic associated devices. Badenes et al. studied the function of Notch ligands and the impact of a Dll4 knockout in colorectal cancer, which led to positive cancer stem cell density accompanied by improved tumor epithelium variation [11]. Another study proved that Dll4 antibodies were able to suppress tumor stem cells in a Small-cell lung cancer subpopulation promoting the importance of Dll4 antibodies in cancer treatment [7]. Other studies have also reported that Dll4 blockage is correlated to inhibition of tumor growth including ovarian, gastric and lung cancer [3][4][12][13][14].
MEDI0639 is an investigational human therapeutic antibody that targets Dll4 to inhibit the interaction between Dll4 and Notch1. The antibody cross-reacts to cynomolgus monkey but not mouse species orthologues. In vitro MEDI0639 inhibits the binding of Notch1 to Dll4, interacting via a novel epitope that has not been previously described. Binding to this epitope translates into MEDI0639 reversing Notch1-mediated suppression of human umbilical vein endothelial cell growth in vitro. MEDI0639 administration resulted in stimulation of tubule formation in a three-dimensional (3D) endothelial cell outgrowth assay, a phenotype driven by disruption of the Dll4-Notch signaling axis. In contrast, in a two-dimensional endothelial cell–fibroblast coculture model, MEDI0639 is a potent inhibitor of tubule formation. In vivo, MEDI0639 shows activity in a human endothelial cell angiogenesis assay promoting human vessel formation and reducing the number of vessels with smooth muscle actin-positive mural cells coverage. Collectively, the data show that MEDI0639 is a potent modulator of Dll4-Notch signaling pathway [15].
The Notch signaling pathway has been proven to be involved in a crosstalk with WNT signaling. Abnormal activation of WNT signaling has been reported in the majority of type-1 endometrial cancer cases with β-catenin mutations in 20–25% of cases. Fatima et al. discussed the Wnt-activating mechanisms in endometrial cancer and reviewed the current advances in anticancer therapy. Given the current lack of therapeutic solutions for advanced and recurrent endometrial cancer, resent evidence support the role of Wnt signaling at early stages of endometrial tumorigenesis, The authors supported that Wnt signaling represents a promising intervention for targeted therapies in endometrial cancer patients. Various inhibitors targeting different molecules of this pathway have been developed including Medroxyprogesterone Acetate (MPA, Levonorgestrel Intrauterine Device, DKN-01 is a humanized monoclonal antibody (Mab) targeting Dickkopf-1 (DKK1), Porcupine Inhibitor, OMP-54F28 -a fusion protein consisting of the extracellular ligand-binding domain of Fzd8 and a human immunoglobulin G1 (IgG1) Fc domain-, Niclosamide, PRI-724 and ICG-001, Salinomycin, Curcumin and miRNA treatment, though only a few studies have addressed the effects of Wnt inhibitors in endometrial cancer and they are still at an early phase and far away from clinical trials [16].
A simultaneous blockade of VEGF/VEGFR and DLL4/Notch signaling pathways leads to more potent anti-cancer effects by synergistic anti-angiogenic mechanisms in xenograft models. A bispecific antibody targeting VEGF and DLL4 (ABL001/NOV1501/TR009) demonstrates more potent in vitro and in vivo biological activity compared to VEGF or DLL4 targeting monoclonal antibodies alone and is currently being evaluated in a phase 1 clinical study of heavy chemotherapy or targeted therapy pre-treated cancer patients (ClinicalTrials.gov Identifier: NCT03292783). However, the effects of a combination of ABL001 and chemotherapy on tumor vessels and tumors are not known. Hence, the effects of ABL001, with or without paclitaxel and irinotecan were evaluated in human gastric or colon cancer xenograft models. The combination treatment synergistically inhibited tumor progression compared to each monotherapy. More tumor vessel regression and apoptotic tumor cell induction were observed in tumors treated with the combination therapy, which might be due to tumor vessel normalization. Overall, these findings suggest that the combination therapy of ABL001 with paclitaxel or irinotecan would be a better clinical strategy for the treatment of cancer patients [17].
Chiorean et al. studied the Enoticumab (REGN421), a human IgG1 monoclonal antibody that binds human Dll4 and disrupts Notch-mediated signaling, in order to determine the safety, dose-limiting toxicities (DLT), pharmacokinetics (PK), and recommended phase II dose (RP2D) of enoticumab. Enoticumab was administered intravenously in 53 patients with the most frequent adverse events (AE) being fatigue, nausea, vomiting, hypertension, headache, and anorexia. Brain natriuretic peptide increase, troponin I increase, right ventricular dysfunction and pulmonary hypertension, and left ventricular dysfunction and pulmonary hypertension were reported in four patients while Enoticumab was characterized by nonlinear, target-mediated PK, and had a terminal half-life of 8 to 9 days. The authors reported that Enoticumab was tolerated, and that good response was noted for both ovarian cancer and other solid tumors [18].
3. Conclusions
Dll4 reveals a major key role in endometrial cancer formation while it seems to have a critical role in both tumor angiogenesis and cancer stem cells activation. Immunotherapies represent a promising novel therapy however, there are still ongoing research that will lead to important information considering the appropriate protocols for the different types of cancer. Taking into consideration the presence and the role of tumor stem cells in endometrial formation, the implication of Dll4 gene in endometrial cancer development and the interaction between them, where Dll4 blockage has proven to be correlated to cancer stem cell inhibition and suspension of tumor development, an interaction between Dll4 and cancer stem cells in endometrial cancer seems quite possible, however, more research is predominant to reach safe conclusions.
This entry is adapted from the peer-reviewed paper 10.3390/cancers14071649
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