Hypoxia Regulated Inhibin Promotes Tumor Growth and Vascular Permeability By ACVRL1 and CD105 Dependent VE-Cadherin Internalization

Hypoxia, a driver of tumor growth and metastasis, regulates angiogenic pathways that are targets for vessel normalization and ovarian cancer management. However, toxicities and resistance to anti-angiogenics limits their use making identification of new targets vital. Inhibin, a heteromeric TGFb ligand, is a contextual regulator of tumor progression acting as an early tumor suppressor, yet also an established biomarker for ovarian cancers. Here, we demonstrate a previously unknown role for inhibins and find that hypoxia increases inhibin levels in ovarian cancer cell lines, xenograft tumors, and patients. Inhibin is regulated specifically through HIF-1, shifting the balance from activins to inhibins. Hypoxia regulated inhibin promotes tumor growth, endothelial cell invasion and permeability. Targeting inhibin in vivo through knockdown and anti-inhibin strategies robustly reduces permeability in vivo and alters the balance of pro and anti-angiogenic mechanisms resulting in vascular normalization. Mechanistically, inhibin regulates permeability by increasing VE-cadherin internalization via ACVRL1 and CD105, a receptor complex that we find stabilized directly by inhibin. Our findings are the first to demonstrate direct roles for inhibins in vascular normalization via TGF-b receptors providing new insights into the therapeutic significance of inhibins as a strategy to normalize the tumor vasculature in ovarian cancer.

Effective Suppression of Hypoxia Induced Angiogenesis by Synergism of Simvastatin and Metformin via Inhibiting ET-1-ETBR-Hif1α Signaling Axis

Background: Hypoxic stress accelerates metabolic reprogramming to promote malignant progression, which contains huge and interesting drug targets for cancer therapy. According to recently reports and our previously researches, simvastatin (SVA) or metformin (MET), two metabolic relevant drugs, play an important role in inhibiting tumor growth, angiogenesis, improvement hypoxic microenvironment. However, the signal networks of hypoxia induced metabolic reprogramming is enormous and intricacy, blocking a signal target can’t play an effective role in antitumor, whether combination of SVA and MET could exert a more effective antitumor effect is not clear.Methods: The antitumor effect of synergism of SVA and MET were detected in mouse models, breast cancer patient-derived organoid (PDO) and multiple tumor cell lines compared with untreated, SVA or MET alone. Transcriptome sequencing were performed for exploring the possible mechanisms. Inhibition of endothelin 1 (ET-1) induced Hif1α by synergism of SVA and MET were contrasted with bosentan, an ETBR antagonist.Results: Our results show that synergism of SVA and MET can inhibit tumor cell proliferation and promote apoptosis, alleviate hypoxia, decrease angiogenesis and increase vessel normalization within tumor than use of SVA or MET alone. RNA-sequencing result implies that just synergism of SVA and MET can inhibit EDN1 expression, which encodes endothelin 1, an important regulator of angiogenesis and hypoxia-related pathway, but not in use of SVA or MET alone. More specifically, synergism of SVA and MET suppresses the ET-1 induced Hif1α expression by inhibiting ET-1-ETBR signaling pathway and increasing PHD2 expression. In addition, the antitumor effect of synergism of SVA and MET is more efficient than bosentan in tumor cells and breast cancer PDO by inhibiting ET-1-ETBR-Hif1α signaling axis.Conclusions: Thus, our data show that synergism of SVA and MET can be a viable therapy for antitumor.

The Efficacy of Anti-PD-L1 Treatment in Melanoma Is Associated with the Expression of the ECM Molecule EMILIN2

The use of immune checkpoint inhibitors has revolutionized the treatment of melanoma patients, leading to remarkable improvements in the cure. However, to ensure a safe and effective treatment, there is the need to develop markers to identify the patients that would most likely respond to the therapies. The microenvironment is gaining attention in this context, since it can regulate both the immunotherapy efficacyand angiogenesis, which is known to be affected by treatment. Here, we investigated the putative role of the ECM molecule EMILIN-2, a tumor suppressive and pro-angiogenic molecule. We verified that the EMILIN2 expression is variable among melanoma patients and is associated with the response to PD-L1 inhibitors. Consistently, in preclinical settings,the absence of EMILIN-2 is associated with higher PD-L1 expression and increased immunotherapy efficacy. We verified that EMILIN-2 modulates PD-L1 expression in melanoma cells through indirect immune-dependent mechanisms. Notably, upon PD-L1 blockage, Emilin2−/− mice displayed improved intra-tumoral vessel normalization and decreased tumor hypoxia. Finally, we provide evidence indicating that the inclusion of EMILIN2 in a number of gene expression signatures improves their predictive potential, a further indication that the analysis of this molecule may be key for the development of new markers to predict immunotherapy efficacy.

Anlotinib induces tumor blood vessel normalization to strengthen the anticancer effect of radiotherapy on esophageal cancer by inhibiting EphA2

Background Anlotinib has anti-tumor activity in diverse solid tumors. Given that, our study was designed to unearth the mechanism of Anlotinib in radioresistant esophageal cancer (EC) cells by modulating Ephrin type-A receptor 2 (EphA2). Methods EC cells (TE-1 and KYSE-150) were induced to radioresistant EC cells (TE-1R and KYSE-150R). EphA2 expression in TE-1R and KYSE-150R cells was measured. Then, TE-1R and KYSE-150R cells were treated with Anlotinib and/or transfected with the plasmids that altered EphA2 expression. Otherwise, TE-1R and KYSE-150R cells were transfected with si-EphA2 or OE-EphA2 plasmids independently. In vitro experiments were conducted to monitor cell proliferation, angiogenesis, migration and invasion. In vivo experiment was also implemented to observe tumor growth. Results EphA2 expression was raised in TE-1R and KYSE-150R cells. Anlotinib inhibited proliferation, angiogenesis, migration and invasion of TE-1R and KYSE-150R cells in vitro, as well as tumor growth and MVD in vivo. Inhibiting EphA2 enhanced Anlotinib-mediated effects on TE-1R and KYSE-150R cells. Down-regulating EphA2 restrained proliferation, angiogenesis, migration and invasion of TE-1R and KYSE-150R cells. Conclusion It is concluded that Anlotinib suppresses EC development under radiotherapy by inhibiting EphA2, providing another perspective to overcome radioresistance in EC.

Hot and Cold Tumors: Is Endoglin (CD105) a Potential Target for Vessel Normalization?

Tumors are complex masses formed by malignant but also by normal cells. The interaction between these cells via cytokines, chemokines, growth factors, and enzymes that remodel the extracellular matrix (ECM) constitutes the tumor microenvironment (TME). This TME can be determinant in the prognosis and the response to some treatments such as immunotherapy. Depending on their TME, two types of tumors can be defined: hot tumors, characterized by an immunosupportive TME and a good response to immunotherapy; and cold tumors, which respond poorly to this therapy and are characterized by an immunosuppressive TME. A therapeutic strategy that has been shown to be useful for the conversion of cold tumors into hot tumors is vascular normalization. In this review we propose that endoglin (CD105) may be a useful target of this strategy since it is involved in the three main processes involved in the generation of the TME: angiogenesis, inflammation, and cancer-associated fibroblast (CAF) accumulation. Moreover, the analysis of endoglin expression in tumors, which is already used in the clinic to study the microvascular density and that is associated with worse prognosis, could be used to predict a patient’s response to immunotherapy.