Disrupting tumor angiogenesis serves as an important strategy for cancer therapy. Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has exhibited potent anti-angiogenic activity. However, the molecular mechanisms underlying this effect have not been fully understood. The present study aimed to investigate the role of DHA on endothelial cell proliferation, the essential process in angiogenesis. Human umbilical vein endothelial cells (HUVECs) treated with DHA were examined for proliferation, apoptosis and activation of the extracellular signal-regulated kinase (ERK) signaling pathway. Proliferation of HUVECs was inhibited by 20 µM DHA without induction of apoptosis. DHA also reduced the phosphorylation of ERK1/2, and downregulated the mRNA and protein expression of ERK1/2 in HUVECs. In addition, DHA suppressed the transcription and protein expression of ERK1/2 downstream effectors c-Fos and c-Myc. Electrical cell-substrate impedance sensing real-time analysis demonstrated that ERK signaling inhibitor PD98059 comprises the anti-proliferative effects of DHA. Thus, DHA inhibits endothelial cell proliferation by suppressing the ERK signaling pathway. The present study strengthened the potential of DHA as an angiogenesis inhibitor for cancer treatment.

Cadmium (Cd) is a heavy metal and environmental toxin. Exposure to Cd has been associated with a variety of human cancers. In this study, we performed in vitro assays to examine the effects of cadmium chloride (CdCl₂) on A549 cells, a human lung adenocarcinoma cell line. Cd does not affect proliferation, migration, or apoptosis of A549 cells at concentrations of 0.1–10 μM. At 0.5 and 1 μM, Cd increases the expression of vascular endothelial growth factor (VEGF) (p < 0.05, p < 0.01, respectively), but not basic fibroblast growth factor (b-FGF) in A549 cells. The conditioned media were collected from the A549 cells treated with 1 μM Cd and were co-cultured with human umbilical vein endothelial cells (HUVECs). Upon treatment with the conditioned media, the proliferation and migration of HUVECs significantly increased (p < 0.01, p < 0.05, respectively), while apoptosis remained unchanged. In addition, 1 μM Cd increases the level of hypoxia inducible factor 1-α (HIF1-α), which is a positive regulator of VEGF expression. Although low-dose Cd does not directly affect the growth of lung adenocarcinoma cells, it might facilitate the development of tumors through its pro-angiogenic effects.

Gallbladder cancer is the most common biliary tract malignancy with the worst overall prognosis. CD109 is a co-receptor of TGF-β1 and suppresses TGF-β signaling. In this study, CD109 protein expression in three subtypes of gallbladder cancer was examined by immunohistochemistry on human tissue samples and tissue microarrays. We found that CD109 is specifically expressed in malignant squamous cells in squamous cell carcinomas (86.7 %) and adenosquamous carcinomas (91.7 %), but not in adenocarcinomas or normal gallbladder tissues. Thus, CD109 may be a potential pathology marker for gallbladder squamous cell/adenosquamous carcinomas.

Squamous cell carcinoma (SCC) is well-known for its high rate of metastasis with poor prognosis. CD109 is a glycosylphosphatidylinositol-anchored cell-surface glycoprotein. Recently, CD109 emerges as a potential biomarker and a therapeutic target for SCCs. Accumulating studies have reported that CD109 is highly expressed in human SCCs of multiple organs, and may contribute to the progression of SCCs. In this review, we summarized the findings on expression pattern of CD109 in SCCs, and discussed the molecular mechanisms underlying the roles of CD109 in pathogenesis of SCCs.

Understanding the complexity of the tumor microenvironment is vital for improving immunotherapy outcomes. Here, we report that the T cell costimulatory molecule OX40 was highly expressed in tumor endothelial cells (ECs) and was negatively associated with the prognosis of patients, which is irrelevant to T cell activation. Analysis of conditional OX40 loss- and gain-of-function transgenic mice showed that OX40 signal in ECs counteracted the antitumor effects produced in T cells by promoting angiogenesis. Mechanistically, leucine-rich repeat–containing GPCR5 (Lgr5 ⁺ ) cancer stem cells induced OX40 expression in tumor ECs via EGF/STAT3 signaling. Activated OX40 interacted with Spns lysolipid transporter 2 (Spns2), obstructing the export of sphingosine 1-phosphate (S1P) and resulting in S1P intracellular accumulation. Increased S1P directly bound to Yes 1–associated protein (YAP), disrupting its interaction with large tumor suppressor kinase 1 (LATS1) and promoting YAP nuclear translocation. Finally, the YAP inhibitor verteporfin enhanced the antitumor effects of the OX40 agonist. Together, these findings reveal an unexpected protumor role of OX40 in ECs, highlighting the effect of nonimmune cell compartments on immunotherapy.