Despite decades of research, the survival rate of ovarian cancer patients is largely unchanged. Current chemotherapeutic drugs are effective only transiently because patients with advanced disease eventually develop resistance. Thus, there is a pressing need for identifying novel therapeutic targets in ovarian cancer. Mounting evidence suggests that angiopoietins (Angpts) may play an essential role in cancer progression; however, the expression profiles and biological effects of Angpts on ovarian cancer remain largely unknown. Here, we show that, compared with their normal counterparts, expressions of Angpt1, Angpt2, and Angpt4 are increased in ovarian cancer cells and tissues and that human ovarian cancer cells also express the Angpt receptor Tie-2-receptor tyrosine kinase. We show that increased expression of Angpt1, Angpt2, or Angpt4 promotes intraperitoneal growth of ovarian cancers and shortens survival of the experimental mice. We further show, for the first time, that Angpts promote accumulation of cancer-associated fibroblasts and tumor angiogenesis in the ovarian cancer microenvironment, as well as enhance ovarian cancer cell proliferation and invasion in vivo. In addition, we establish a novel function of Angpts in promoting proliferation and invasion and inducing Tie-2 and extracellular signal-regulated kinase 1/2 activation in ovarian cancer-associated fibroblasts. Taken together, these data suggest that the Angpt-Tie-2 functional axis is an important player in ovarian cancer progression and an attractive target for ovarian cancer therapy.
Abstract Despite advances in surgical debulking, radiation, and chemotherapy over the past few decades, ovarian carcinoma remains the most deadly gynecological malignancy. This is largely due to the lack of early stage detection manifesting in approximately 80% of patients presenting with metastatic disease at the time of diagnosis. Current chemotherapeutic drugs are effective only for a short period as patients with advance disease eventually develop resistance despite significant initial responses. Thus, there is a pressing need for the identification of novel therapeutic targets in ovarian cancer. Mounting evidence suggests that the Angiopoietin/Tie-2 functional axis has wide-ranging effects on tumor angiogenesis and progression of a variety of cancer types, however, the expression profiles and biological effects of the Angiopoietin family members on ovarian cancer remain largely unknown. Our data show for the first time that Ang-1, Ang-2 and Ang-4 are expressed in ovarian cancer cell lines and patient samples from both primary and secondary tumor lesions. More specifically, patient tumors revealed a unique localization pattern of Angiopoietin family members whereby Ang-1 and Ang-2 are robustly expressed in tumor cells and stroma, whereas Ang-4 expression is predominately in the tumor stroma. In addition, we show that overexpression of Ang-4 and Ang-2 and, to a lesser extent, Ang-1, promotes subcutaneous growth of ovarian cancer cells and results in accelerated ascites formation and poor survival in an orthotopic ovarian cancer mouse model. Immunohistochemical analysis of orthotopic tumors suggests the pro-growth effects of Ang-1 and Ang-4 are mediated through increased tumor cell proliferation as determined by positive Ki67 staining. Our results also demonstrated that ovarian cancer cells express Tie-2 receptor tyrosine kinase (RTK), the angiopoietin receptor. The expression of Tie-2, as well as angiopoietin family members, by ovarian cancer cells suggests the potential of an Angiopoietin/Tie-2 autocrine loop. Lastly, further analysis suggests the potential role of angiopoietins in increasing the amount of cancer associated fibroblasts (CAFs) in the tumor microenvironment. Taken together, our data suggest that the Angiopoietin/Tie-2 functional axis is a significant player in ovarian cancer progression and is a potential target for ovarian cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1485. doi:1538-7445.AM2012-1485
Ulcerative colitis (UC) and Crohn’s disease (CD) are two forms of chronic inflammatory bowel disease (IBD) representing major clinical challenges in need of new treatment modalities to improve patient care. Store-operated calcium entry (SOCE) is the predominant calcium influx pathway in immune cells regulating many of their functional properties. However, it is currently unknown whether the pharmacologic inhibition of SOCE is a suitable drug target in IBD.
Glioblastoma multiforme (GBM) is a highly invasive and vascularized aggressive brain tumor. Less than 10% of GBM patients survive >5 years after diagnosis. Angiogenesis plays an important role in GBM growth, and antiangiogenesis-based therapies have shown clinical efficacy for GBM patients. Unfortunately, therapeutic resistance often develops in these patients, suggesting that GBM cells are capable of switching their dependency on one proangiogenic signaling pathway to an alternative one. Therefore, it is important to identify novel angiogenic factors that play essential roles in tumor angiogenesis and GBM progression. Angiopoietins (Ang-1, Ang-2, and Ang-4) are the ligands of the Tie-2 receptor tyrosine kinase (RTK). The roles of Ang-1 and Ang-2 in tumor angiogenesis have been established. However, little is known about how Ang-4 affects tumor angiogenesis and GBM progression and the mechanism underlying its effects. In our current study, we establish that Ang-4 is upregulated in human GBM tissues and cells. We show that, like endothelial cells, human GBM cells express Tie-2 RTK. We first establish that Ang-4 promotes in vivo growth of human GBM cells by promoting tumor angiogenesis and directly activating extracellular signal-regulated kinase 1/2 (Erk1/2) in GBM cells. Our results establish the novel effects of Ang-4 on tumor angiogenesis and GBM progression and suggest that this pro-GBM effect of Ang-4 is mediated by promoting tumor angiogenesis and activating Erk1/2 kinase in GBM cells. Together, our results suggest that the Ang-4-Tie-2 functional axis is an attractive therapeutic target for GBM.
Ovarian carcinoma is the most deadly gynecological malignancy. Current chemotherapeutic drugs are only transiently effective and patients with advance disease often develop resistance despite significant initial responses. Mounting evidence suggests that anti-apoptotic proteins, including those of the inhibitor of apoptosis protein (IAP) family, play important roles in the chemoresistance. There has been a recent emergence of compounds that block the IAP functions. Here, we evaluated AT-406, a novel and orally active antagonist of multiple IAP proteins, in ovarian cancer cells as a single agent and in the combination with carboplatin for therapeutic efficacy and mechanism of action. We demonstrate that AT-406 has significant single agent activity in 60% of human ovarian cancer cell lines examined in vitro and inhibits ovarian cancer progression in vivo and that 3 out of 5 carboplatin-resistant cell lines are sensitive to AT-406, highlighting the therapeutic potential of AT-406 for patients with inherent or acquired platinum resistance. Additionally, our in vivo studies show that AT-406 enhances the carboplatin-induced ovarian cancer cell death and increases survival of the experimental mice, suggesting that AT-406 sensitizes the response of these cells to carboplatin. Mechanistically, we demonstrate that AT-406 induced apoptosis is correlated with its ability to down-regulate XIAP whereas AT-406 induces cIAP1 degradation in both AT-406 sensitive and resistance cell lines. Together, these results demonstrate, for the first time, the anti-ovarian cancer efficacy of AT-406 as a single agent and in the combination with carboplatin, suggesting that AT-406 has potential as a novel therapy for ovarian cancer patients, especially for patients exhibiting resistance to the platinum-based therapies.
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