Cervical cancer cell–derived angiopoietins promote tumor progression

Abstract

Metastatic or recurrent cervical cancer has limited treatment options and a high rate of mortality. Although anti-vascular endothelial growth factor drugs have shown great promise as a therapeutic target for treatment of advanced cervical cancer, drug resistance and class-specific side effects negate long-term benefits. The identification of alternative anti-angiogenic factors will be critical for future drug development for advanced or recurrent cervical cancer. In this study, we found that angiopoietins and Tie receptors were highly expressed in cervical cancer cells. Tie-2 expression in tumor cells predicted poorer prognosis. Wound closure assay and Transwell assay showed that upregulated or downregulated Ang-1 and Ang-2 expression promoted or reduced cervical cancer cell lines migration and invasion, respectively. In subcutaneous xenograft models of cervical cancer, downregulation of Ang-1 and Ang-2 attenuated tumor growth. The expression of vimentin and endomucin and microvessel density were all significantly decreased in the siAng-1 group and siAng-2 group relative to the infection control group. Our data support that dual inhibition of Ang-1 and Ang-2 may be an alternative target for anti-angiogenic adjuvant therapy in advanced or recurrent cervical squamous cell cancer.

Role of Angiopoietin-2 in Vascular Physiology and Pathophysiology

“…Ang2 expression was increased in lung cancer cell lines and its knockdown inhibited the EMT process, promoting E-cadherin expression and down-regulating vimentin, Twist, and Snail expression. Similarly, blockade of Ang2 expression in cervical cancer cells decreased vimentin expression and micro-vessel density, demonstrating its role on EMT and eventually cancer metastasis [80,81].…”

Potential lymphangiogenesis therapies: Learning from current antiangiogenesis therapies—A review

“…201 Ang-1 and Ang-2 have a direct promoting effect on cervical cancer migration and invasion, and their downregulation has predictably attenuated tumor growth. 202 The same study found that TIE2 expression in cervical tumor cells is associated with significantly poor prognosis. Furthermore, treatment with Ang-2 inhibitors significantly improves outcomes of corneal grafts.…”

“…For instance, therapeutic agents that target the Ang‐TIE pathway are currently in clinical development for oncological and ophthalmological applications . Ang‐1 and Ang‐2 have a direct promoting effect on cervical cancer migration and invasion, and their downregulation has predictably attenuated tumor growth . The same study found that TIE2 expression in cervical tumor cells is associated with significantly poor prognosis.…”

Alternative Splicing in Angiogenesis

“…Several studies have implicated Ang-1 and Ang-2 in the promotion and inhibition of tumourigenesis [159,160,161,162]. There could be a few reasons for the discrepancies in tumorigenic function of Ang-1 and Ang-2, including: the effects of Ang-1 or Ang-2 may be cell-type specific; both angiopoietins may be increased and so determining the function of one may be construed as the function exerted by the other highly expressed angiopoietin [153]; or the variation could be due to differential expression of Ang-1 or Ang-2 splice variants.…”