VEGF165b Mutant Promotes the Apoptosis of Murine Breast Cancer Cells Induced by Paclitaxel by Inducing Tumor Vessel Maturation.

The anti-angiogenic agent vascular endothelial growth factor 165b (VEGF165b) mutant (mVEGF165b), which was developed by our laboratory, has superior antitumor activity to that of native VEGF165b; however, its mechanism of action and druggability need further exploration. Using the commercial anti-angiogenic drug bevacizumab as a positive control, the mechanism and developability of mVEGF165b were evaluated and explored. The Cell Counting Kit-8 assay was performed to evaluate the effects of mVEGF165b and bevacizumab alone on the proliferation of human umbilical vein endothelial cells (HUVECs). Meanwhile, the inhibitory effects of mVEGF165b and bevacizumab combined with paclitaxel in a mouse model of breast cancer were assessed. Immunohistochemistry was used to detect their effects on tumor vascular maturation, and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was used to detect the apoptosis of tumor cells. In vitro cell experiments confirmed that mVEGF165b inhibited the proliferation of HUVECs with an efficacy equivalent to that of bevacizumab. mVEGF165b and bevacizumab combined with paclitaxel significantly delayed the growth of breast cancer in mice. Immunohistochemistry and the TUNEL assay showed that mVEGF165b and bevacizumab combined with paclitaxel-induced higher vascular maturity and more apoptosis than paclitaxel alone. mVEGF165b showed similar efficacy and mechanism of action as bevacizumab, indicating its potential to be developed into a safe and effective anti-angiogenic drug.

Liang C ，Li Y ，Guo E ，Bai S ，Wang Y ，Zhang H ... -  《-》

The effect of paclitaxel and nab-paclitaxel in combination with anti-angiogenic therapy in breast cancer cell lines.

Tonissi F ，Lattanzio L ，Merlano MC ，Infante L ，Lo Nigro C ，Garrone O ... -  《-》

Combined anti-angiogenic therapy against VEGF and integrin alphaVbeta3 in an orthotopic model of ovarian cancer.

Kim TJ ，Landen CN ，Lin YG ，Mangala LS ，Lu C ，Nick AM ，Stone RL ，Merritt WM ，Armaiz-Pena G ，Jennings NB ，Coleman RL ，Tice DA ，Sood AK ... -  《-》

VEGF165b and its mutant demonstrate immunomodulatory, not merely anti-angiogenic functions, in tumor-bearing mice.

A great deal of evidence has shown that anti-angiogenic molecules and antibodies targeting the VEGF-A/VEGFRs signal pathway can also reverse tumor-induced immunosuppression to an extent. VEGF165b, an anti-angiogenic VEGF-A isoform, has demonstrated capacity as an efficacious anti-tumor therapy in mice as an anti-angiogenic agent. However, whether VEGF165b also plays an immunomodulatory role in anti-tumor field remains unclear. mVEGF165b effect on regulatory T cells (Tregs) in vitro were evaluated using flow cytometry and Cell Counting Kit-8 (CCK-8) methods. Its effects on Tregs (or Foxp3 expressing cells) and myeloid-derived suppressor cells (MDSCs) were analyzed in vivo using flow cytometry and immunostaining techniques. In this study, we found VEGF165b and its mutant (its half-life in plasma was extended 10 times while retaining its bioactivity; the VEGF165b mutant is called mVEGF165b for short) inhibited the proliferation of Tregs in vitro. In addition, mVEGF165b dramatically inhibited the accumulation of MDSCs and Tregs (or Foxp3 expressing cells) in the spleen and tumor in tumor-bearing mice. In conclusion, our findings demonstrated for the first time that VEGF165b and its mutant has immunoregulatory functions. It may be used as a potential immunomodulatory agent, beyond its anti-angiogenic capacities, in cancer therapies.

Zhang H ，Xia W ，Liang C ，Wang X ，Zhi L ，Guo C ，Niu Z ，Zhu W ... -  《-》

Targeting the insulin growth factor and the vascular endothelial growth factor pathways in ovarian cancer.

Antiangiogenic therapy is emerging as a highly promising strategy for the treatment of ovarian cancer, but the clinical benefits are usually transitory. The purpose of this study was to identify and target alternative angiogenic pathways that are upregulated in ovarian xenografts during treatment with bevacizumab. For this, angiogenesis-focused gene expression arrays were used to measure gene expression levels in SKOV3 and A2780 serous ovarian xenografts treated with bevacizumab or control. Reverse transcription-PCR was used for results validation. The insulin growth factor 1 (IGF-1) was found upregulated in tumor and stromal cells in the two ovarian xenograft models treated with bevacizumab. Cixutumumab was used to block IGF-1 signaling in vivo. Dual anti-VEGF and IGF blockade with bevacizumab and cixutumumab resulted in increased inhibition of tumor growth. Immunohistochemistry measured multivessel density, Akt activation, and cell proliferation, whereas terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay measured apoptosis in ovarian cancer xenografts. Bevacizumab and cixutumumab combination increased tumor cell apoptosis in vivo compared with therapy targeting either individual pathway. The combination blocked angiogenesis and cell proliferation but not more significantly than each antibody alone. In summary, IGF-1 activation represents an important mechanism of adaptive escape during anti-VEGF therapy in ovarian cancer. This study provides the rationale for designing bevacizumab-based combination regimens to enhance antitumor activity.

Shao M ，Hollar S ，Chambliss D ，Schmitt J ，Emerson R ，Chelladurai B ，Perkins S ，Ivan M ，Matei D ... -  《-》