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Anti-vascular endothelial growth factor (VEGF) therapy has demonstrated efficacy in treating human metastatic cancers, but therapeutic resistance is a practical limitation and most tumors eventually become unresponsive. To identify microenvironmental factors underlying the resistance of cancer to antiangiogenesis therapy, we conducted genomic analyses of intraperitoneal ovarian tumors in which adaptive resistance to anti-VEGF therapy (B20 antibody) developed. We found that expression of the microseminoprotein, prostate-associated (MSMP) gene was substantially upregulated in resistant compared with control tumors. MSMP secretion from cancer cells was induced by hypoxia, triggering MAPK signaling in endothelial cells to promote tube formation in vitro. Recruitment of the transcriptional repressor CCCTC-binding factor (CTCF) to the MSMP enhancer region was decreased by histone acetylation under hypoxic conditions in cancer cells. MSMP siRNA, delivered in vivo using the DOPC nanoliposomes, restored tumor sensitivity to anti-VEGF therapy. In ovarian cancer patients treated with bevacizumab, serum MSMP concentration increased significantly only in non-responders. These findings imply that MSMP inhibition combined with the use of antiangiogenesis drugs may be a new strategy to overcome resistance to antiangiogenesis therapy.

The aim of this study is to investigate the significance of lymphatic space invasion (LSI) and tumor VEGF-C expression in the lymphatic spread of ovarian cancer. By performing immunostaining using human ovarian cancer specimens, we first investigated the association between the extent of LSI and tumor VEGF-C expression, tumor lymphangiogenesis, or the lymphatic metastasis. Moreover, by performing in vitro and in vivo experiments, we elucidated the role of VEGF-C in tumor lymphangiogenesis and lymph node metastasis as well as its role as a therapeutic target in ovarian cancer. The presence of LSI was associated with lymph node metastasis in patients with ovarian cancer. VEGF-C overexpression was significantly associated with the increased LSI and LVD in ovarian cancer. VEGF-C stimulated the lymphangiogenesis in vitro, induced the new lymph vessel formation, and increased the lymph node metastasis in mice models of ovarian cancer. The attenuation of VEGF-C expression by the treatment with mTORC1 inhibitor significantly inhibited lymphangiogenesis, and decreased lymph node metastasis in mice models of ovarian cancer. The presence of LSI is an indicator of nodal metastasis and is associated with higher tumor VEGF-C expression and worse clinical outcome of ovarian cancer patients. VEGF-C plays a crucial role in tumor lymphangiogenesis and lymph node metastasis of ovarian cancer.

We investigated the role of physical examination, CT scan, chest X-ray, and Pap smear in the routine follow-up program for cervical cancer patients previously treated with radiotherapy.The records of women who had developed recurrent cervical cancer after radiotherapy were retrospectively reviewed. The optimal procedure for the detection of recurrence was evaluated according to the disease-free interval (DFI). Survival analysis was performed based on the Kaplan-Meier method and comparisons between groups were made using the log-rank test.A total of 146 recurrent cervical cancer patients were included in our database. The majority of recurrences were diagnosed either by symptoms, physical examination, or CT scan. The patients whose recurrent disease was detected by Pap smear, physical examination, or CT scan had a significantly longer survival than those detected by symptoms. When analyzed according to DFI, physical examination, and CT scan led to the detection of recurrence in patients with a DFI of 1-5 years. In contrast, chest X-ray and Pap smear only had a clinical impact on the diagnosis of recurrence in patients with a DFI of 1-2 years.Chest X-ray and Pap smear can be routinely performed for the first 2 years after radiotherapy, but can be omitted or used sparingly thereafter.