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Objective: Abnormal tumor vascular network contributes to aberrant blood perfusion and reduced oxygenation in tumors, which lead to poor efficacy of chemotherapy and radiotherapy. We aimed to explore the effects of the tumor-derived exosomes (TDEs) and C188-9 (a small molecule inhibitor of signal transducer and activator of transcription 3, STAT3) on tumor microvascular hemodynamics and determine which blood flow oscillations for various frequency intervals are responsible for these changes., Methods: Microvascular hemodynamics parameters were recorded using a PeriFlux 6000 EPOS system in tumor surface in a nude mouse subcutaneous xenograft model. Oscillations of laser Doppler flowmetry (LDF) signal were investigated by wavelet transform analysis., Results: TDEs facilitated tumor growth at least partially was associated with increasing blood flow in smaller vessels with lower speed and decreasing the blood flow at larger vessels with higher speed. Lower oxyhemoglobin saturation (SO 2 ) on tumor surface was aggravated by TDEs, and C188-9 treatment significantly alleviated this decrease. Wavelet transform spectral analysis revealed that TDEs increased the amplitude of oscillations in four frequency intervals related to endothelial (NO-dependent and -independent), myogenic and neurogenic activities, and C188-9 had no effect on this increase., Conclusions: TDEs facilitated tumor growth partially was associated with increasing blood flow in distributing vessels, reducing blood perfusion in larger vessels, and lowering SO 2 on tumor surface. Enhanced vascular smooth muscle, endothelial and neurogenic activities occurred in tumor superficial zone., (© 2024 John Wiley & Sons Ltd.)

Multifaceted functions of the so-called "oncogene" Wip1 have been reported in a previous study, while its actual role remains to be explored in serous ovarian cancer (SOC). In this study, by performing bioinformatic analysis with a public database and immunohistochemical staining of Wip1 in tumour tissue from SOC, we concluded that decreased expression of Wip1 was associated with a higher rate of tumour metastasis and platinum-based therapy resistance and increased ascites volume, which led to poorer prognosis in SOC patients. We also found that overexpression of Wip1 in SKOV3 cells decreased the levels of several cytokines, including VEGF, by secretome profiling analysis, and Wip1 overexpression suppressed angiogenesis both in vitro and in vivo. Mechanistic studies indicated that overexpression of Wip1 decreased the expression of VEGF at both the protein and mRNA levels and that the inhibitory effect was mediated by dephosphorylation of STAT3 at Ser727. Our study uncovered the role of Wip1 in SOC and provides a novel therapeutic strategy for suppressing angiogenesis., (© 2022. The Author(s).)

Growth factor receptor bound protein 7 (GRB7) plays an important role in regulating the growth and metastasis of ovarian cancer. Angiogenesis is the basis for the growth, invasion, and metastasis of malignant tumors. In the current study, we aimed to determine whether GRB7 plays a role in regulating angiogenesis in ovarian cancer. Immunohistochemistry on tissue microarray showed that GRB7 and platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) protein expression were positively correlated in ovarian cancer tissues. GRB7 knockdown suppressed vascular endothelial growth factor A (VEGFA) expression and reduced VEGFA secretion. The effects of GRB7 -silenced SKOV-3 cells on human umbilical vein endothelial cells (HUVECs) were evaluated using a transwell cell co-culture model, which showed that knockdown of GRB7 in SKOV-3 cells suppressed HUVEC proliferation, migration, invasion, and tube formation. Moreover, knockdown of GRB7 in SKOV-3 cells downregulated the expression of proteins associated with angiogenesis, including vascular endothelial growth factor receptor-2 (VEGFR2), mitogen-activated protein kinase kinase 1 (MAP2K1/MEK1), extracellular signal-regulated kinases 1 and 2 (ERK1/2), notch receptor 1 (NOTCH1), and delta-like canonical Notch ligand 4 (DLL4) in HUVECs. In conclusion, knockdown of GRB7 in ovarian cancer cells is an attractive potential therapeutic target for the suppression of angiogenesis in ovarian cancer. GRB7 may regulate angiogenesis through VEGFA/VEGFR2 signaling and its downstream pathways.