Suppression of ovarian cancer by muscle‐mediated expression of soluble VEGFR‐1/Flt‐1 using adeno‐associated virus serotype 1‐derived vector

Abstract

Vascular endothelial growth factor (VEGF) is known to play a major role in angiogenesis in a variety of tumors. A soluble form of Flt-1 (sFlt-1), a VEGF receptor, is potentially useful as an antagonist of VEGF, and accumulating evidences suggest the applicability of sFlt-1 in tumor suppression by means of anti-angiogenesis. We previously demonstrated the efficacy of sflt-1 gene expression in situ to suppress tumor growth and ascites in ovarian cancer. Here, we demonstrate the therapeutic applicability of muscle-mediated expression of sFlt-1 in tumor-bearing mice. Initially, tumor suppressive action was confirmed by inoculating sFlt-1-expressing ovarian cancer (SHIN-3) cells into mice, both subcutaneously and intraperitoneally. To validate the therapeutic efficacy in a more clinically relevant model, adeno-associated virus vectors encoding sflt-1 were introduced into mouse skeletal muscles and were subsequently inoculated with tumor cells. As a result, high serum sFlt-1 levels were constantly observed, and the growth of both subcutaneously-and intraperitoneally-inoculated tumors was significantly suppressed. No delay in wound healing or adverse events of neuromuscular damage were noted, body weight did not change, and laboratory data, such as those representing liver and renal functions, were not affected. These results indicate that sFlt-1 suppresses growth and peritoneal dissemination of ovarian cancer by the inhibition of angiogenesis, and thus suggest the usefulness of gene therapy for ovarian cancer. ' 2006 Wiley-Liss, Inc.

Development of a mouse model for lymph node metastasis with endometrial cancer

“…According to our previous experiments, introducing pCMV-LUC-IRES-bsr does not alter the growth, migration, invasive capacity, anticancer drug sensitivity, or the radiosensitivity of cells. (13) Cells were selected in the presence of 10 lg ⁄ mL blasticidin S hydrochloride (Funakoshi, Tokyo, Japan) for 2 weeks, and the resistant cells were collected as HEC1A ⁄ VEGF-C and HEC1A ⁄ LUC.…”

Indoleamine 2,3-dioxygenase promotes peritoneal dissemination of ovarian cancer through inhibition of natural killercell function and angiogenesis promotion

“…Also, in ovarian cancer, a correlation between the intratumoral vascular density and clinical stage or prognosis was reported (23). Our previous basic studies have also shown that angiogenesis is important for ovarian cancer peritoneal dissemination, and that molecular or gene therapy targeting angiogenesis inhibits ovarian cancer peritoneal dissemination (24)(25)(26)(27). Currently, there are very few reports on the relationship between IDO expression and angiogenesis.…”

Cetuximab inhibits growth, peritoneal dissemination, and lymph node and lung metastasis of endometrial cancer, and prolongs host survival

“…On the other hand, Luwor et al reported that the inhibitory effect of cetuximab on VEGF-A production was mediated by hypoxia-inducible factor-1 · (HIF-1·) (24). Angiogenesis is closely involved in the progression of malignant tumors (25,26). Since VEGF-A is the most important angiogenesis factor, the inhibition of VEGF-A production by cetuximab has the potential to inhibit angiogenesis in malignant tumors, leading to increased anti-tumor effects.…”