Bevacizumab terminates homeobox B9-induced tumor proliferation by silencing microenvironmental communication

Background: Homeobox B9 (HOXB9), a transcriptional factor, regulates developmental processes and tumor progression and has recently been recognized as one of important transcriptional factors related to angiogenesis. This study aimed to investigate the role of HOXB9 in tumorigenesis and angiogenesis. Methods: We examined the expression of HOXB9 in colorectal cancer using qPCR and in situ hybridization. We also examined the effect of HOXB9 overexpression in colorectal cancer using a proliferation assay, ELISA, a multiplex assay, and xenograft models. The clinical significance of HOXB9 was statistically evaluated in resected specimens. Results: HOXB9 was expressed in colorectal cancer specimens. HOXB9 induced angiogenesis and tumor proliferation in vitro, which resulted in high tumorigenicity in vivo and poor overall survival. Bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, remarkably suppressed tumor proliferation by inhibiting angiogenesis in HOXB9-overexpressing xenografts, and it improved overall survival and provided prolonged progression-free survival in HOXB9-overexpressing patients. A comprehensive multiplex assay of the supernatant of cancer cells co-cultured with human vascular endothelial cells and fibroblasts indicated significantly higher interleukin-6 (IL6) levels than those in the supernatant of monocultured cells. HOXB9 overexpression in clinical specimens was significantly correlated with increased IL6 expression. An IL6-neutralizing antibody inhibited VEGF secretion and tumor proliferation in the co-culture system. Conclusions: HOXB9 promotes the secretion of angiogenic factors, including VEGF, to induce tumor proliferation through microenvironmental production of cytokines including IL6 signaling. Moreover, silencing of VEGF or IL6 terminates cytokine release in tumor microenvironment. Thus, HOXB9 and IL6 may be potential biomarkers for bevacizumab treatment

Open Access

Bevacizumab terminates homeobox B9-induced tumor proliferation by silencing microenvironmental communicatio

Simultaneously Diagnosed and Successfully Treated Rectovaginal and Vesicovaginal Fistulae after Low Anterior Resection with Concomitant Resection of Female Genitalia

Rectovaginal fistula (RVF) and vesicovaginal fistula (VVF) are infrequent but distressing complications after pelvic surgery. However, their adequate treatment is not well described. Here, we simultaneously encountered and successfully treated RVF and VVF after radical surgery for rectal cancer. A 70-year-old woman underwent low anterior resection (LAR) combined with resection of the uterus, the bilateral adnexa, and the upper side of the vagina, as well as diverted ileostomy for rectal cancer. A month after the surgery, she developed urinary incontinence and underwent medical treatment, but her symptoms did not improve. Evaluation with contrast enema before stoma closure revealed the presence of RVF and VVF. We repaired the VVF and RVF via transabdominal and transperineal approaches. After 6 months, ileostomy was closed and the patient had no recurrence of cancer and fistula. In LAR with hysterectomy and resection of the vaginal wall, there is a risk of RVF and VVF. The excision and closure of the fistula tract and omental flap can be effective to treat both fistulae