Targeting multiple tyrosine kinase receptors with Dovitinib blocks invasion and the interaction between tumor cells and cancer-associated fibroblasts in breast cancer.

A constitutive and dynamic interaction between tumor cells and their surrounding stroma is a prerequisite for tumor invasion and metastasis. Fibroblasts and myofibroblasts (collectively called cancer associated fibroblasts, CAFs) often represent the major cellular components of tumor stroma. Tumor cells secret different growth factors which induce CAFs proliferation and differentiation, and, consequently, CAFs secrete different chemokines, cytokines or growth factors which induce tumor cell invasion and metastasis. In this study we showed here that CAFs from breast cancer surgical specimens significantly induced the invasion of breast cancer cells in vitro. Most interestingly, the novel multiple tyrosine kinase inhibitor Dovitinib significantly blocked the CAFs-induced invasion of breast cancer cells by, at least in part, inhibition of the expression and secretion of CCL2, CCL5 and VEGF in CAFs. Inhibition of PI3K/Akt/mTOR signaling could be responsible for the effects of Dovitinib, since Dovitinib antagonized the promoted phosphorylated Akt after treatment with PDGF, FGF or breast cancer cell-conditioned media. Treatment with Dovitinib in combination with PI3K/Akt/mTOR signaling inhibitors Ly294002 or RAD001 resulted in additive inhibition of cell invasion. This is the first in vitro study to show that the multiple tyrosine kinase inhibitor has therapeutic activities against breast cancer metastasis by targeting both tumor cells and CAFs.

Acrylamido polyvinyl alcohol microspheres for uterine artery embolization: 12-month clinical and MR imaging results.

PURPOSE: To report the 12-month clinical and magnetic resonance (MR) imaging results of an ongoing two-center registry involving acrylamido polyvinyl alcohol (PVA) microspheres for uterine artery embolization (UAE) for leiomyomas. MATERIALS AND METHODS: A total of 69 patients underwent UAE with 500-700-microm, 700-900-microm, and 900-1,200-mum acrylamido PVA microspheres (BeadBlock). Thirty-three patients underwent UAE with a limited embolization (protocol A) and 36 patients underwent UAE with stasis as the angiographic endpoint (protocol B). Primary objectives were clinical efficacy measured by a leiomyoma-specific quality of life (QOL) questionnaire and infarction rate of leiomyomas on early contrast agent-enhanced MR imaging. Secondary objectives were in-hospital complications, patient satisfaction, and frequency of clinical failure. RESULTS: Bilateral embolization was technically successful in 68 of 69 patients. A significant decrease (P < .001) in symptom severity and increase in health-related QOL was observed at 3 and 12 months with no significant differences between embolization protocols. However, contrast agent-enhanced MR imaging showed a significantly lower rate of completely infarcted leiomyomas in protocol A compared with protocol B (P < .05). Early clinical failures in patients treated according to protocol A were caused by incomplete tumor infarction. Minor complications occurred in five of 69 patients. Patient satisfaction was similar between protocols. CONCLUSIONS: Acrylamido PVA microspheres are a clinically effective and safe embolic agent for UAE. The use of 500-700-microm spheres and a limited embolization results in an unacceptably high rate of failed tumor infarction. Superior imaging results and fewer repeat interventions can be achieved with use of 700-900-microm spheres and stasis as the angiographic endpoint.