No abstract

Based on identified molecular cross-talk between the two contiguous cell populations, a mechanistic model that spurs invasion is proposed, that shows breast cancer invasion proceeds through the acquisition of a motile phenotype in tumor epithelial cells and a reactive phenotype in cancer associated fibroblasts.

Cancer associated fibroblasts (CAFs) are believed to promote tumor growth and progression. Our objective was to measure the effect of TGF-beta1 on fibroblasts isolated from invasive breast cancer patients. Fibroblasts were isolated from tissue obtained at surgery from patients with invasive breast cancer (CAF; n = 28) or normal reduction mammoplasty patients (normal; n = 10). Myofibroblast activation was measured by counting cells immunostained for smooth muscle alpha actin (ACTA2) in cultures +/- TGF-beta 1. Conditioned media (CM) was collected for invasion assays and RNA was isolated from cultures incubated in media +/- TGF-beta1 for 24 h. Q-PCR was used to measure expression of cyclin D1, fibronectin, laminin, collagen I, urokinase, stromelysin-1, and ACTA2 genes. Invasion rate was measured in chambers plated with MDA-MB-231 cells and exposed to CM in the bottom chamber; the number of cells that invaded into the bottom chamber was counted. Wilcox Rank Sum tests were used to evaluate differences in CAFs and normal fibroblasts and the effect of TGF-beta 1. There was no difference in percent myofibroblasts or invasion rate between normal and CAF cultures. However, TGF-beta1 significantly increased the percent of myofibroblasts (P < 0.01) and invasion rate (P = 0.02) in CAF cultures. Stromelysin-1 expression was significantly higher in normal versus CAF cultures (P < 0.01). TGF-beta 1 significantly increased ACTA2 expression in both normal and CAF cultures (P < 0.01). Expression of fibronectin and laminin was significantly increased by TGF-beta in CAF cultures (P < 0.01). CAFs were measurably different from normal fibroblasts in response to TGF-beta 1, suggesting that TGF-beta stimulates changes in CAFs that foster tumor invasion.

SUMMARY Elevated levels of circulating tissue factor-bearing microparticles (TFMP) have been associated with an increased risk of developing venous thromboembolism (VTE) in cancer patients. We performed a randomized phase II study to evaluate the cumulative incidence of VTE in advanced cancer patients with lower levels of TFMP not receiving thromboprophylaxis and those with higher levels of circulating TFMP randomized to enoxaparin or observation. The cumulative incidence of VTE at 2 months in the higher TFMP group randomized to enoxaparin (N=23) was 5.6% while the higher TFMP group observation arm (N=11) was 27.3% (Gray test P=0.06). The cumulative incidence of VTE in the low TFMP was 7.2% (N=32). No major haemorrhages were observed in the enoxaparin arm. The median survival for patients with higher levels of TFMP followed by observation was 11.8 months compared with 17.8 months on enoxaparin (P=0.58). In a prospective randomized trial, increased numbers of circulating TFMP detected by impedance flow cytometry identified cancer patients with a high incidence of VTE. Enoxaparin demonstrated a clear trend towards reducing the rate of VTE in patients with elevated levels of TFMP, with an overall rate of VTE similar in magnitude to the lower TFMP group.

Partnering with in-patients to prevent adverse drug events is a promising strategy but requires further study to document its efficacy.