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.

The purpose of this study was to evaluate the impact of polymer-coated urea on nitrogen retention, rumen microbial growth, and milk production and composition. Coated urea (CU) that is more slowly hydrolyzed to ammonia than unprotected urea could potentially be used more efficiently by rumen microorganisms. Eight cows were offered each of three diets in a randomized crossover design. Each treatment period consisted of a 14-d adjustment period and a 5-d collection period. Diets were formulated to maintain milk production while reducing plasma urea nitrogen concentrations and urinary nitrogen excretion. Diets consisted of corn silage, mixed grass/legume haylage, chopped alfalfa hay, corn meal, protein, vitamin and mineral supplements, in a total mixed ration and fed ad libitum. The diets contained 17.9%, 18.1%, and 16.4% CP and 0, 0.77%, and 0.77% CU (dry matter basis) and are denoted as CP18-CU, CP18+CU, and CP16+CU, respectively. Individual feed intakes were measured, and total fecal, and urine collections were conducted. Cows were milked twice daily at 0500 and 1700 h, and the milk sampled for composition and milk urea N analysis. Dry matter intake averaged 23.5 +/- 0.2 kg/d and was not altered by diet. Also, milk fat and true protein were not altered by diet and averaged 3.72 and 3.07%, respectively. Milk yield was highest for diets CP18-CU and CP18+CU. Significant differences were observed in N intake and excretion in urine, feces, and milk between dietary treatments. Cows fed CP16+CU consumed 11% less N than in CP18-CU. Cows fed CP18+CU showed the highest excretion of N in urine, and together with CP16+CU, the lowest N excretion in feces. Nitrogen excretion in milk was lower for cows fed CP16+CU. Calculated N balance was not significantly different between diets nor was it significantly different from zero. Efficiency of N capture in milk protein as a function of N intake was higher for animals on CP16+CU. Urinary excretion of purine derivatives was not different between diets, and estimated microbial CP was also similar. Coated urea was not effective at reducing nitrogen excretion by dairy cattle.

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.

Background -Traditional Chinese Medicine (TCM) has been used for thousands of years to treat or prevent diseases, including cancer. Good manufacturing practices (GMP) and sophisticated product analysis (PhytomicsQC) to ensure consistency are now available allowing the assessment of its utility. Polychemical Medicines, like TCM, include chemicals with distinct tissue-dependent pharmacodynamic properties that result in tissue-specific bioactivity. Determining the mode of action of these mixtures was previously unsatisfactory; however, information rich RNA microarray technologies now allow for thorough mechanistic studies of the effects complex mixtures. PHY906 is a long used four herb TCM formula employed as an adjuvant to relieve the side effects associated with chemotherapy. Animal studies documented a decrease in global toxicity and an increase in therapeutic effectiveness of chemotherapy when combined with PHY906.Methods -Using a systems biology approach, we studied tumor tissue to identify reasons for the enhancement of the antitumor effect of CPT-11 (CPT-11) by PHY906 in a well-characterized pre-clinical model; the administration of PHY906 and CPT-11 to female BDF-1 mice bearing subcutaneous Colon 38 tumors.Results -We observed that 1) individually PHY906 and CPT-11 induce distinct alterations in tumor, liver and spleen; 2) PHY906 alone predominantly induces repression of transcription and immune-suppression in tumors; 3) these effects are reverted in the presence of CPT-11, with prevalent induction of pro-apoptotic and pro-inflammatory pathways that may favor tumor rejection.Conclusions -PHY906 together with CPT-11 triggers unique changes not activated by each one alone suggesting that the combination creates a unique tissue-specific response.