atic cancer has the highest stromal volume of all solid purchase DHMEQ tumors, and strategies to reduce the pro-tumorigenic stroma may improve delivery of chemotherapy drugs to TCs and increase treatment efficacy in this fatal disease. We investigated the hypothesis that miR-21 expression in the PDAC stroma increases invasion and metastasis of TCs. We found that miR-21 in activated peritumoral myofibroblasts is associated with LN metastasis and shorter survival. Our results also suggest that the TCs induce the fibroblasts to express miR-21. Importantly, inhibition of miR-21 in PDAC TAFs decreases TC invasion. In multiple independent studies, high miR-21 expression in human PDAC TCs is correlated with shorter survival. As an explanation of this prognostic significance, in vitro modulation of miR-21 in PDAC TCs increases proliferation, invasion, and gemcitabine chemoresistance. However, miR-21 expression in the non-TC compartment 
plays a role in the histopathologic progression of cancer and non-cancerous conditions. In situ hybridization of 130 19219009 colon and 67 rectal cancer specimens revealed that miR-21 expression in the stroma predicts shorter disease-free survival of stage II patients. In the lung, miR-21 expression is increased in myofibroblasts of patients with pulmonary fibrosis as compared to healthy lung tissue. Its increase is driven by TGF-b released from the epithelial cells, and it potentiates the development of worsening scar tissue. In the heart, miR-21 expression increases in cardiac fibroblasts of the failing heart. In an in vivo pressure-overload-induced disease model, inhibition of miR-21 using an antagomiR decreased interstitial fibrosis and cardiac hypertrophy. In the kidney, miR-21 expression increases fibrosis due to ureteral obstruction in a murine model. Inhibition of miR-21 in vivo significantly attenuated fibrosis development. The architecture of each of these three non-cancerous conditions resembles that of the PDAC stromal environment. Furthermore, in regards to drug delivery, miR-21 in the stromal environment has been shown 15325591 to decrease angiogenesis by inhibiting RhoB in endothelial cells. These mechanisms are likely present in the majority of patients with PDAC as we show miR-21 expression in TAFs of 78.4% of earlystage PDACs. In our previous analysis, we identified a prognostic gene signature of 171 genes in PDAC TCs. However, genes with prognostic significance are not just limited to the TC compartment but have also been identified in the stroma of other malignancies. In breast cancer, 53 laser capture microdissected human samples were used to identify gene expression changes that clustered to angiogenesis, immune and hypoxic responses. These stromal changes stratified survival outcome for multiple subtypes of breast cancer and were independent of standard clinicopathologic factors. Combining the stromal gene expression changes with standard prognostic factors enhanced the survival prediction accuracy in independent datasets. Likewise, in non-small cell lung MicroRNA-21 in Fibroblasts Promotes Metastasis cancer, using 15 patient-matched cancer-associated and normal fibroblasts, 46 differentially expressed genes were identified. A subset of 11 of these genes formed a prognostic signature and were associated with survival in independent patient cohorts. While a similar analysis has not been done for PDAC, these studies provide proof of principle that stromal gene expression changes are important for biologic progression of dise
