Interactions between tumor cells and cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TMEN) significantly influence cancer growth and metastasis. Transforming growth factor-β (TGF-β) is known to be a critical mediator of the CAF phenotype, and osteopontin (OPN) expression in tumors is associated with more aggressive phenotypes and poor patient outcomes. The potential link between these two pathways has not been previously addressed. Utilizing in vitro studies using human mesenchymal stem cells (MSCs) and MDA-MB231 (OPN+) and MCF7 (OPN−) human breast cancer cell lines, we demonstrate that OPN induces integrin-dependent MSC expression of TGF-β1 to mediate adoption of the CAF phenotype. This OPN-TGF-β1 pathway requires the transcription factor, myeloid zinc finger 1 (MZF1). In vivo studies with xenotransplant models in NOD-scid mice showed that OPN expression increases cancer growth and metastasis by mediating MSC-to-CAF transformation in a process that is MZF1- and TGF-β1-dependent. We conclude that tumor-derived OPN engenders MSC-to-CAF transformation in the microenvironment to promote tumor growth and metastasis via the OPN-MZF1-TGF-β1 pathway.

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Background There is growing concern that the quality of inpatient care may differ on weekends versus weekdays. We assessed the “weekend effect” in common urgent general operative procedures. Methods The Healthcare Cost and Utilization Project Florida State Inpatient Database (2007–2010) was queried to identify inpatient stays with urgent or emergent admissions and surgery on the same day. Included were patients undergoing appendectomy, cholecystectomy for acute cholecystitis, and hernia repair for obstructed/gangrenous hernia. Outcomes included duration of stay, inpatient mortality, hospital-adjusted charges, and postoperative complications. Controlling for hospital and patient characteristics and type of surgery, we used multilevel mixed-effects regression modeling to examine associations between patient outcomes and admissions day (weekend vs weekday). Results A total of 80,861 same-day surgeries were identified, of which 19,078 (23.6%) occurred during the weekend. Patients operated on during the weekend had greater charges by $185 (P < .05), rates of wound complications (odds ratio [OR] 1.29, 95% confidence interval [95% CI] 1.05–1.58; P <.05), and urinary tract infection (OR 1.39, 95% CI 1.05–1.85; P < .05). Patients undergoing appendectomy had greater rates of transfusion (OR 1.43, 95% CI 1.09–1.87; P = .01), wound complications (OR 1.32, 95% CI 1.04–1.68; P < .05), urinary tract infection (OR 1.76, 95% CI 1.17–2.67; P < .01), and pneumonia (OR 1.41, 95% CI 1.05–1.88; P < .05). Patients undergoing cholecystectomy had a greater duration of stay (P = .001) and greater charges (P = .003). Conclusion Patients undergoing weekend surgery for common, urgent general operations are at risk for increased postoperative complications, duration of stay, and hospital charges. Because the cause of the “weekend effect” is still unknown, future studies should focus on elucidating the characteristics that may overcome this disparity.

The epithelial to mesenchymal transition (EMT) is implicated in many processes, ranging from tissue and organogenesis to cancer and metastatic spread. Understanding the key regulatory mechanisms and mediators within this process offers the opportunity to develop novel therapeutics with broad clinical applicability. To date, several components of EMT already are targeted using pharmacologic agents in fibrosis and cancer. As our knowledge of EMT continues to grow, the potential for novel therapeutics will also increase. This review focuses on the role of EMT both as a necessary part of development and a key player in disease progression, specifically the similarity in pathways used during both processes as targets for drug development. Also, the key role of the tumor microenvironment with EMT is outlined, focusing on both co-factors and cell types with the ability to modulate the progression of EMT in cancer and metastatic disease. Lastly, we discuss the current status of clinical therapies both in development and those progressed to clinical trial specifically targeting pathologic EMTs including small molecule inhibitors, non-coding RNAs, exogenous co-factors, and adjunctive therapies to current chemotherapeutics.