Interactions between tumor cells and cancer-associated fibroblasts (CAFs) in the tumor microenvironment 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.

The interaction between cancer and its local microenvironment can determine properties of growth and metastasis. A critical component of the tumor microenvironment in this context is the cancer-associated fibroblast (CAF), which can promote tumor growth, angiogenesis and metastasis. It has been hypothesized that CAF may be derived from mesenchymal stromal cells (MSC), derived from local or distant sources. However, the signaling mechanisms by which tumors and MSCs interact to promote CAF-dependent cancer growth are largely unknown. In this study with in vitro and in vivo models using MDA-MB231 human breast cancer cells, we demonstrate that tumor-derived osteopontin (OPN) induces MSC production of CCL5; the mechanism involves OPN binding to integrin cell surface receptors and activator protein-1 c-jun homodimer transactivation. In a murine xenograft model, concomitant inoculation of MSC with MDA-MB231 cells induces: (i) significantly increased growth and metastasis of MB231 cells and (ii) increased MSC migration to metastatic sites in lung and liver; this mechanism is both OPN and CCL5 dependent. MSCs retrieved from sites of metastases exhibit OPN-dependent expression of the CAF markers, α-smooth muscle actin, tenascin-c, CXCL12 (or stromal cell-derived factor 1) and fibroblast-specific protein-1 and the matrix metalloproteinases (MMP)-2 and MMP-9. Based upon these results, we propose that tumor-derived OPN promotes tumor progression via the transformation of MSC into CAF.

Objective: This study aims to evaluate the trends in cancer (CA) admissions and surgeries after the Affordable Care Act (ACA) Medicaid expansion. Methods: This is a retrospective study using HCUP-SID analyzing inpatient CA (pancreas, esophagus, lung, bladder, breast, colorectal, prostate, and gastric) admissions and surgeries pre- (2010–2013) and post- (2014) Medicaid expansion. Surgery was defined as observed resection rate per 100 cancer admissions. Nonexpansion (FL) and expansion states (IA, MD, and NY) were compared. A generalized linear model with a Poisson distribution and logistic regression was used with incidence rate ratios (IRR) and difference-in-differences (DID). Results: There were 317, 858 patients in our sample which included those with private insurance, Medicaid, or no insurance. Pancreas, breast, colorectal, prostate, and gastric CA admissions significantly increased in expansion states but decreased in nonexpansion states. (IRR 1.12, 1.14, 1.11, 1.34, 1.23; P < .05) Lung and colorectal CA surgeries (IRR 1.30, 1.25; P < .05) increased, while breast CA surgeries (IRR 1.25; P < .05) decreased less in expansion states. Government subsidized, or self-pay patients had greater odds of undergoing lung, bladder, and colorectal CA surgery (OR 0.45 vs 0.33; 0.60 vs 0.48; 0.47 vs 0.39; P < .05) in expansion states after reform. Conclusions: In states that expanded Medicaid coverage under the ACA, the rate of surgeries for colorectal and lung CA increased significantly, while breast CA surgeries decreased less. Parenthetically, these cancers are subject to population screening programs. We conclude that expanding insurance coverage results in enhanced access to cancer surgery.

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.