Stromal Carcinoma Associated Fibroblasts Promote Drug Resistance of Human Pancreatic Cancer Cells by Modulation of ROS via CXCR4/CXCL12 Signaling

Resistance of human tumors to anticancer drugs is most often ascribed to gene mutations, gene amplification, or epigenetic changes that influence the uptake, metabolism, or export of drugs from single cells. Another important yet little-appreciated cause of anticancer drug resistance is the limited ability of drugs to penetrate tumor tissue and to reach all of the tumor cells in a potentially lethal concentration. To reach all viable cells in the tumor, anticancer drugs must be delivered efficiently through the tumor vasculature, cross the vessel wall, and traverse the tumor tissue. In addition, heterogeneity within the tumor microenvironment leads to marked gradients in the rate of cell proliferation and to regions of hypoxia and acidity, all of which can influence the sensitivity of the tumor cells to drug treatment. In this review, we describe how the tumor microenvironment may be involved in the resistance of solid tumors to chemotherapy and discuss potential strategies to improve the effectiveness of drug treatment by modifying factors relating to the tumor microenvironment. Show more

The host stromal response to an invasive epithelial carcinoma is frequently called a desmoplastic reaction (DR) and is a universal feature of pancreatic ductal adenocarcinoma (PDA). This DR is characterized by a complex interplay between the normal host epithelial cells, invading tumor cells, stromal fibroblasts, inflammatory cells, proliferating endothelial cells, an altered extracellular matrix, and growth factors activating oncogenic signaling pathways by autocrine and paracrine mechanisms. Hence, the tumor microenvironment is a dynamic process promoting tumor growth and invasion through mechanisms likely to include anoikis resistance, genomic instability, and drug resistance. Cell coculture models, murine models (xenograft and genetic), and gene expression profiling studies on human PDA biopsies have identified several key molecules, such as collagen type I, fibronectin, laminin, matrix metalloproteinases (MMP) and their inhibitors (tissue inhibitors of MMP), growth factors (transforming growth factor beta, platelet-derived growth factor, connective tissue growth factor, and hepatocyte growth factor), chemokines, and integrins as constituents of the DR. Despite these findings, it is unclear which molecular-cellular events initiate and drive desmoplasia in PDA. Accumulating evidence indicates that pancreatic stellate cells when activated switch to a myofibroblast phenotype that produces components of the extracellular matrix, MMPs, and tissue inhibitors of MMPs by activating the mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2) pathway. Based on current evidence, several therapeutic strategies are been evaluated on identified potential therapeutic targets. This review summarizes our current understanding of the mechanisms that potentially drive the DR in PDA and future possibilities for therapeutic targeting of this critical process. Show more

Gemcitabine (GEM, 2′,2′-difluorodeoxycytidine) is currently used in advanced pancreatic adenocarcinoma, with a response rate of < 20%. The purpose of our work was to improve GEM activity by addition of cannabinoids. Here, we show that GEM induces both cannabinoid receptor-1 (CB1) and cannabinoid receptor-2 (CB2) receptors by an NF-κB-dependent mechanism and that its association with cannabinoids synergistically inhibits pancreatic adenocarcinoma cell growth and increases reactive oxygen species (ROS) induced by single treatments. The antiproliferative synergism is prevented by the radical scavenger N-acetyl--cysteine and by the specific NF-κB inhibitor BAY 11-7085, demonstrating that the induction of ROS by GEM/cannabinoids and of NF-κB by GEM is required for this effect. In addition, we report that neither apoptotic nor cytostatic mechanisms are responsible for the synergistic cell growth inhibition, which is strictly associated with the enhancement of endoplasmic reticulum stress and autophagic cell death. Noteworthy, the antiproliferative synergism is stronger in GEM-resistant pancreatic cancer cell lines compared with GEM-sensitive pancreatic cancer cell lines. The combined treatment strongly inhibits growth of human pancreatic tumor cells xenografted in nude mice without apparent toxic effects. These findings support a key role of the ROS-dependent activation of an autophagic program in the synergistic growth inhibition induced by GEM/cannabinoid combination in human pancreatic cancer cells. Show more