Elevated rates of reactive oxygen species (ROS) have been detected in almost all cancers, where they promote many aspects of tumor development and progression. However, tumor cells also express increased levels of antioxidant proteins to detoxify from ROS, suggesting that a delicate balance of intracellular ROS levels is required for cancer cell function. Further, the radical generated, the location of its generation, as well as the local concentration is important for the cellular functions of ROS in cancer. A challenge for novel therapeutic strategies will be the fine tuning of intracellular ROS signaling to effectively deprive cells from ROS-induced tumor promoting events, towards tipping the balance to ROS-induced apoptotic signaling. Alternatively, therapeutic antioxidants may prevent early events in tumor development, where ROS are important. However, to effectively target cancer cells specific ROS-sensing signaling pathways that mediate the diverse stress-regulated cellular functions need to be identified. This review discusses the generation of ROS within tumor cells, their detoxification, their cellular effects, as well as the major signaling cascades they utilize, but also provides an outlook on their modulation in therapeutics.
SUMMARY Initiation of pancreatic ductal adenocarcinoma (PDA) is definitively linked to activating mutations in the KRAS oncogene. However, PDA mouse models show that mutant Kras expression early in development gives rise to a normal pancreas, with tumors forming only after a long latency or pancreatitis induction. Here we show that oncogenic KRAS upregulates endogenous EGFR expression and activation, the latter being dependent upon the EGFR ligand sheddase, ADAM17. Genetic ablation or pharmacological inhibition of EGFR or ADAM17 effectively eliminates KRAS-driven tumorigenesis in vivo. Without EGFR activity, active RAS levels are not sufficient to induce robust MEK/ERK activity, a requirement for epithelial transformation.
Macrophages infiltrating the pancreas in response to inflammation induce cellular transdifferentiation by secreting cytokines that activate NF-κB signaling and matrix metalloproteinase expression.
SUMMARY The development of pancreatic cancer requires the acquisition of oncogenic Kras mutations and up-regulation of growth factor signaling, but the relationship between these is not well established. We here show that mutant Kras alters mitochondrial metabolism in pancreatic acinar cells, resulting in increased generation of mitochondrial reactive oxygen species (mROS). Mitochondrial ROS then drives the dedifferentiation of acinar cells to a duct-like progenitor phenotype and progression to PanIN. This is mediated via the ROS-receptive kinase Protein Kinase D1 and the transcription factors NF-κB1 and NF-κB2, which up-regulate expression of the epidermal growth factor, its ligands and their sheddase ADAM17. In vivo, intercepting Kras-mediated generation of mROS reduced the formation of pre-neoplastic lesions. Hence, our data provide insight into how oncogenic Kras interacts with growth factor signaling to induce the formation of pancreatic cancer.
Desmoplasia and an inflammatory environment are defining features of pancreatic cancer. Unclear is how pancreatic cells that undergo oncogenic transformation can crosstalk with immune cells and how this contributes to the development of pancreatic lesions. Here we demonstrate that pancreatic acinar cells expressing mutant Kras can expedite their transformation to a duct-like phenotype by inducing local inflammation. Specifically, we show that KrasG12D induces the expression of intercellular adhesion molecule-1 (ICAM-1), which serves as chemoattractant for macrophages. Infiltrating macrophages amplify the formation of KrasG12D-caused abnormal pancreatic structures by re-modulating the extracellular matrix and providing cytokines such as tumor necrosis factor (TNF). Depletion of macrophages or treatment with a neutralizing antibody for ICAM-1 in mice expressing oncogenic Kras under an acinar cell-specific promoter both resulted in a decreased formation of abnormal structures and decreased progression of ADM to PanIN lesions.
Purpose: In a previous genome-wide gene expression profiling analysis using an invasion cancer cell lines model, we have identified Slug as selectively overexpressed in the highly invasive cancer cells. Here, we investigated the clinical significance of Slug in lung adenocarcinoma and the role of Slug in the process of cancer cell invasion and metastasis. Experimental Design: Real-time quantitative reverse transcription-PCR was used to investigate Slug mRNA in surgically resected lung adenocarcinoma of 54 patients and its correlation with survival.We overexpressed Slug in a lung adenocarcinoma cell line with very low Slug levels and investigated the in vitro and in vivo effects of Slug expression. Results: High expression of Slug mRNA in lung cancer tissue was significantly associated with postoperative relapse (P = 0.03) and shorter patient survival (P < 0.001). The overexpression of Slug enhanced xenograft tumor growth and increased microvessel counts in angiogenesis assay. Both inducible and constitutive overexpression of Slug suppressed the expression of E-cadherin and increased the in vitro invasive ability. Zymography revealed increased matrix metalloproteinase-2 activity in Slug overexpressed cells. ELISA, reverse transcription-PCR, and immunohistochemistry confirmed the increase of matrix metalloproteinase-2 proteins and mRNA in Slug overexpressed cells and xenograft tumors. Conclusions: Slug expression can predict the clinical outcome of lung adenocarcinoma patients. Slug is a novel invasion-promoting gene in lung adenocarcinoma.Lung cancer is the leading cause of cancer death worldwide.Metastasis is the most common cause of death in lung cancer patients and is a major obstacle to the successful treatment. The spread of tumor cells from a primary tumor to the secondary sites within the body is a complicated process involving cell proliferation and migration, degradation of basement membrane, invasion, adhesion, and angiogenesis (1). A variety of positive and negative factors are involved in this highly sophisticated process of metastasis (2). Current clinical means cannot accurately identify those patients who will develop metastasis. To develop effective new strategies for the prediction, diagnosis, and treatment of metastasis of lung cancer, molecular mechanisms controlling metastasis must be identified (3).Cancers are a mass of heterogeneous neoplastic cells with different properties, including metastatic potential (4). During cancer development, some tumor cells acquire metastatic phenotypes, overexpression of metastasis-promoting genes or loss of expression of metastasis-suppressing genes. Recently, several groups have successfully used gene expression profiling techniques and model systems with different invasive or metastatic ability to identify genes that correlate with invasiveness or metastatic potential (5 -9).Multiple rounds of in vitro and in vivo selection of subclones of cancer cells originating from the same primary lung adenocarcinoma may result in the establishment of several ...
The transdifferentiation of pancreatic acinar cells to a ductal phenotype (acinar-to-ductal metaplasia, ADM) occurs after injury or inflammation of the pancreas and is a reversible process. However, in the presence of activating Kras mutations or persistent epidermal growth factor receptor (EGF-R) signaling, cells that underwent ADM can progress to pancreatic intraepithelial lesions (PanINs) and eventually pancreatic cancer. In transgenic animal models, ADM and PanINs are initiated by high-affinity ligands for EGF-R or activating Kras mutations, but the underlying signaling mechanisms are not well understood. Here, using a conditional knockout approach, we show that Protein Kinase D1 (PKD1) is sufficient to drive the reprogramming process to a ductal phenotype and progression to PanINs. Moreover, using 3D explant culture of primary pancreatic acinar cells, we show that PKD1 acts downstream of TGFα and Kras to mediate formation of ductal structures through activation of the Notch pathway.
SUMMARY The contributions of the innate immune system to the development of pancreatic cancer are still ill-defined. Inflammatory macrophages can initiate metaplasia of pancreatic acinar cells to a duct-like phenotype (ADM), which then give rise to pancreatic intraepithelial neoplasia (PanIN) when oncogenic KRas is present. However, it remains unclear when and how this inflammatory macrophage population is replaced by tumor-promoting macrophages. We here demonstrate presence of interleukin-13 (IL-13), which can convert inflammatory into Ym1+ alternatively-activated macrophages, at ADM/PanIN lesions. We further show that Ym1+ macrophages release factors such as IL-1ra and CCL2 to drive pancreatic fibrogenesis and tumorigenesis. Treatment of mice expressing oncogenic KRas under an acinar cell-specific promoter with a neutralizing antibody for IL-13 significantly-decreased the accumulation of alternatively-activated macrophages at these lesions, resulting in decreased fibrosis and lesion growth.
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