Chronic inflammation initiates multiple forms of K-Ras-independent mouse pancreatic cancer in the absence of TP53

Świdnicka-Siergiejko, Agnieszka Katarzyna; Gomez-Chou, Sobeyda B.; Cruz‐Monserrate, Zobeida; Deng, Defeng; Liu, Y; Huang, Haojie; Ji, Baoan; Azizian, Nancy G.; Daniluk, Jarosław; Wang, Lu; Wang, H; Maitra, Anirban; Logsdon, Craig D.

doi:10.1038/onc.2016.461

Cited by 47 publications

(35 citation statements)

References 37 publications

(40 reference statements)

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“…Specifically, we envisage that KRAS mutations increase the intensity and duration of the growth-promoting signaling network. The model can accommodate multiple experimental results, including the induction of PDAC in KC mice by mutations in other genes such as the recent findings showing that chronic inflammation in mice lacking p53 develop (inefficiently) PDAC with hyperactive YAP but without KRAS mutations [261]. As YAP plays a critical role in the network, we conclude that the rationale for targeting the network (at different points) is therefore compelling.…”

Section: Discussionmentioning

confidence: 82%

KRAS, YAP, and obesity in pancreatic cancer: A signaling network with multiple loops

Eibl

Rozengurt

2019

Seminars in Cancer Biology

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Pancreatic ductal adenocarcinoma (PDAC) continues to be a lethal disease with no efficacious treatment modalities. The incidence of PDAC is expected to increase, at least partially because of the obesity epidemic. Increased efforts to prevent or intercept this disease are clearly needed. Mutations in KRAS are initiating events in pancreatic carcinogenesis supported by genetically engineered mouse models of the disease. However, oncogenic KRAS is not entirely sufficient for the development of fully invasive PDAC. Additional genetic mutations and/or environmental, nutritional, and metabolic stressors, e.g. inflammation and obesity, are required for efficient PDAC formation with activation of KRAS downstream effectors. Multiple factors "upstream" of KRAS associated with obesity, including insulin resistance, inflammation, changes in gut microbiota and GI peptides, can enhance/modulate downstream signals. Multiple signaling networks and feedback loops "downstream" of KRAS have been described that respond to obesogenic diets. We propose that KRAS mutations potentiate a signaling network that is promoted by environmental factors. Specifically, we envisage that KRAS mutations increase the intensity and duration of the growth-promoting signaling network. As the transcriptional activator YAP plays a critical role in the network, we conclude that the rationale for targeting the network (at different points), e.g. with FDA approved drugs such as statins and metformin, is therefore compelling.

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Section: Discussionmentioning

confidence: 82%

KRAS, YAP, and obesity in pancreatic cancer: A signaling network with multiple loops

Eibl

Rozengurt

2019

Seminars in Cancer Biology

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“…Chronic inflammation has been shown to initiate pancreatic carcinogenesis without a K-ras mutation and in the absence of a tumor protein 53 (p53) mutation [167].…”

Section: Disruption Of Gut Bacteria Composition As Internal Pathogenimentioning

confidence: 99%

Chronic inflammation evoked by pathogenic stimulus during carcinogenesis

Brücher

Jamall

2019

4open

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A pathogenic (biological or chemical) stimulus is the earliest information received by a cell that can result in the disruption of homeostasis with consequent development of disease. Chronic inflammation involves many cell types with numerous cytokines and signaling pathways, the release of different components by the cells, and the crosstalk provoked by such stimuli involving subclinical chronic inflammation and is mechanistically manifold. Exosomes secrete chemicals that trigger the epithelium to produce exosome-like nanoparticles promoting chronic inflammation. Small molecules, together with various cytokines, selectively target signaling pathways inducing crosstalk that suppress apoptosis. 16S rRNA gene sequencing has become routine to provide information on the composition and abundance of bacteria found in human tissues and in reservoirs. The deregulation of autophagy with chronic stimulation of inflammation is an early phenomenon in carcinogenesis. The disruption of cell–cell integrity enables transcellular CagA migration and triggers deregulation of autophagy with the net result being chronic inflammation. The complex and insidious nature of chronic inflammation can be seen both inside and outside the cell and even with intracellular nuclear fragments such as chromatin, which itself can elicit a chronic inflammatory response within the cytoplasm and affect autophagy. The ultimate result of unresolved chronic inflammation is fibrosis, a step before tissue remodeling results in the formation of a precancerous niche (PCN). Various pathogenic stimuli associated with different neoplasms result in persistent inflammation. This ongoing disruption of homeostasis in the micromilieu of cells, tissues, and organs is an essential preamble to carcinogenesis and occurs early in that process.

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“…Studies in nongestational tissues have reported the K-Ras and H-Ras isoforms to regulate inflammation [ 42 , 43 ]. In contrast, there is limited information on the role of N-Ras and inflammation.…”

Section: Resultsmentioning

confidence: 99%

Placental Ras Regulates Inflammation Associated with Maternal Obesity

Liong

Barker

Lappas

2018

Mediators of Inflammation

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Heightened placental inflammation and dysfunction are commonly associated in pregnant obese women compared to their pregnant lean counterparts. The small GTPase superfamily members known as the rat sarcoma viral oncogene homolog (Ras) proteins, in particular, the K-Ras and H-Ras isoforms, have been implicated to regulate inflammation. The aims were to determine the placental Ras expression and activity with maternal obesity and its role in regulating placental inflammation. Human placenta was obtained at term Caesarean section from lean and obese pregnant women to determine the effect of maternal obesity on Ras protein expression and activity. To determine the effect of Ras on inflammation induced by bacterial endotoxin LPS and proinflammatory cytokines TNF-α or IL-1β, the chemical inhibitor lonafarnib (total Ras inhibitor) and siRNA (siKRAS and siHRAS) were used. Total Ras protein expression together with combined K-Ras and H-Ras activity was significantly increased in the placenta of obese pregnant women and when stimulated with LPS, IL-1β, or TNF-α. Lonafarnib significantly suppressed LPS-, IL-1β-, or TNF-α-induced IL-6, IL-8, MCP-1, and GRO-α expression and secretion in placental tissue. Primary trophoblast cells transfected with siKRAS or siHRAS demonstrated only K-Ras silencing significantly decreased IL-1β-, TNF-α-, or LPS-induced IL-6, IL-8, and MCP-1 expression and secretion. Furthermore, siKRAS significantly reduced downstream ERK-1/2 activation induced by LPS. In trophoblast cells, ERK-1/2 signalling is required for IL-6, IL-8, MCP-1, and GRO-α secretion. These studies implicate a role for K-Ras in regulating inflammation in human placenta. Suppressing overactive placental K-Ras function may prevent adverse fetal outcomes complicated by maternal obesity.

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Chronic inflammation initiates multiple forms of K-Ras-independent mouse pancreatic cancer in the absence of TP53

Cited by 47 publications

References 37 publications

KRAS, YAP, and obesity in pancreatic cancer: A signaling network with multiple loops

KRAS, YAP, and obesity in pancreatic cancer: A signaling network with multiple loops

Chronic inflammation evoked by pathogenic stimulus during carcinogenesis

Placental Ras Regulates Inflammation Associated with Maternal Obesity

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