Metastatic pancreatic cancer: old drugs, new paradigms

Conroy, Thierry; Gavoille, Céline; Adenis, Antoine

doi:10.1097/cco.0b013e3283473610

Cited by 31 publications

(14 citation statements)

References 50 publications

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“…Despite this, we did not observe increased metastasis of the primary Panc02 tumor to the liver upon exogenous TNF treatment. Whereas PDA readily metastasizes in other models [17], [38] and in human patients [39], [40], the Panc02 tumor does not appear to have the capabilities to metastasize spontaneously. The tumor cells showed very little gelatinolytic capacity and in vitro neither their invasive nor their adhesive capabilities were modulated by TNF stimulation.…”

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor Induces Tumor Promoting and Anti-Tumoral Effects on Pancreatic Cancer via TNFR1

et al. 2013

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Multiple activities are ascribed to the cytokine tumor necrosis factor (TNF) in health and disease. In particular, TNF was shown to affect carcinogenesis in multiple ways. This cytokine acts via the activation of two cell surface receptors, TNFR1, which is associated with inflammation, and TNFR2, which was shown to cause anti-inflammatory signaling. We assessed the effects of TNF and its two receptors on the progression of pancreatic cancer by in vivo bioluminescence imaging in a syngeneic orthotopic tumor mouse model with Panc02 cells. Mice deficient for TNFR1 were unable to spontaneously reject Panc02 tumors and furthermore displayed enhanced tumor progression. In contrast, a fraction of wild type (37.5%), TNF deficient (12.5%), and TNFR2 deficient mice (22.2%) were able to fully reject the tumor within two weeks. Pancreatic tumors in TNFR1 deficient mice displayed increased vascular density, enhanced infiltration of CD4+ T cells and CD4+ forkhead box P3 (FoxP3)+ regulatory T cells (Treg) but reduced numbers of CD8+ T cells. These alterations were further accompanied by transcriptional upregulation of IL4. Thus, TNF and TNFR1 are required in pancreatic ductal carcinoma to ensure optimal CD8+ T cell-mediated immunosurveillance and tumor rejection. Exogenous systemic administration of human TNF, however, which only interacts with murine TNFR1, accelerated tumor progression. This suggests that TNFR1 has basically the capability in the Panc02 model to trigger pro-and anti-tumoral effects but the spatiotemporal availability of TNF seems to determine finally the overall outcome.

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Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor Induces Tumor Promoting and Anti-Tumoral Effects on Pancreatic Cancer via TNFR1

et al. 2013

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“…Thus, each year nearly 37 000 patients in the United States and >213 000 people worldwide die from this form of cancer. 1, 2 Despite extensive efforts and the considerable progress made toward improving its detection 3, 4, 5, 6 and survival rates over the past few decades, 7, 8, 9 the 5-year survival rate for pancreatic cancer has not changed significantly, increasing – according to data from surveillance, epidemiology and end results 2 – from 3% in 1975 to only 5.4% in 2005 (see other reviews Conroy et al, 10 Muller et al 11 and Poruk et al 12 ).…”

Section: Open Questionsmentioning

confidence: 99%

Metabolism addiction in pancreatic cancer

2014

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Pancreatic ductal adenocarcinoma, an aggressively invasive, treatment-resistant malignancy and the fourth leading cause of cancer deaths in the United States, is usually detectable only when already inevitably fatal. Despite advances in genetic screening, mapping and molecular characterization, its pathology remains largely elusive. Renewed research interest in longstanding doctrines of tumor metabolism has led to the emergence of aberrant signaling pathways as critical factors modulating central metabolic networks that fuel pancreatic tumors. Such pathways, including those of Ras signaling, glutamine-regulatory enzymes, lipid metabolism and autophagy, are directly affected by genetic mutations and extreme tumor microenvironments that typify pancreatic tumor cells. Elucidation of these metabolic networks can be expected to yield more potent therapies against this deadly disease.

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“…It is a reality that conventional and targeted therapies which work wonderfully in vitro or in animal experiments, fail to show a similar effect in clinical trials (Kessenbrock et al, 2010; Kindler et al, 2010; Conroy et al, 2011). This observation can be explained by various differences between human and mouse pancreatic tumors.…”

Section: Antifibrotic Therapy In Pancreatic Cancer: Theoretic Benefitmentioning

confidence: 99%

How fibrosis influences imaging and surgical decisions in pancreatic cancer

Erkan¹,

Hausmann²,

Michalski³

et al. 2012

Front. Physio.

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Our understanding of pancreatic ductal adenocarcinoma (PDAC) is shifting away from a disease of malignant ductal cells-only, toward a complex system where tumor evolution is a result of interaction of cancer cells with their microenvironment. This change has led to intensification of research focusing on the fibrotic stroma of PDAC. Pancreatic stellate cells (PSCs) are the main fibroblastic cells of the pancreas which are responsible for producing the desmoplasia in chronic pancreatitis (CP) and PDAC. Clinically, the effect of desmoplasia is two-sided; on the negative side it is a hurdle in the diagnosis of PDAC because the fibrosis in cancer resembles that of CP. It is also believed that PSCs and pancreatic fibrosis are partially responsible for the therapy resistance in pancreatic cancer. On the positive side, a fibrotic pancreas is safer to operate on compared to a fatty and soft pancreas which is prone for postoperative pancreatic fistula. In this review the impact of pancreatic fibrosis on diagnosis of pancreatic cancer and surgical decisions are discussed from a clinical point of view.

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Metastatic pancreatic cancer: old drugs, new paradigms

Abstract: Gemcitabine (with or without erlotinib or capecitabine) is still the reference treatment in patients with ECOG performance status 2. Folfirinox is a new more toxic and more efficient regimen that may be considered in patients with good performance status.

Cited by 31 publications

References 50 publications

Tumor Necrosis Factor Induces Tumor Promoting and Anti-Tumoral Effects on Pancreatic Cancer via TNFR1

Tumor Necrosis Factor Induces Tumor Promoting and Anti-Tumoral Effects on Pancreatic Cancer via TNFR1

Metabolism addiction in pancreatic cancer

How fibrosis influences imaging and surgical decisions in pancreatic cancer

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