New signals from the invasive front

Christofori, Gerhard

doi:10.1038/nature04872

Cited by 871 publications

(726 citation statements)

References 71 publications

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“…One of these barriers is formed by the basement membrane, which invading tumor cells need to cross to invade surrounding tissues or to intravasate into blood or lymphatic vessels. Epithelial-mesenchymal transition (EMT) is thought to have an important role in this process (Thiery, 2002;Christofori, 2006). EMT denotes a process that makes epithelial cells loose their typical cell-cell contacts, thereby providing them with increased migratory skills.…”

Section: Introductionmentioning

confidence: 99%

Zeb1 is required for TrkB-induced epithelial-mesenchymal transition, anoikis resistance and metastasis

Smit

Peeper

2011

Oncogene

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Anoikis (detachment-induced apoptosis) prevents the survival of cells at inappropriate sites of the body and can therefore act as a barrier to metastasis. In a functionbased genome-wide screen, we have previously identified the neurotrophic tyrosine kinase receptor TrkB as a potent suppressor of anoikis. Consistently, activated TrkB oncogenically transforms non-malignant epithelial cells and causes them to invade and produce metastatic tumors in vivo. Overexpression of activated TrkB also results in morphological transformation, resembling epithelial-mesenchymal transition (EMT). E-cadherin, an important EMT regulator, and two E-cadherin repressors, Twist and Snail, are critical for these TrkB functions. As Snail has been shown to induce Zeb1, another E-cadherin repressor, we hypothesized that Zeb1 could be a TrkB target, too. We show here that Zeb1 is required for TrkB-induced EMT in epithelial cells, as RNAi-mediated knockdown of Zeb1 reverted the morphological changes induced by TrkB. Furthermore, Zeb1 is involved in TrkB-induced anoikis resistance, migration and invasion. In vivo, knockdown of Zeb1 strongly reduced TrkB-induced metastasis. Finally, epistasis experiments showed that Zeb1 acts downstream of Twist and Snail. We conclude that Zeb1 is required for several TrkB-induced effects in vitro and in vivo, including metastasis.

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Section: Introductionmentioning

confidence: 99%

Zeb1 is required for TrkB-induced epithelial-mesenchymal transition, anoikis resistance and metastasis

Smit

Peeper

2011

Oncogene

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“…Complement proteins enhance EMT, disrupt the ECM through proteases such as MMP-9, provide chemotactic stimuli, and induce production of growth factors including hepatocyte growth factor-1 and TGF-β, complex events that can prime and encourage tumor invasion and migration (134,135).…”

Section: Complement Proteins Facilitate Invasion and Migrationmentioning

confidence: 99%

Cancer and the Complement Cascade

Rutkowski

Sughrue

Kane

et al. 2010

Molecular Cancer Research

220

249

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Despite significant research on the role of inflammation and immunosurveillance in the immunologic microenvironment of tumors, little attention has been given to the oncogenic capabilities of the complement cascade. The recent finding that complement may contribute to tumor growth suggests an insidious relationship between complement and cancer, especially in light of evidence that complement facilitates cellular proliferation and regeneration. We address the hypothesis that complement proteins promote carcinogenesis and suggest mechanisms by which complement can drive the fundamental features of cancer. Evidence shows that this diverse family of innate immune proteins facilitates dysregulation of mitogenic signaling pathways, sustained cellular proliferation, angiogenesis, insensitivity to apoptosis, invasion and migration, and escape from immunosurveillance. Given that the traditionally held functions for the complement system include innate immunity and cancer defense, our review suggests a new way of thinking about the role of complement proteins in neoplasia.

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“…Approximately 90% of all cancer deaths arise from the metastatic dissemination of primary tumors. 1,2 To date, primary colorectal carcinomas cannot be sufficiently distinguished with respect to clinical outcome parameters, such as local recurrence and metastasis, by means of conventional clinical and histopathological/immunhistochemical examination. The tumor-node-metastasis (TNM) classification represents the main tool for identifying prognostic differences among patients with early-stage colorectal cancer.…”

mentioning

confidence: 99%

Diagnostic and Prognostic Value of Metastasis Inducer S100A4 Transcripts in Plasma of Colon, Rectal, and Gastric Cancer Patients

Stein

Burock

Herrmann

et al. 2011

The Journal of Molecular Diagnostics

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Early detection of tumors and metastases is critical for improving treatment strategies and patient outcomes.The development of molecular markers and simple tests that are clinically applicable for detection, prognostication, and therapy monitoring is strongly needed. The gene S100A4 has long been known to act as a metastasis inducer. High S100A4 levels in the primary tumor are prognostic for metachronous metastasis and correlate with reduced patient survival. We provide, for the first time, a plasma-based assay for transcript quantification of S100A4 in gastrointestinal patients' plasma. We conducted a study to define the diagnostic and prognostic power of S100A4 transcripts using 466 plasma samples from colon, rectal, and gastric cancer patients. Plasma was separated, RNA was isolated, and S100A4 mRNA was determined by quantitative RT-PCR. S100A4 transcripts were increased in cancer patients of each entity (P < 0.0001) and all disease stages (P < 0.05), compared with tumor-free volunteers (sensitivities of 96%, 74%, and 90% and specificities of 59%, 82%, and 71%, for colon, rectal, and gastric cancer patients, respectively). Prospectively analyzed follow-up patients who later experienced metastasis showed higher S100A4 levels than follow-up patients without metastasis. Disease-free survival was decreased in high S100A4-expressing follow-up colorectal cancer patients (P ‫؍‬ 0.013). In summary, we developed a method for quantitative S100A4 transcript determination in plasma that allows clinical application routinely. We demonstrated the diagnostic and prognostic potential of this method for early defining cancer staging and patients' risk for metastasis. Gastrointestinal cancers, such as colon, rectal, and gastric cancers, belong to the malignancies with the highest incidences and mortalities worldwide. Approximately 90% of all cancer deaths arise from the metastatic dissemination of primary tumors. 1,2 To date, primary colorectal carcinomas cannot be sufficiently distinguished with respect to clinical outcome parameters, such as local recurrence and metastasis, by means of conventional clinical and histopathological/immunhistochemical examination. The tumor-node-metastasis (TNM) classification represents the main tool for identifying prognostic differences among patients with early-stage colorectal cancer. 3 This is also true for gastric cancer, currently evaluated by histological staging as well. 4 Therefore, early detection of tumors and metastasis is critical for improving treatment strategies and patient outcomes. There is a clear need for development of molecular markers and of simple tests that can clinically be used for detection, prognostication, and therapy monitoring of cancer. A noninvasive blood test for the early identification of high-risk cancer patients is therefore of special interest. Circulating nucleic acids and, in particular, cell-free mRNA can be detected in plasma and permit plasma-based expression profiling. 5-9 It was recently reported that extracellular plasma RNA from colon cancer pa...

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New signals from the invasive front

Cited by 871 publications

References 71 publications

Zeb1 is required for TrkB-induced epithelial-mesenchymal transition, anoikis resistance and metastasis

Zeb1 is required for TrkB-induced epithelial-mesenchymal transition, anoikis resistance and metastasis

Cancer and the Complement Cascade

Diagnostic and Prognostic Value of Metastasis Inducer S100A4 Transcripts in Plasma of Colon, Rectal, and Gastric Cancer Patients

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