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ABSTRACT: INTRODUCTION: The chemokine fractalkine/CX3CL1 and its highly selective receptor CX3CR1 mediate critical physiological events during inflammatory responses. The fractalkine/CX3CR1 axis has been shown to play a key role in the pathogenesis and the progression of a large number of diseases in which imbalance of the immune response is frequently seen. Since our last review published in early 2010, the fractalkine/CX3CR1 axis has gained vast attention as a potential therapeutic target in the scientific community, which can be clearly seen in the large number of studies that have been published on this issue since then. AREAS COVERED: A Medline/PubMed search was performed to detect all recently published studies on the role of the fractalkine/CX3CR1 axis as a therapeutic target in a wide range of clinical diseases. EXPERT OPINION: Recently published studies further underline the high potential of the fractalkine/CX3CR1 axis as a major target for future treatment of pain, inflammation and cancer. However, no clinical trials on novel therapeutics targeting fractalkine or CX3CR1 have been initiated so far, so that the fractalkine/CX3CR1 axis does still not find application in daily clinical practice.
Expert opinion on therapeutic targets 04/2012; 16(6):613-8. · 3.72 Impact Factor
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ABSTRACT: Fractalkine, also known as CX3CL1, is the unique member of the fourth class of chemokines and mediates both chemotaxis and adhesion of inflammatory cells via its highly selective receptor CX3CR1. Fractalkine mediates inflammatory responses and pain sensation and is involved in the pathogenesis and progression of numerous inflammatory disorders and malignancies.
We performed a Medline/PubMed search to detect all published studies that explored the role of fractalkine and CX3CR1 and the possibilities of therapeutic intervention in the fractalkine/CX3CR1 axis in a wide range of clinical disorders, using CX3CR1 blocking antibodies, different fractalkine antagonists, CX3CR1 depletion or transfection of fractalkine expression vectors.
This review summarizes the role of fractalkine and its receptor CX3CR1 in various diseases, focusing on their high potential as novel therapeutic targets, with special emphasis on pancreatic diseases.
The reviewed studies provide promising results demonstrating fractalkine and CX3CR1 as potential target molecules for future therapeutics that may attenuate pain, inflammation and furthermore serve as an anti-cancer therapy. However, to date, no therapeutics targeting fractalkine or CX3CR1 are in clinical use.
Expert opinion on therapeutic targets 02/2010; 14(2):207-19. · 3.72 Impact Factor
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Maria-Theresa Mueller,
Patrick C Hermann,
Juliane Witthauer,
Belen Rubio-Viqueira,
Simon F Leicht,
Stephan Huber,
Joachim W Ellwart,
Mona Mustafa,
Peter Bartenstein, Jan G D'Haese,
Michael H Schoenberg,
Frank Berger,
Karl-Walter Jauch,
Manuel Hidalgo,
Christopher Heeschen
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ABSTRACT: Pancreatic cancers contain exclusively tumorigenic cancer stem cells (CSCs), which are highly resistant to chemotherapy, resulting in a relative increase in CSC numbers during gemcitabine treatment. Signaling through sonic hedgehog and mammalian target of rapamycin (mTOR), respectively, may be essential for CSC self-renewal and could represent putative targets for novel treatment modalities.
We used in vitro and in vivo models of pancreatic cancer to examine the effects of sonic hedgehog inhibition (cyclopamine/CUR199691) and mTOR blockade (rapamycin) on the tumorigenic CSC population.
Surprisingly, neither cyclopamine nor rapamycin alone or as supplements to chemotherapy were capable of effectively diminishing the CSC pool. Only the combined inhibition of both pathways together with chemotherapy reduced the number of CSCs to virtually undetectable levels in vitro and in vivo. Most importantly, in vivo administration of this triple combination in mice with established patient-derived pancreatic tumors was reasonably tolerated and translated into significantly prolonged long-term survival.
The combined blockade of sonic hedgehog and mTOR signaling together with standard chemotherapy is capable of eliminating pancreatic CSCs. Further preclinical investigation of this promising approach may lead to the development of a novel therapeutic strategy to improve the devastating prognosis of patients with pancreatic cancer.
Gastroenterology 06/2009; 137(3):1102-13. · 11.68 Impact Factor
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ABSTRACT: The t(14;18)(q32.3;q21), hallmark of follicular lymphoma (FL), is less frequently observed in Asian patients than in Westerners. Little is known about additional chromosomal aberrations in Asian FL patients. We applied comparative genomic hybridization (CGH) to screen for genomic imbalances in 32 biopsy samples from 23 Japanese patients with nodal FL. The t(14;18) was assessed with polymerase chain reaction (PCR) using primers for the major (MBR), 3'MBR, minor (mcr), 5'mcr, and intermediate breakpoint cluster regions (icr). In 17 of 23 patients, CGH analyses detected genomic imbalances. Gains frequently affected chromosomes 18p (6 of 23), X (5 of 23), 5 (4 of 23), 12 (4 of 23), 2 (3 of 23), and 16 (3 of 23). The only recurrent loss affected chromosome 6q (2 of 23). A t(14;18) was detected in 13 of 23 patients (56.5%). Breakpoints were located in the MBR (10 patients), in the 3'MBR, in the mcr, and in the icr (1 patient each). The frequency of aberrations detected by CGH as well as relapse-free survival were not distinctly different between patients with and without a t(14;18). In summary, no significant difference in the overall frequency of aberrations compared with Westerners was found. Despite the extended primer set used, the frequency of PCR-detected t(14;18) remained low. Additional studies are required to assess the reasons for geographic variation in FL.
Cancer Genetics and Cytogenetics 11/2005; 162(2):107-14. · 1.39 Impact Factor
