The role of chemerin and ChemR23 in stimulating the invasion of squamous oesophageal cancer cells

Kumar, J. Dinesh; Kandola, Sandhir; Tiszlavicz, László; Reisz, Zita; Dockray, Graham J.; Varró, Andrea

doi:10.1038/bjc.2016.93

Cited by 50 publications

(58 citation statements)

References 35 publications

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“…Dysregulated expression of Chemerin has been correlated with tumor progression in glioma [52], squamous cell carcinoma of oral tongue [28], esophageal cancer [30] and with tumor suppression in melanoma [53]. However, the biological effects of differential expression of Chemerin in tumor and stromal cells in the context of tumor migration have not been sufficiently explored.…”

Section: Discussionmentioning

confidence: 99%

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Senescent fibroblast-derived Chemerin promotes squamous cell carcinoma migration

et al. 2016

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Aging is associated with a rising incidence of cutaneous squamous cell carcinoma (cSCC), an aggressive skin cancer with the potential for local invasion and metastasis. Acquisition of a senescence-associated secretory phenotype (SASP) in dermal fibroblasts has been postulated to promote skin cancer progression in elderly individuals. The underlying molecular mechanisms are largely unexplored. We show that Chemerin, a previously unreported SASP factor released from senescent human dermal fibroblasts, promotes cSCC cell migration, a key feature driving tumor progression. Whereas the Chemerin abundance is downregulated in malignant cSCC cells, increased Chemerin transcripts and protein concentrations are detected in replicative senescent fibroblasts in vitro and in the fibroblast of skin sections from old donors, indicating that a Chemerin gradient is built up in the dermis of elderly. Using Transwell® migration assays, we show that Chemerin enhances the chemotaxis of different cSCC cell lines. Notably, the Chemerin receptor CCRL2 is remarkably upregulated in cSCC cell lines and human patient biopsies. Silencing Chemerin in senescent fibroblasts or the CCRL2 and GPR1 receptors in the SCL-1 cSCC cell line abrogates the Chemerin-mediated chemotaxis. Chemerin triggers the MAPK cascade via JNK and ERK1 activation, whereby the inhibition impairs the SASP- or Chemerin-mediated cSCC cell migration.Taken together, we uncover a key role for Chemerin, as a major factor in the secretome of senescent fibroblasts, promoting cSCC cell migration and possibly progression, relaying its signals through CCRL2 and GPR1 receptors with subsequent MAPK activation. These findings might have implications for targeted therapeutic interventions in elderly patients.

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Section: Discussionmentioning

confidence: 99%

“…To our knowledge, this is the first report on the role of Chemerin in cSCC cell migration, although Chemerin has been previously reported to promote gastric cancer and esophageal cancer cell invasion via induction of VEGF, MMPs and IL-6 [30, 31]. …”

Section: Discussionmentioning

confidence: 99%

Senescent fibroblast-derived Chemerin promotes squamous cell carcinoma migration

et al. 2016

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“…Our lab has recently characterized CMKLR1 as a target overexpressed in breast cancer, esophageal squamous cell carcinoma (ESCC) and pancreatic adenocarcinoma (manuscript in preparation). Increased CMKLR1 expression, chemerin-mediated tumor cell migration and invasion in ESCC were also found by Kumar et al [27]. Likewise, CMKLR1 has been implicated in neuroblastoma proliferation [28], hepatocellular carcinoma metastasis [29] and migration/invasion of gastric cancer [30].…”

Section: Introductionmentioning

confidence: 72%

“…Although known for its role in inflammation and metabolic regulation for many years, CMKLR1 and its chemokine-like ligand chemerin were only recently recognized as modulators of tumor proliferation and expansion. While other labs have reported overexpression and functional involvement of CMKLR1 in esophageal squamous cell carcinoma, hepatocellular carcinoma, neuroblastoma and gastric cancer [27-30], we have recently found CMKLR1 overexpression in breast cancer and pancreatic adenocarcinoma and have consequently developed two peptide analogs of chemerin for use in receptor-mediated tumor targeting (manuscript in preparation). These peptide analogs were based on chemerin-9, which has full agonistic activity towards the receptor CMKLR1 and corresponds to the C-terminal nine amino acids of processed chemerin [32].…”

Section: Discussionmentioning

confidence: 91%

CMKLR1-targeting peptide tracers for PET/MR imaging of breast cancer

Erdmann

Niederstadt

Koziolek

et al. 2019

Preprint

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42Molecular targeting remains to be a promising approach in cancer medicine. Knowledge 43 about molecular properties such as overexpression of G protein-coupled receptors 44 (GPCRs) is thereby offering a powerful tool for tumor-selective imaging and treatment of 45 cancer cells. We utilized chemerin-based peptides for CMKLR1 receptor targeting in a 46 breast cancer xenograft model. By conjugation with radiolabeled chelator 1,4,7,10-47 tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), we obtained a family of highly 48 specific and affine tracers for hybrid in vivo imaging with positron emission tomography 49 (PET)/ magnetic resonance (MR) and concomitant biodistribution studies. 50 Methods 51We developed five highly specific and affine peptide tracers targeting CMKLR1 by linker-52 based conjugation of chemerin peptide analogs (CG34 and CG36) with radiolabeled 53 ( 68 Ga) chelator DOTA. Our established xenograft model with target-positive DU4475 and 54 negative A549 tumors in immunodeficient nude mice enabled CMKLR1-specific imaging 55 in vivo. Therefore, we acquired small animal PET/MR images, assessed biodistribution by 56 ex vivo measurements and investigated the tracer specificity by blocking experiments. 57 Results 58The family of five CMKLR1-targeting peptide tracers demonstrated high biological activity 59 and affinity in vitro with EC50 and IC50 values being below 2 nM. Our target-positive 60 (DU4475) and target-negative (A549) xenograft model could be confirmed by ex vivo 61 analysis of CMKLR1 expression and binding. After preliminary PET imaging, the three 62 most promising tracers 68 Ga-DOTA-AHX-CG34, 68 Ga-DOTA-KCap-CG34 and 68 Ga-63 DOTA-ADX-CG34 with apparent DU4475 tumor uptake were further analyzed. Hybrid 64 PET/MR imaging along with concomitant biodistribution studies revealed distinct 65 3 CMKLR1-specific uptake (5.1% IA/g, 4.5% IA/g and 6.2% IA/g 1 h post-injection) of our 66 targeted tracers in DU4475 tumor tissue. More strikingly, the tumor uptake could be 67 blocked by excess of unlabeled peptide (6.4-fold, 7.2-fold and 3.4-fold 1 h post-injection) 68 and further confirmed the CMKLR1 specificity. As our five tracers, each with particular 69 degree of hydrophobicity, showed different results regarding tumor uptake and organ 70 distribution, we identified these three tracers with moderate, balanced properties to be the 71 most potent in receptor-mediated tumor targeting. 72 Conclusion 73 With the breast cancer cell line DU4475, we established a model endogenously 74 expressing our target CMKLR1 to evaluate our chemerin-based peptide tracers as highly 75 affine and specific targeting agents. Eventually, we demonstrated the applicability of our 76 68 Ga-labeled tracers by visualizing CMKLR1-positive breast cancer xenografts in PET/MR 77 imaging and thus developed promising theranostics for tumor treatment.78 79 Keywords 80 Tumor targeting, PET tracer, Chemokine-like receptor 1, peptide ligand, breast cancer 81 82 83 84 Molecular targeting remains to be one of the most promising approa...

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“…Proliferating cells were detected using 5-ethynyl-2 0 -deoxyuridine (EdU) as previously described (Holmberg et al 2012;Kumar et al 2016). Myofibroblasts were synchronized by incubation in serum free (SF) media for 48 h followed by treatment with medium containing 10% fetal bovine serum (full medium, FM), or hG17, or fresh SF, and incubation with EdU reagent for up to 24 h. After EdU incorporation cells were fixed in paraformaldehyde and processed using Click-iT ™ Alexa Fluor 594 (300 lL) according to the manufacturer's instructions.…”

Section: Edu Incorporationmentioning

confidence: 99%

Cell cycle dependent expression of the CCK2 receptor by gastrointestinal myofibroblasts: putative role in determining cell migration

et al. 2017

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The well‐known action of the gastric hormone gastrin in stimulating gastric acid secretion is mediated by activation of cholecystokinin‐2 receptors (CCK2R). The latter are expressed by a variety of cell types suggesting that gastrin is implicated in multiple functions. During wound healing in the stomach CCK2R may be expressed by myofibroblasts. We have now characterized CCK2R expression in cultured myofibroblasts. Immunocytochemistry showed that a relatively small proportion (1–6%) of myofibroblasts expressed the receptor regardless of the region of the gut from which they were derived, or whether from cancer or control tissue. Activation of CCK2R by human heptadecapeptide gastrin (hG17) increased intracellular calcium concentrations in a small subset of myofibroblasts indicating the presence of a functional receptor. Unexpectedly, we found over 80% of cells expressing CCK2R were also labeled with 5‐ethynyl‐2′‐deoxyuridine (EdU) which is incorporated into DNA during S‐phase of the cell cycle. hG17 did not stimulate EdU incorporation but increased migration of both EdU‐labeled and unlabelled myofibroblasts; the migratory response was inhibited by a CCK2R antagonist and by an inhibitor of IGF receptor tyrosine kinase; hG17 also increased IGF‐2 transcript abundance. The data suggest myofibroblasts express CCK2R in a restricted period of the cell cycle during S‐phase, and that gastrin accelerates migration of these cells; it also stimulates migration of adjacent cells probably through paracrine release of IGF. Together with previous findings, the results raise the prospect that gastrin controls the position of dividing myofibroblasts which may be relevant in wound healing and cancer progression in the gastrointestinal tract.

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The role of chemerin and ChemR23 in stimulating the invasion of squamous oesophageal cancer cells

Cited by 50 publications

References 35 publications

Senescent fibroblast-derived Chemerin promotes squamous cell carcinoma migration

Senescent fibroblast-derived Chemerin promotes squamous cell carcinoma migration

CMKLR1-targeting peptide tracers for PET/MR imaging of breast cancer

Cell cycle dependent expression of the CCK2 receptor by gastrointestinal myofibroblasts: putative role in determining cell migration

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