CXCL12 and Its Isoforms: Different Roles in Pancreatic Cancer?

Righetti, Alessandra; Giulietti, Matteo; Sabanovic, Berina; Occhipinti, Giulia; Principato, Giovanni; Piva, Francesco

doi:10.1155/2019/9681698

Cited by 35 publications

(32 citation statements)

References 86 publications

(191 reference statements)

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“…A single gene, CXCL12, codes for six protein isoforms in human (three in mouse), all deriving from alternative splicing of the fourth and final exon. The various forms are differentially expressed and have different affinities to glycosaminoglycans present on the cell surface and in the extracellular matrix ( 11 ). CXCL12α, an 89 amino acid protein, is the shorter and most expressed isoform ( 12 , 13 ).…”

Section: Cxcr4 and Its Ligandsmentioning

confidence: 99%

The Chemokine Receptor CXCR4 in Cell Proliferation and Tissue Regeneration

2020

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The CXCR4 receptor upon binding its ligands triggers multiple signaling pathways that orchestrate cell migration, hematopoiesis and cell homing, and retention in the bone marrow. However, CXCR4 also directly controls cell proliferation of non-hematopoietic cells. This review focuses on recent reports pointing to its pivotal role in tissue regeneration and stem cell activation, and discusses the connection to the known role of CXCR4 in promoting tumor growth. The mechanisms may be similar in all cases, since regeneration often recapitulates developmental processes, and cancer often exploits developmental pathways. Moreover, cell migration and cell proliferation appear to be downstream of the same signaling pathways. A deeper understanding of the complex signaling originating from CXCR4 is needed to exploit the opportunities to repair damaged organs safely and effectively.

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Section: Cxcr4 and Its Ligandsmentioning

confidence: 99%

The Chemokine Receptor CXCR4 in Cell Proliferation and Tissue Regeneration

2020

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“…Widely secreted in different tissues by stromal cells, fibroblasts, and epithelial cells, it binds to the extracellular matrix through a cluster of basic residues—the BBXB motif (B for basic amino acid and X any amino acid) [ 5 ]. CXCL12 binds the seven α-helical transmembrane domains (7TM), G protein-coupled (GPCR) conventional receptor CXCR4 and Atypical ChemoKine Receptor 3 (ACKR3, also known as CXCR7), and plays a key role in physiological and pathological processes, including embryogenesis, hematopoiesis, angiogenesis, and inflammation, regulating the migration of hematopoietic progenitor and stem cells, endothelial cells, and leukocytes [ 6 , 7 , 8 ]. CXCR4 is expressed in a great variety of cell types, including lymphocytes, hematopoietic stem cells, endothelial cells, epithelial cells, stromal fibroblasts, and cancer cells.…”

Section: Cxcl12/cxcr4 Axis In Tumorsmentioning

confidence: 99%

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

et al. 2020

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Deciphering the molecular alterations leading to disease initiation and progression is currently crucial to identify the most relevant targets for precision therapy in cancer patients. Cancers express a complex chemokine network influencing leucocyte infiltration and angiogenesis. Moreover, malignant cells also express a selective repertoire of chemokine receptors that sustain their growth and spread. At present, different cancer types have been shown to overexpress C-X-C chemokine receptor type 4 (CXCR4) and to respond to its ligand C-X-C motif chemokine 12 (CXCL12). The CXCL12/CXCR4 axis influences cancer biology, promoting survival, proliferation, and angiogenesis, and plays a pivotal role in directing migration of cancer cells to sites of metastases, making it a prognostic marker and a therapeutic target. More recently, mutations in the C-terminus of CXCR4 have been identified in the genomic landscape of patients affected by Waldenstrom’s macroglobulinemia, a rare B cell neoplasm. These mutations closely resemble those occurring in Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis (WHIM) syndrome, an immunodeficiency associated with CXCR4 aberrant expression and activity and with chemotherapy resistance in clinical trials. In this review, we summarize the current knowledge on the relevance of CXCR4 mutations in cancer biology, focusing on its importance as predictors of clinical presentation and response to therapy.

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“…In PDAC setting, it acts through highly expressed receptors namely CXCR4 and CXCR7[ 11 ]. Although six different CXCL12 splicing variants have been described (α, β, γ, δ, ε, θ), only some properties of α, β and γ isoforms are known[ 12 ]. The sequence of the isoforms differ significantly one from another, thus also the function of the isoforms which are not yet characterized could be different or even contrary[ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of CXCL12 isoforms in a pancreatic pre-tumour cellular model: Microarray analysis

Cecati¹,

Giulietti²,

Righetti³

et al. 2021

WJG

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BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of death among cancers, it is characterized by poor prognosis and strong chemoresistance. In the PDAC microenvironment, stromal cells release different extracellular components, including CXCL12. The CXCL12 is a chemokine promoting the communication between tumour and stromal cells. Six different splicing isoforms of CXCL12 are known (α, β, γ, δ, ε, θ) but their role in PDAC has not yet been characterized. AIM To investigate the specific role of α, β, and γ CXCL12 isoforms in PDAC onset. METHODS We used hTERT-HPNE E6/E7/KRasG12D (Human Pancreatic Nestin-Expressing) cell line as a pancreatic pre-tumour model and exposed it to the α, β, and γ CXCL12 isoforms. The altered expression profiles were assessed by microarray analyses and confirmed by Real-Time polymerase chain reaction. The functional enrichment analyses have been performed by Enrichr tool to highlight Gene Ontology enriched terms. In addition, wound healing assays have been carried out to assess the phenotypic changes, in terms of migration ability, induced by the α, β, and γ CXCL12 isoforms. RESULTS Microarray analysis of hTERT-HPNE cells treated with the three different CXCL12 isoforms highlighted that the expression of only a few genes was altered. Moreover, the α and β isoforms showed an alteration in expression of different genes, whereas γ isoform affected the expression of genes also common with α and β isoforms. The β isoform altered the expression of genes mainly involved in cell cycle regulation. In addition, all isoforms affected the expression of genes associated to cell migration, adhesion and cytoskeleton. In vitro cell migration assay confirmed that CXCL12 enhanced the migration ability of hTERT-HPNE cells. Among the CXCL12 splicing isoforms, the γ isoform showed higher induction of migration than α and β isoforms. CONCLUSION Our data suggests an involvement and different roles of CXCL12 isoforms in PDAC onset. However, more investigations are needed to confirm these preliminary observations.

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CXCL12 and Its Isoforms: Different Roles in Pancreatic Cancer?

Cited by 35 publications

References 86 publications

The Chemokine Receptor CXCR4 in Cell Proliferation and Tissue Regeneration

The Chemokine Receptor CXCR4 in Cell Proliferation and Tissue Regeneration

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

Effects of CXCL12 isoforms in a pancreatic pre-tumour cellular model: Microarray analysis

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