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Primary pancreatic tumor microenvironment. PDAC stromal cells, like cancer-associated fibroblasts (CAFs) and cancer stellate cells, release the different CXCL12 isoforms in the tumor microenvironment. Cancer cells, which expressed the CXCL12-receptor on their surface, can bind the ligand. This ligand-receptor binding can cause tumor invasion, cellular proliferation, angiogenesis, epithelial to mesenchymal transition (EMT), and metastasis.
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CXCL12 is a chemokine that acts through CXCR4 and ACKR3 receptors and plays a physiological role in embryogenesis and haematopoiesis. It has an important role also in tumor development, since it is released by stromal cells of tumor microenvironment and alters the behavior of cancer cells. Many studies investigated the roles of CXCL12 in order to u...
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Citations
... In addition, the CXCR4-stromal cell-derived factor 1 axis contributes to the formation of distant organs during embryogenesis and is a recognized pathway regulating immune responses and angiogenesis [4 -6]. This axis has also been implicated in tumor invasion and metastasis in various cancers, including breast cancer [7][8][9], and has been associated with tumor growth and survival through participation in angiogenesis in glioblastoma and pancreatic cancer, emerging as a novel tumor angiogenesis pathway [10][11][12][13]. Notably, numerous studies have reported the expression of CXCR4 in tumor cells in oral squamous cell carcinoma (OSCC), a prevalent form of oral cancer, especially in cases with CXCR4/stromal cell-derived factor 1 expression, linking it to recurrence and lymph node metastasis [14,15]. ...
Cisplatin is a platinum-based compound that is widely used for treating inoperable oral squamous cell carcinoma (OSCC) in Japan; however, resistance to cisplatin presents a challenge and innovative approaches are required. We aimed to investigate the therapeutic potential of targeting the chemokine receptor CXCR4, which is involved in angiogenesis and tumor progression, using the CXCR4 inhibitor AMD3100, in combination with cisplatin. AMD3100 induced necrosis and bleeding in OSCC xenografts by inhibiting angiogenesis. We investigated the combined ability of AMD3100 plus cisplatin to enhance the antitumor effect in cisplatin-resistant OSCC. An MTS assay identified HSC-2 cells as cisplatin-resistant cells in vitro. Mice treated with the cisplatin-AMD combination exhibited the most significant reduction in tumor volume, accompanied by extensive hemorrhage and necrosis. Histological examination indicated thin and short tumor vessels in the AMD and cisplatin–AMD groups. These results indicated that cisplatin and AMD3100 had synergistic antitumor effects, highlighting their potential for vascular therapy of refractory OSCC. Antitumor vascular therapy using cisplatin combined with a CXCR4 inhibitor provides a novel strategy for addressing cisplatin-resistant OSCC.
... As a result of its selective gene splicing, seven isoforms of CXCL12 have been identified: α, β, γ, δ, ε, θ, and iso7. Among these isoforms, α and β are the most prevalent and have been extensively studied [2]. The seven isoforms are encoded by the same CXCL12 gene and share the first three exons. ...
The reciprocal modulation between the CXCL12/CXCR4/ACKR3 axis and the STAT3 signaling pathway plays a crucial role in the progression of various diseases and neoplasms. Activation of the CXCL12/CXCR4/ACKR3 axis triggers the STAT3 pathway through multiple mechanisms, while the STAT3 pathway also regulates the expression of CXCL12. This review offers a thorough and systematic analysis of the reciprocal regulatory mechanisms between the CXCL12/CXCR4/ACKR3 signaling axis and the STAT3 signaling pathway in the context of diseases, particularly tumors. It explores the potential clinical applications in tumor treatment, highlighting possible therapeutic targets and novel strategies for targeted tumor therapy.
... Furthermore, analogous outcomes have been noted in prior investigations involving diverse preclinical. In particular, elevated levels of distinct splice variants of MUC4, CXCL12, and RHAMM were identified, linking them to heightened invasiveness and metastatic potential [64,65]. While the exact mechanism of action remains unclear, it is plausible that the inhibition of migration and the expression of specific splice variants play a crucial role. ...
Pancreatic ductal adenocarcinoma (PDAC) poses significant challenges in terms of prognosis and treatment. Recent research has identified splicing deregulation as a new cancer hallmark. Herein, we investigated the largely uncharacterized alternative splicing profile and the key splicing factor SF3B1 in PDAC pancreatic cells and tissues as a potential discovery source of plausible drug targets and new predictive biomarkers of clinical outcome. The research involved a transcriptome-wide analysis, comparing profiles of splicing profiles in PDAC primary cells with normal ductal cells. This revealed more than 400 significant differential splicing events in genes involved in regulation of gene expression, primarily related to mRNA splicing, and metabolism of nucleic acids. PDAC cultures were highly sensitive to the SF3B1 modulators, E7107 and Pladienolide-B, showing IC50s in the low nanomolar range. These compounds induced apoptosis, associated to induction of the MCL-1/S splice variant. and reduced cell migration, associated to RON mis-splicing. In an orthotopic mouse model, E7107 showed promising results. Furthermore, we evaluated SF3B1 expression in specimens from 87 patients and found a significant association of SF3B1 expression with progression-free and overall survival. In conclusion, SF3B1 emerges as both a potential prognostic factor and therapeutic target in PDAC, impacting cell proliferation, migration, and apoptosis. These findings warrant future studies on this new therapeutic strategy against PDAC.
... Among the 50 types of chemokines known today, the chemokine CXCL12, which is also recognized as stromal cell-derived factor-1 (SDF-1) [4], has some characteristics that make it different from the rest of its family. Firstly, it is the only cytokine whose mRNA can be subjected to a process known as differential splicing, which is why up to six variants of this molecule have been recognized in humans (α to ϕ) [5,6]. Secondly, it is a chemokine with an almost exclusive affinity for a single receptor, with nothing to do with the promiscuity of the rest of the cytokines [7]. ...
Simple Summary
Neuroendocrine neoplasms are a heterogeneous group of malignant tumors that originate from the diffuse endocrine system. They generally have a slow course and somatostatin receptor-targeted based management is the first line of treatment. However, high-grade tumors and neuroendocrine carcinomas have a poor prognosis and somatostatin receptor-targeted therapy is not effective. The membrane receptor CXCR4 has been studied in several neoplasms and it is known to be overexpressed in aggressive tumors and associated with a worse prognosis. However, there is a lack of evidence of its use in neuroendocrine neoplasms. For that reason, this review describes the significance of CXCR4 and its possible clinical applications in the diagnostic and therapeutic management of neuroendocrine neoplasms.
Abstract
There are several well-described molecular mechanisms that influence cell growth and are related to the development of cancer. Chemokines constitute a fundamental element that is not only involved in local growth but also affects angiogenesis, tumor spread, and metastatic disease. Among them, the C-X-C motif chemokine ligand 12 (CXCL12) and its specific receptor the chemokine C-X-C motif receptor 4 (CXCR4) have been widely studied. The overexpression in cell membranes of CXCR4 has been shown to be associated with the development of different kinds of histological malignancies, such as adenocarcinomas, epidermoid carcinomas, mesenchymal tumors, or neuroendocrine neoplasms (NENs). The molecular synapsis between CXCL12 and CXCR4 leads to the interaction of G proteins and the activation of different intracellular signaling pathways in both gastroenteropancreatic (GEP) and bronchopulmonary (BP) NENs, conferring greater capacity for locoregional aggressiveness, the epithelial–mesenchymal transition (EMT), and the appearance of metastases. Therefore, it has been hypothesized as to how to design tools that target this receptor. The aim of this review is to focus on current knowledge of the relationship between CXCR4 and NENs, with a special emphasis on diagnostic and therapeutic molecular targets.
... Among the 50 types of chemokines known today, the chemokine CXCL12, which is also recognised as stromal cell-derived factor-1 (SDF-1) [4], has some characteristics that make it different from the rest of its family. Firstly, it is the only cytokine whose mRNA can be subjected to a process known as differential splicing, which is why up to 6 variants of this molecule have been recognized in humans (α to ϕ) [5,6]. Secondly, it is a chemokine with an almost exclusive affinity for a single receptor, nothing to do with the promiscuity of the rest of cytokines [7]. ...
... (www.preprints.org) | NOT PEER-REVIEWED | Posted: 15 April 2024 doi:10.20944/preprints202404.0951.v16 ...
There are several well-described molecular mechanisms that influence cell growth and are relat-ed to the development of cancer. Chemokines constitute a fundamental element which are not only involved in local growth but also affect angiogenesis, tumor spread and metastatic disease. Among them, the C-X-C motif chemokine ligand 12 (CXCL12) and its specific receptor the chemo-kine C-X-C motif receptor 4 (CXCR4) have been widely studied. The overexpression in cell mem-branes of CXCR4 has been shown to be associated with the development of different kinds of his-tological malignancies, such as adenocarcinomas, epidermoid carcinomas, mesenchymal tumors or neuroendocrine neoplasms (NENs). The molecular synapsis between CXCL12 and CXCR4 leads to the interaction of G proteins and activation of different intracellular signaling pathways in both gastroenteropancreatic (GEP) and bronchopulmonary (BP) NENs conferring greater ca-pacity for locoregional aggressiveness, epithelial-mesenchymal transition (EMT) and the ap-pearance of metastases. Therefore, it has been hypothesized how to design tools that target this receptor. The aim of this review is to focus on current knowledge of the relationship between CXCR4 and NENs, with a special emphasis on diagnostic and therapeutic molecular targets.
... Six isoforms have been identified (α, β, γ, δ, ε, and θ isoforms), and SDF-1α and SDF-1β are the most abundant. All isoforms were derived from CXCL12 via alternative splicing [81,82]. CXCL12 is the only CXC chemokine with alternative splicing variants, and it is regulated and processed more at the post-translational level than at the transcriptional level. ...
... CXCL12 is the only CXC chemokine with alternative splicing variants, and it is regulated and processed more at the post-translational level than at the transcriptional level. The six isoforms only differ in the length of the last exon, with the amino acid (AA) sequence determining the specific length for each isoform, including 89 AAs for α-isoform, 93 AAs for β-isoform, 119 AAs for γ-isoform, 140 AAs for δ-isoform, 90 AAs for ε-isoform, and 100 AAs for θ-isoform [82][83][84]. Most studies regarding CXCL12 focus only on the α isoform or do not distinguish among isoforms. ...
Cartilage plays a crucial role in the human body by forming long bones during development and growth to bear loads on joints and intervertebral discs. However, the increasing prevalence of cartilage degenerative disorders is a growing public health concern, especially due to the poor innate regenerative capacity of cartilage. Chondrocytes are a source of several inflammatory mediators that play vital roles in the pathogenesis of cartilage disorders. Among these mediators, chemokines have been explored as potential contributors to cartilage degeneration and regeneration. Our review focuses on the progress made during the last ten years in identifying the regulators and roles of chemokines and their receptors in different mechanisms related to chondrocytes and cartilage. Recent findings have demonstrated that chemokines influence cartilage both positively and negatively. Their induction and involvement in either process depends on the local molecular environment and is both site-and time-dependent. One of the challenges in defining the role of chemokines in cartilage pathology or regeneration is the apparent redundancy in the interaction of chemokines with their receptors. Hence, it is crucial to determine, for each situation, whether targeting specific chemokines or their receptors will help in developing effective therapeutic strategies for cartilage repair.
... Cancer-associated fibroblasts (CAFs) and endothelial cells (ECs) release a series of extracellular factors to establish a cellular communication network and regulate the immune response or tumor progression. [16][17][18][19] Although the TME significantly affects tumor progression and clinical outcomes, the association between cellular diversity and NAC response in tumors has not been well investigated. Therefore, there is an urgent need to comprehensively study the TME modulation of NAC and determine how it predicts and reacts to therapy. ...
... CAF_PI16 and CAF_SLIT2 showed high levels of DCN, CXCL12, SLIT2, C7, and C3, which are related to cell differentiation, recruitment, and immunoregulation. 18,24,27 In contrast, CAF_MMP1 highly expressed chemokines (CXCL1, CXCL3, CXCL5, CXCL6, CXCL8, and MIF), CAF_BMP4 expressed tumor necrosis factors (TNFSF11), and CAF_MMP1, CAF_BMP4, and CAF_FAP expressed the growth factor TGFB1, which is associated with the promotion of cell chemotaxis and growth. [28][29][30][31][32] We investigated the correlation between CAF subsets and NAC outcomes and tumor prognosis. ...
Neoadjuvant chemotherapy (NAC) for rectal cancer (RC) shows promising clinical response. The modulation of the tumor microenvironment (TME) by NAC and its association with therapeutic response remain unclear. Here, we use single-cell RNA sequencing and spatial transcriptome sequencing to examine the cell dynamics in 29 patients with RC, who are sampled pairwise before and after treatment. We construct a high-resolution cellular dynamic landscape remodeled by NAC and their associations with therapeutic response. NAC markedly reshapes the populations of cancer-associated fibroblasts (CAFs), which is strongly associated with therapeutic response. The remodeled CAF subsets regulate the TME through spatial recruitment and crosstalk to activate immunity and suppress tumor progression through multiple cytokines, including CXCL12, SLIT2, and DCN. In contrast, the epithelial-mesenchymal transition of malignant cells is upregulated by CAF_FAP through MIR4435-2HG induction, resulting in worse outcomes. Our study demonstrates that NAC inhibits tumor progression and modulates the TME by remodeling CAFs.
... To date, seven CXCL12 subtypes (α, β, γ, δ, ε, θ, and the predicted isoform iso7) have been identified from selective gene splicing on chromosome 10. Among these subtypes, α and β, consisting of 89 and 93 amino acids respectively, have been the most studied [19]. The most common α subtype is involved in various physiological or pathological processes, such as myoblasts migration during myogenesis and muscle regeneration [20], management of hematopoietic stem cell populations in the BM, and neuromodulation in the central nervous system (CNS) [21]. ...
Cancer is a multi-step disease caused by the accumulation of genetic mutations and/or epigenetic changes, and is the biggest challenge around the world. Cytokines, including chemokines, exhibit expression changes and disorders in all human cancers. These cytokine abnormalities can disrupt homeostasis and immune function, and make outstanding contributions to various stages of cancer development such as invasion, metastasis, and angiogenesis. Chemokines are a superfamily of small molecule chemoattractive cytokines that mediate a variety of cellular functions. Importantly, the interactions of chemokine members CXCL12 and its receptors CXCR4 and CXCR7 have a broad impact on tumor cell proliferation, survival, angiogenesis, metastasis, and tumor microenvironment, and thus participate in the onset and development of many cancers including leukemia, breast cancer, lung cancer, prostate cancer and multiple myeloma. Therefore, this review aims to summarize the latest research progress and future challenges regarding the role of CXCL12-CXCR4/CXCR7 signaling axis in cancer, and highlights the potential of CXCL12-CXCR4/CXCR7 as a biomarker or therapeutic target for cancer, providing essential strategies for the development of novel targeted cancer therapies.
... Other transcripts (i.e., ENST00000395795.5) still remain to be experimentally validated (Fig. 7A, B) [323,324]. It is interesting to note that three SVs have been identified in mice, different from the six SVs in humans. ...
... For CXCR4, AP1 is an AP event affecting exon 1, and AP2 is an AP event affecting exon 2.1 hematopoiesis, and angiogenesis, CXCL12 displays inflammatory functions in immune surveillance, the inflammatory response, autoimmune diseases, and tumor growth and metastasis [328]. In fact, the CXCL12/CXCR4 axis is among the most studied chemokine axes in cancer metastasis due to its capacity to support cancer cell proliferation, migration and invasion [324,331]. ...
... Differential expression of SVs Differences in transcriptional related to cancer type may cause functional heterogeneity and differences in clinical outcomes that make it difficult to identify potential prognostic biomarkers for translational studies. CXCL12 is the most primitive chemokine and is highly conserved through evolution, and it may have diverse cellular functions in various biological processes because it has multiple SVs capable of encoding different isoforms [323,324]. As shown in Fig. 7C, an analysis of the AS events of CXCL12 and CXCR4 transcripts between multiple tumor and normal tissues suggested divergent expression of CCL12-or CXCR4-SVs in tumor tissues. ...
Over the past thirty years, the importance of chemokines and their seven-transmembrane G protein-coupled receptors (GPCRs) has been increasingly recognized. Chemokine interactions with receptors trigger signaling pathway activity to form a network fundamental to diverse immune processes, including host homeostasis and responses to disease. Genetic and nongenetic regulation of both the expression and structure of chemokines and receptors conveys chemokine functional heterogeneity. Imbalances and defects in the system contribute to the pathogenesis of a variety of diseases, including cancer, immune and inflammatory diseases, and metabolic and neurological disorders, which render the system a focus of studies aiming to discover therapies and important biomarkers. The integrated view of chemokine biology underpinning divergence and plasticity has provided insights into immune dysfunction in disease states, including, among others, coronavirus disease 2019 (COVID-19). In this review, by reporting the latest advances in chemokine biology and results from analyses of a plethora of sequencing-based datasets, we outline recent advances in the understanding of the genetic variations and nongenetic heterogeneity of chemokines and receptors and provide an updated view of their contribution to the pathophysiological network, focusing on chemokine-mediated inflammation and cancer. Clarification of the molecular basis of dynamic chemokine-receptor interactions will help advance the understanding of chemokine biology to achieve precision medicine application in the clinic.
... These observations support a growing body of evidence for activities of chemokines beyond migration 40 . More specifically, the nELISA captured subtle functional differences between related chemokines, as we identified differences between the response to CXCL12alpha and CXCL12beta, despite these proteins differing by only 4 residues 41,42 . Thus, CXCL12alpha primarily induced IL-1b, whereas CXCL12beta primarily induced IFNg. ...
... Fig. 4). Our results are consistent with other functional assays showing differences in the activity of CXCL12alpha and beta [41][42][43] . This may indicate that the alpha and beta isoforms preferentially signal via different G-protein signals. ...
We present the nELISA, a miniaturised, high-throughput, and high-fidelity protein profiling platform. DNA oligonucleotides are used to pre-colocalize antibody pairs on spectrally encoded microparticles and perform displacement-mediated detection while ensuring spatial separation between non-cognate antibody pairs. Read-out is performed cost-efficiently and at high-throughput using flow cytometry. We assembled an inflammatory panel of 191 targets that were multiplexed without cross-reactivity or impact to performance vs 1-plex signals, with sensitivities as low as 0.1pg/mL and measurements across the platform spanning 8 orders of magnitude. We then performed a large-scale PBMC secretome screen, with cytokines as both perturbagens and read-outs, measuring 7,392 samples and generating ~1.5M protein datapoints in under a week, a significant advance in throughput compared to other highly multiplexed immunoassays. We uncovered 447 significant cytokine responses, including multiple putatively novel cytokine responses, that were conserved across donors and stimulation conditions. We also validated its use in phenotypic screening, and proposed applications for the nELISA in drug discovery.
