The CXCL12-CXCR4/CXCR7 axis as a mechanism of immune resistance in gastrointestinal malignancies

Daniel, Sara K.; Seo, Yongwoo David; Pillarisetty, Venu G.

doi:10.1016/j.semcancer.2019.12.007

Cited by 144 publications

(125 citation statements)

References 204 publications

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“…CXCL12, which belongs to the C-X-C family, binds to CXCR4 and triggers various immunological effects, including stimulation of monocyte, NK, and T cell migration and changes in protein expression. CXCL12 can potentially serve as a prognostic factor for gastrointestinal malignancies, including hepatocellular carcinoma and pancreatic cancer [27][28][29]. CXCR4, which is upregulated during BC progression, interacts with CXCL12 in cancer cells to mediate tumour chemotaxis and invasion through connective tissue, suggesting that CXCR4 may be a potential target for attenuation of BC metastasis [30].…”

Section: Discussionmentioning

confidence: 99%

In silico analysis of the immune microenvironment in bladder cancer

Zhang

Zhuang

et al. 2020

BMC Cancer

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Background: Infiltrating immune and stromal cells are vital components of the bladder cancer (BC) microenvironment, which can significantly affect BC progression and outcome. However, the contribution of each subset of tumour-infiltrating immune cells is unclear. The objective of this study was to perform cell phenotyping and transcriptional profiling of the tumour immune microenvironment and analyse the association of distinct cell subsets and genes with BC prognosis. Methods: Clinical data of 412 patients with BC and 433 transcription files for normal and cancer tissues were downloaded from The Cancer Genome Atlas. The CIBERSORT algorithm was used to determine the relative abundance of 22 immune cell types in each sample and the ESTIMATE algorithm was used to identify differentially expressed genes within the tumour microenvironment of BC, which were subjected to functional enrichment and protein-protein interaction (PPI) analyses. The association of cell subsets and differentially expressed genes with patient survival and clinical parameters was examined by Cox regression analysis and the Kaplan-Meier method. Results: Resting natural killer cells and activated memory CD4 + and CD8 + T cells were associated with favourable patient outcome, whereas resting memory CD4 + T cells were associated with poor outcome. Differential expression analysis revealed 1334 genes influencing both immune and stromal cell scores; of them, 97 were predictive of overall survival in patients with BC. Among the top 10 statistically significant hub genes in the PPI network, CXCL12, FN1, LCK, and CXCR4 were found to be associated with BC prognosis. Conclusion: Tumour-infiltrating immune cells and cancer microenvironment-related genes can affect the outcomes of patients and are likely to be important determinants of both prognosis and response to immunotherapy in BC.

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Section: Discussionmentioning

confidence: 99%

In silico analysis of the immune microenvironment in bladder cancer

Zhang

Zhuang

et al. 2020

BMC Cancer

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“…The increased level of CXCL12, in the TME results in paracrine signaling via a feedback loop that promotes EMT and metastasis. It can also inhibit apoptosis through its upregulated receptors on tumor cells [65]. Fibroblasts in cancer associated status diminish SLIT2 production and subsequently by upregulation of CXCL12 as an agitation signal, promote metastatic behavior of tumor cells.…”

Section: Discussionmentioning

confidence: 99%

The double-edged sword role of fibroblasts in the interaction with cancer cells; an agent-based modeling approach

et al. 2020

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Fibroblasts as key components of tumor microenvironment show different features in the interaction with cancer cells. Although, Normal fibroblasts demonstrate anti-tumor effects, cancer associated fibroblasts are principal participant in tumor growth and invasion. The ambiguity of fibroblasts function can be regarded as two heads of its behavioral spectrum and can be subjected for mathematical modeling to identify their switching behavior. In this research, an agent-based model of mutual interactions between fibroblast and cancer cell was created. The proposed model is based on nonlinear differential equations which describes biochemical reactions of the main factors involved in fibroblasts and cancer cells communication. Also, most of the model parameters are estimated using hybrid unscented Kalman filter. The interactions between two cell types are illustrated by the dynamic modeling of TGFβ and LIF pathways as well as their crosstalk. Using analytical and computational approaches, reciprocal effects of cancer cells and fibroblasts are constructed and the role of signaling molecules in tumor progression or prevention are determined. Finally, the model is validated using a set of experimental data. The proposed dynamic modeling might be useful for designing more efficient therapies in cancer metastasis treatment and prevention.

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“…The role of CXCL12 in tumor development mainly depended on the speci c microenvironment of tumors [33] . In addition, it was found that the CXCL12-CXCR4/CXCR7 axis had a great in uence in gastrointestinal malignancies through immune resistance [34] . Further researches suggested that the mechanisms of immunotherapy resistance might be associated with the CXCL12/CXCR4 axis [35] .…”

Section: Discussionmentioning

confidence: 99%

CXCL12, A Potential Biomarker and A Vital Modulator of Tumor Immune Microenvironment (TIME) of Bladder Cancer: From A Comprehensive Analysis of TCGA Database

Wang

Wang²,

et al. 2020

Preprint

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Background: Tumor immune microenvironment (TIME) played a significant role in the initiation and progression of bladder cancer (BC). However, there are few researches regarding the association between immune-related genes (IRGs) and tumor-infiltrating immune cells (TICs) in TME of BC. Methods: We calculated the proportion of immune/stromal component and TICs in TME of 414 BC samples and 19 normal samples downloaded from The Cancer Genome Atlas (TCGA) database with the help of ESTIMATE and CIBERSORT algorithms. Differentially expressed genes (DEGs) were obtained from the comparison between Stromal and Immune Score and further analyzed by GO and KEGG enrichment analysis, as well as protein–protein interaction (PPI) network and COX regression analysis. CXC chemokine ligand-12 (CXCL12) was overlapping from the above analysis. Afterwards, single gene analysis of CXCL12 was carried out through difference analysis, paired analysis and Gene Set Enrichment Analysis (GSEA). The association between the expression of CXCL12 and TICs was assessed by difference analysis and correlation analysis.Results: The results indicated that immune and stromal component in TME of BC were associated with patients’ clinic-pathological characteristics. We further confirmed that 284 DEGs were primarily enriched in immune-associated activities and CXCL12 was the most significant gene, which shared the leading nodes in PPI network and closely related with BC patients’ survival. Single gene analysis revealed that CXCL12 was down-regulated in BC samples and significantly related with the clinic-pathological characteristics of patients. Further analysis indicated that CXCL12 greatly participated in immune-associated activities through closely communicating with TICs in TIME of BC.Conclusions: CXCL12 might be a potential biomarker and a vital modulator of TIME through communicating with multiple TICs, which might provide an extra insight for the immunotherapy of BC.

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The CXCL12-CXCR4/CXCR7 axis as a mechanism of immune resistance in gastrointestinal malignancies

Cited by 144 publications

References 204 publications

In silico analysis of the immune microenvironment in bladder cancer

In silico analysis of the immune microenvironment in bladder cancer

The double-edged sword role of fibroblasts in the interaction with cancer cells; an agent-based modeling approach

CXCL12, A Potential Biomarker and A Vital Modulator of Tumor Immune Microenvironment (TIME) of Bladder Cancer: From A Comprehensive Analysis of TCGA Database

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