CXCL10 and CCL21 Promote Migration of Pancreatic Cancer Cells Toward Sensory Neurons and Neural Remodeling in Tumors in Mice, Associated With Pain in Patients

Hirth, Michael; Gandla, Jagadeesh; Höper, Christiane; Gaida, Matthias M.; Agarwal, Nitin; Simonetti, Manuela; Demir, Aykut; Xie, Yong; Weiss, C.; Michalski, Christoph; Hackert, Thilo; Ebert, Matthias; Kuner, Rohini

doi:10.1053/j.gastro.2020.04.037

Cited by 94 publications

(61 citation statements)

References 23 publications

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“…In this research, a 17 immune gene survival signature (including RPRM, APOH, SSX1, MSGN1, HPR, ISM2, FGA, LBP, HAS1, CSF2, RETN, CCL2, CCL21, MMP19, PTGIS, F13A1, C1QTNF1) was generated from 401 tumor samples of early stage LUSC. Most of these genes were involved in the proliferation, invasion, and differentiation of tumor cells (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). For example, wt-p53 downstream gene RPRM could be activated by HspB2 and further inhibited pancreatic cancer cell proliferation (42).…”

Section: Discussionmentioning

confidence: 99%

A Novel Immune-Related Seventeen-Gene Signature for Predicting Early Stage Lung Squamous Cell Carcinoma Prognosis

Fan

Liu

et al. 2021

Front. Immunol.

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With the increasingly early stage lung squamous cell carcinoma (LUSC) being discovered, there is an urgent need for a comprehensive analysis of the prognostic characteristics of early stage LUSC. Here, we developed an immune-related gene signature for outcome prediction of early stage LUSC based on three independent cohorts. Differentially expressed genes (DEGs) were identified using CIBERSORT and ESTMATE algorithm. Then, a 17-immune-related gene (RPRM, APOH, SSX1, MSGN1, HPR, ISM2, FGA, LBP, HAS1, CSF2, RETN, CCL2, CCL21, MMP19, PTGIS, F13A1, C1QTNF1) signature was identified using univariate Cox regression, LASSO regression and stepwise multivariable Cox analysis based on the verified DEGs from 401 cases in The Cancer Genome Atlas (TCGA) database. Subsequently, a cohort of GSE74777 containing 107 cases downloaded from Gene Expression Omnibus (GEO) database and an independent data set consisting of 36 frozen tissues collected from National Cancer Center were used to validate the predictive value of the signature. Seventeen immune-related genes were identified from TCGA cohort, which were further used to establish a classification system to construct cases into high- and low-risk groups in terms of overall survival. This classifier was still an independent prognostic factor in multivariate analysis. In addition, another two independent cohorts and different clinical subgroups validated the significant predictive value of the signature. Further mechanism research found early stage LUSC patients with high risk had special immune cell infiltration characteristics and gene mutation profiles. In conclusion, we characterized the tumor microenvironment and established a highly predictive model for evaluating the prognosis of early stage LUSC, which may provide a lead for effective immunotherapeutic options tailored for each subtype.

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Section: Discussionmentioning

confidence: 99%

A Novel Immune-Related Seventeen-Gene Signature for Predicting Early Stage Lung Squamous Cell Carcinoma Prognosis

Fan

Liu

et al. 2021

Front. Immunol.

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“…Considering our results, use of agonists for the receptor CXCR3 at stages of low-grade lesions may be useful to modulate macrophage polarization in the microenvironment such that a predominantly inflammatory population (M1) can be sustained. However, it needs to be noted that in pancreatic cancer expression of both CXCL10 and CXCR3 in tumor tissue have been correlated with metastasis and poor prognosis ( Cannon et al, 2020 ; Hirth et al, 2020 ; Liu et al, 2011 ; Lunardi et al, 2014 ; Romero et al, 2020 ). Therefore, it is unclear if treatment of pancreatic tumors with a CXCR3 agonist will result in a polarization switch of tumor-associated macrophages that renders the lesion microenvironment less supportive for tumors, and increases efficiency of chemotherapy, or if it has a tumor-promoting effect.…”

Section: Discussionmentioning

confidence: 99%

CXCL10/CXCR3 signaling contributes to an inflammatory microenvironment and its blockade enhances progression of murine pancreatic precancerous lesions

Pandey

Martinez

Bastea

et al. 2021

eLife

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The development of pancreatic cancer requires recruitment and activation of different macrophage populations. However, little is known about how macrophages are attracted to the pancreas after injury or an oncogenic event, and how they crosstalk with lesion cells or other cells of the lesion microenvironment. Here, we delineate the importance of CXCL10/CXCR3 signaling during the early phase of murine pancreatic cancer. We show that CXCL10 is produced by pancreatic precancerous lesion cells in response to IFNγ signaling, and that inflammatory macrophages are recipients for this chemokine. CXCL10/CXCR3 signaling in macrophages mediates their chemoattraction to the pancreas, enhances their proliferation and maintains their inflammatory identity. Blocking of CXCL10/CXCR3 signaling in vivo shifts macrophage populations to a tumor promoting (Ym1+, Fizz+, Arg1+) phenotype, increases fibrosis and mediates progression of lesions, highlighting the importance of this pathway in PDA development. This is reversed when CXCL10 is overexpressed in PanIN cells.

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“…Furthermore, cytokines such as CCL5 ( Hang et al, 2013 ; Pevida et al, 2014 ), CXCL13 ( Bu et al, 2019 ), Il10 ( Huo et al, 2018 ; Apryani et al, 2020 ) and cytokines associate receptors including CCR7 ( Hirth et al, 2020 ), CXCR2 ( Xu et al, 2014 ), CXCR3 ( Bu et al, 2014 ; Hirth et al, 2020 ) have been reported to be involved in BCP. It is worth mentioning that CXCR3, CCR7, and IL10 have been reported to be the underlying mechanisms in cancer metastasis-induced BCP in human ( An et al, 2019 ; Hirth et al, 2020 ). Especially, activation of CXCR3 has also been reported to attenuate morphine analgesia in cancer pain ( Ye et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Distinct Gene Expression Patterns of Ion Channels and Cytokines in Rat Primary Sensory Neurons During Development of Bone Cancer and Cancer Pain

Zhai

Yang

Lin

et al. 2021

Front. Mol. Neurosci.

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Cancer and cancer pain processes a major clinical challenge and the underlined mechanisms of pathogenesis remain elusive. We examined the specific changes in the transcriptomic profiles in the dorsal root ganglion (DRG) neurons of rats with bone cancer and bone cancer pain (BCP) using RNA sequencing technology. The bone cancer and BCP was induced by tumor cells implantation (TCI) into the tibia bone cavity in adult female rats. One week after treatment, TCI caused up- and down-regulation of thousands of genes in DRG. These genes were mainly involved in the immune process, inflammatory response, and intracellular signaling transduction of carbohydrate and cytokine. The cAMP and calcium signaling pathways were the major processes in the initial responses. Differentially expressed gene (DEG) analysis further showed that the genes for ion channels increased during day 1-7, while the genes for cytokine signaling pathways sustainedly increased during day 7-14 after TCI. The time courses of gene expression for ion channels and cytokines support their distinct roles in the early induction and late maintenance of BCP development. In addition, among the top 500 up- and down-regulated genes, 80-90% were unique for bone cancer pain as well as neuropathic and inflammatory pain, while less than 2% were shared among the three different forms of pain. This study reveals the uniqueness of mechanisms underlying bone cancer with pain, which is, to a large extent, differently from pain after acute inflammatory and nerve injury and provides novel potential targets of DEGs for bone cancer with pain.

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CXCL10 and CCL21 Promote Migration of Pancreatic Cancer Cells Toward Sensory Neurons and Neural Remodeling in Tumors in Mice, Associated With Pain in Patients

Cited by 94 publications

References 23 publications

A Novel Immune-Related Seventeen-Gene Signature for Predicting Early Stage Lung Squamous Cell Carcinoma Prognosis

A Novel Immune-Related Seventeen-Gene Signature for Predicting Early Stage Lung Squamous Cell Carcinoma Prognosis

CXCL10/CXCR3 signaling contributes to an inflammatory microenvironment and its blockade enhances progression of murine pancreatic precancerous lesions

Distinct Gene Expression Patterns of Ion Channels and Cytokines in Rat Primary Sensory Neurons During Development of Bone Cancer and Cancer Pain

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