RETRACTED: HIF-1α mediates tumor-nerve interactions through the up-regulation of GM-CSF in pancreatic ductal adenocarcinoma

Wang, Haotian; Jia, Rujiang; Zhao, Tiansuo; Li, Xin; Lang, Mingxiao; Lan, Chungen; Wang, Hongwei; Li, Zengxun; Zhou, Bodong; Wu, Liangliang; Sun, Yan; Wang, Xiuchao; Ren, He; Hao, Jihui

doi:10.1016/j.canlet.2019.03.036

Cited by 23 publications

(32 citation statements)

References 38 publications

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“…In particular, granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), a monomeric glycoprotein secreted by immune cells and fibroblasts, acted as a key intercellular cytokine in a pancreatic hypoxic tumor microenvironment during the formation of PNI [ 59 ]. The expression of GM‐CSF was upregulated by the oxygen‐dependent transcriptional activator hypoxia‐inducible factor 1 subunit alpha (HIF1A) [ 60 ]. Consequently, the activation of the HIF1A‐GM‐CSF pathway mediated PNI by promoting the migration and accumulation of Schwann cells in tumor tissues, resulting in a poor prognosis [ 60 ].…”

Section: Cellular Mediators Of Pnimentioning

confidence: 99%

Cellular and molecular mechanisms of perineural invasion of pancreatic ductal adenocarcinoma

Kang

Tang

2021

Cancer Communications

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a unique tumor microenvironment surrounded by an interlaced network of cancer and noncancerous cells. Recent works have revealed that the dynamic interaction between cancer cells and neuronal cells leads to perineural invasion (PNI), a clinical pathological feature of PDAC. The formation and function of PNI are dually regulated by molecular (e.g., involving neurotrophins, cytokines, chemokines, and neurotransmitters), metabolic (e.g., serine metabolism), and cellular mechanisms (e.g., involving Schwann cells, stromal cells, T cells, and macrophages). Such integrated mechanisms of PNI not only support tumor development, growth, invasion, and metastasis but also mediate the formation of pain, all of which are closely related to poor disease prognosis in PDAC. This review details the modulation, signaling pathways, detection, and clinical relevance of PNI and highlights the opportunities for further exploration that may benefit PDAC patients.

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Section: Cellular Mediators Of Pnimentioning

confidence: 99%

Cellular and molecular mechanisms of perineural invasion of pancreatic ductal adenocarcinoma

Kang

Tang

2021

Cancer Communications

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“…A hypoxic microenvironment has been correlated with tumor cell metastasis, invasiveness, angiogenesis, and chemoresistance, all of which contribute to poor long-term overall survival 39 , 40 . HIF-1α, as a principal regulatory response to hypoxia tolerance, has been shown to mediate genes associated with pancreatic cancer progression, prognosis, and surgical outcomes 13 , 14 , 16 , 41 , 42 . HIF-1α overexpression is correlated with aberrant p53 accumulation, and promotes the development of pancreatic cancer by activating downstream signaling pathways 43 , 44 .…”

Section: Discussionmentioning

confidence: 99%

“…HIF-1 plays crucial roles in regulating various downstream signaling pathways for tumor cells under hypoxic stress tolerance 11,12 . In the last decade, our group reported that several downstream factors regulated by HIF-1α were closely associated with tumor proliferation, angiogenesis, and the epithelial-mesenchymal transition [13][14][15][16][17] . Clinical trials and preclinical studies showed that targeting HIF-1α was an efficient strategy for healing pancreatic cancer 11,[18][19][20] .…”

Section: Introductionmentioning

confidence: 99%

VHH212 nanobody targeting the hypoxia-inducible factor 1α suppresses angiogenesis and potentiates gemcitabine therapy in pancreatic cancer <i>in vivo</i>

Kang

Ren

et al. 2021

Cancer Biol. Med.

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Objective: We aimed to develop a novel anti-HIF-1α intrabody to decrease gemcitabine resistance in pancreatic cancer patients. Methods: Surface plasmon resonance and glutathione S-transferase pull-down assays were conducted to identify the binding affinity and specificity of anti-HIF-1α VHH212 [a single-domain antibody (nanobody)]. Molecular dynamics simulation was used to determine the protein-protein interactions between hypoxia-inducible factor-1α (HIF-1α) and VHH212. The real-time polymerase chain reaction (PCR) and Western blot analyses were performed to identify the expressions of HIF-1α and VEGF-A in pancreatic ductal adenocarcinoma cell lines. The efficiency of the VHH212 nanobody in inhibiting the HIF-1 signaling pathway was measured using a dual-luciferase reporter assay. Finally, a PANC-1 xenograft model was developed to evaluate the anti-tumor efficiency of combined treatment. Immunohistochemistry analysis was conducted to detect the expressions of HIF-1α and VEGF-A in tumor tissues. Results: VHH212 was stably expressed in tumor cells with low cytotoxicity, high affinity, specific subcellular localization, and neutralization of HIF-1α in the cytoplasm or nucleus. The binding affinity between VHH212 and the HIF-1α PAS-B domain was 42.7 nM. Intrabody competitive inhibition of the HIF-1α heterodimer with an aryl hydrocarbon receptor nuclear translocator was used to inhibit the HIF-1/VEGF pathway in vitro. Compared with single agent gemcitabine, co-treatment with gemcitabine and a VHH212-encoding adenovirus significantly suppressed tumor growth in the xenograft model with 80.44% tumor inhibition. Conclusions:We developed an anti-HIF-1α nanobody and showed the function of VHH212 in a preclinical murine model of PANC-1 pancreatic cancer. The combination of VHH212 and gemcitabine significantly inhibited tumor development. These results suggested that combined use of anti-HIF-1α nanobodies with first-line treatment may in the future be an effective treatment for pancreatic cancer.

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“…22 For example, HIF-1α mediates CSF1 expression in pancreatic ductal adenocarcinoma cells via direct binding to the hypoxia response element in the CSF-1 promoter. 23 Therefore we hypothesized that HIF-1α mediated hypoxiainduced CSF-1 expression.…”

Section: Discussionmentioning

confidence: 99%

CSF1/CSF1R-mediated Crosstalk Between Choroidal Vascular Endothelial Cells and Macrophages Promotes Choroidal Neovascularization

Zhou

Zeng

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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Purpose This study examined the role of the CSF1/CSF1Raxis in the crosstalk between choroidal vascular endothelial cells (CVECs) and macrophages during the formation of choroidal neovascularization (CNV). Methods Quantitative reverse transcriptase (QRT)-PCR, Western blot and ELISA measured the production and release of CSF1 from human choroidal vascular endothelial cells (HCVECs) under hypoxic conditions. Western blot detected CSF1 released from HCVECs under hypoxic conditions that activated the PI3K/AKT/FOXO1 axis in human macrophages via binding to CSF1R. Transwell migration assay, qRT-PCR, and Western blot detected the effect of CSF1 released from HCVECs on macrophage migration and M2 polarization via the CSF1R/PI3K/AKT/FOXO1 pathway. Incorporation of 5-ethynyl-20-deoxyuridine, transwell migration, and tube formation assays detected the effects of CSF1/CSF1R on the behaviors of HCVECs. Fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA), and immunofluorescence detected the effect of blockade of CSF1/CSF1R on mouse laser-induced CNV. Color fundus photograph, ICGA, and FFA detected CNV lesions in neovascular AMD (nAMD) patients. ELISA detected CSF1 and CSF1R in the aqueous humor of age-related cataract and nAMD patients. Results CSF1 released from HCVECs under hypoxic conditions activated the PI3K/AKT/FOXO1 axis in human macrophages via binding to CSF1R, promoting macrophage migration and M2 polarization via up-regulation of the CSF1R/PI3K/AKT/FOXO1 pathway. Human macrophages promoted the proliferation, migration, and tube formation of HCVECs in a CSF1/CSFR1-dependent manner under hypoxic conditions. CSF1/CSF1R blockade ameliorated the formation of mouse laser-induced CNV. CSF1 and CSF1R were increased in the aqueous humor of nAMD patients. Conclusions Our results affirmed the crucial role of CSF1/CSF1R in boosting the formation of CNV and offered potential molecular targets for the treatment of nAMD.

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RETRACTED: HIF-1α mediates tumor-nerve interactions through the up-regulation of GM-CSF in pancreatic ductal adenocarcinoma

Cited by 23 publications

References 38 publications

Cellular and molecular mechanisms of perineural invasion of pancreatic ductal adenocarcinoma

Cellular and molecular mechanisms of perineural invasion of pancreatic ductal adenocarcinoma

VHH212 nanobody targeting the hypoxia-inducible factor 1α suppresses angiogenesis and potentiates gemcitabine therapy in pancreatic cancer <i>in vivo</i>

CSF1/CSF1R-mediated Crosstalk Between Choroidal Vascular Endothelial Cells and Macrophages Promotes Choroidal Neovascularization

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