Tumor vessel normalization and immunotherapy in gastric cancer

Yu, Xianzhe; He, Shan; Shen, Jian; Huang, Qiushi; Peng, Yang; Huang, Lin; Pu, Dan; Wang, Li; Li, Lü; Liu, Jinghua; Liu, Zelong; Zhu, Lingling

doi:10.1177/17588359221110176

Cited by 6 publications

(5 citation statements)

References 176 publications

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“…The crosstalk between angiogenesis and immunosuppression mechanisms within the tumor microenvironment and the therapeutic potential for the combination of antiangiogenic therapy and immunotherapy are now well-recognized ( 47 – 49 ). Based on the finding of this study, multitarget antiangiogenic combination therapy opens the avenue for the addition of an immunotherapy agent to achieve the best antitumor response in GAC.…”

Section: Discussionmentioning

confidence: 99%

Enhancing gastric cancer conventional chemotherapy effects by triple angiokinase inhibitor nintedanib in preclinical models

et al. 2023

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BackgroundGastric adenocarcinoma (GAC) is the fourth leading cause of cancer death worldwide. Systemic chemotherapy is a preferred treatment option for advanced and recurrent GAC, but response rates and survival prolongation remain limited. Tumor angiogenesis plays a critical role in GAC growth, invasion and metastasis. We investigated the antitumor efficacy of nintedanib, a potent triple angiokinase inhibitor for VEGFR-1/2/3, PDGFR-α/β and FGFR-1/2/3, alone or in combination with chemotherapy, in preclinical models of GAC.MethodsAnimal survival studies were performed in peritoneal dissemination xenografts in NOD/SCID mice using human GAC cell lines MKN-45 and KATO-III. Tumor growth inhibition studies were performed in subcutaneous xenografts in NOD/SCID mice using human GAC cell lines MKN-45 and SNU-5. The mechanistic evaluation involved Immunohistochemistry analyses in tumor tissues obtained from subcutaneous xenografts. In vitro cell viability assays were performed using a colorimetric WST-1 reagent.ResultsIn MKN-45 GAC cell-derived peritoneal dissemination xenografts, animal survival was improved by nintedanib (33%), docetaxel (100%) and irinotecan (181%), while oxaliplatin, 5-FU and epirubicin had no effect. The addition of nintedanib to docetaxel (157%) or irinotecan (214%) led to a further extension in animal survival. In KATO-III GAC cell-derived xenografts carrying FGFR2 gene amplification, nintedanib extended survival by 209%. Again, the addition of nintedanib further enhanced the animal survival benefits of docetaxel (273%) and irinotecan (332%). In MKN-45 subcutaneous xenografts, nintedanib, epirubicin, docetaxel and irinotecan reduced tumor growth (range: 68-87%), while 5-FU and oxaliplatin had a smaller effect (40%). Nintedanib addition to all chemotherapeutics demonstrated a further reduction in tumor growth. Subcutaneous tumor analysis revealed that nintedanib attenuated tumor cell proliferation, reduced tumor vasculature and increased tumor cell death.ConclusionNintedanib showed notable antitumor efficacy and significantly improved taxane or irinotecan chemotherapy responses. These findings indicate that nintedanib, alone and in combination with a taxane or irinotecan, has the potential for improving clinical GAC therapy.

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Section: Discussionmentioning

confidence: 99%

Enhancing gastric cancer conventional chemotherapy effects by triple angiokinase inhibitor nintedanib in preclinical models

et al. 2023

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“…Here, we found that rhMIF restored ART‐induced downregulation of VEGF and IL‐8 expression, tumour inhibition, vascular normalisation, and the efficiency of cisplatin transport, implicating the crucial roles of MIF in ART‐mediated antitumor effects. Moreover, tumour vascular normalisation and immune reprogramming have a synergistic effect and can enter a mutually reinforcing virtuous circle by improving the tumour microenvironment (Luo et al, 2022; Viallard & Larrivée, 2017; Yu et al, 2022). Our study demonstrated that ART could promote tumour vascular normalisation through MIF and also affect the expression of MIF, IL‐8 and VEGF, which are associated with immune response.…”

Section: Discussionmentioning

confidence: 99%

Artemisinin suppressed tumour growth and induced vascular normalisation in oral squamous cell carcinoma via inhibition of macrophage migration inhibitory factor

Fan

et al. 2022

Oral Diseases

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BackgroundTumour vascular normalisation therapy advocates a balance between pro‐angiogenic factors and anti‐angiogenic factors in tumours. Artemisinin (ART), which is derived from traditional Chinese medicine, has been shown to inhibit tumour growth; however, the relationship between ART and tumour vascular normalisation in oral squamous cell carcinoma (OSCC) has not been previously reported.MethodsDifferent concentrations(0 mg/kg, 25 mg/kg, 50 mg/kg, 100 mg/kg)of ART were used to treat the xenograft nude mice model of OSCC. The effects of ART on migration and proliferation of OSCC and human umbilical vein endothelial cells (HUVEC) cells were detected by scratch assay and CCK‐8 assay. OSCC cells with macrophage migration inhibitory factor (MIF) silenced were constructed to explore the effect of MIF.ResultsTreatment with ART inhibited the growth and angiogenesis of OSCC xenografts in nude mice and downregulated vascular endothelial growth factor (VEGF), IL‐8, and MIF expression levels. ART reduced the proliferation, migration, and tube formation of HUVEC, as well as the expression of VEGFR1 and VEGFR2. When the dose of ART was 50 mg/kg, vascular normalisation of OSCC xenografts was induced. Moreover, VEGF and IL‐8 were needed in rhMIF restoring tumour growth and inhibit vascular normalisation after the addition of rhMIF to ART‐treated cells.ConclusionArtemisinin might induce vascular normalisation and inhibit tumour growth in OSCC through the MIF‐signalling pathway.

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“…Although these possible interactions were not validated at the protein level, these findings suggest an involvement of CCL2 + ECs in establishing an immunosuppressive TME in deep layers of gastric cancer 84 . Although current AATs did not show a beneficial effect in gastric cancer, continuous efforts have shown encouraging results of combining AATs with immunotherapies in this cancer type 88 .…”

Section: [H3] Stomachmentioning

confidence: 97%

Understanding tumour endothelial cell heterogeneity and function from single-cell omics

et al. 2023

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Anti-angiogenic therapies (AATs) are used to treat different types of cancers. However, their success is limited due to insufficient efficacy and resistance. Recently, single-cell omics studies of tumour endothelial cells (TECs) have provided new mechanistic insight. Here, we overview the heterogeneity of human TECs of all tumour types studied to date, at the single cell level. Notably, most human tumour types contain varying numbers but only a small population of angiogenic TECs, the presumed targets of AATs, possibly contributing to the limited efficacy of and resistance to AATs. In general, TECs are heterogeneous within and across all tumour types, but comparing TEC phenotypes across tumours is currently challenging, due to lack of a uniform nomenclature for endothelial cells and consistent single cell analysis protocols, urgently raising the need for a more consistent approach. Nonetheless, across most tumour types, universal TEC markers (ACKR1, PLVAP, IGFBP3) can be identified. Besides angiogenesis, biological processes such as immunomodulation and extracellular matrix (ECM) organization are among the most commonly predicted enriched signatures of TECs across different tumour types.While angiogenesis and ECM targets have been considered for AAT (without the hoped success), the immunomodulatory properties of TECs have not been fully considered as a novel anti-cancer therapeutic approach. Therefore, we also discuss progress, limitations, solutions and novel targets for AAT development.

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Tumor vessel normalization and immunotherapy in gastric cancer

Cited by 6 publications

References 176 publications

Enhancing gastric cancer conventional chemotherapy effects by triple angiokinase inhibitor nintedanib in preclinical models

Enhancing gastric cancer conventional chemotherapy effects by triple angiokinase inhibitor nintedanib in preclinical models

Artemisinin suppressed tumour growth and induced vascular normalisation in oral squamous cell carcinoma via inhibition of macrophage migration inhibitory factor

Understanding tumour endothelial cell heterogeneity and function from single-cell omics

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