Cathepsin L promotes angiogenesis by regulating the CDP/Cux/VEGF-D pathway in human gastric cancer

Jin, Zhijian; Zhou, Yu; Xin, Wu; Chang, Xiaohong; Fan, Zhiyuan; Li, Fangyuan; Li, Zhen; Zhou, Quan; Li, Jianfang; Liu, Bingya

doi:10.1007/s10120-020-01080-6

Cited by 19 publications

(13 citation statements)

References 35 publications

(38 reference statements)

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“…This finding suggests that cathepsin L has a direct impact on angiogenesis in the host microenvironment, which would then have an impact on tumor progression and metastasis since both need to rapidly remodel the microvasculature to succeed. Cathepsin L having a direct effect on angiogenesis has recently been published in the literature, [52][53][54] which verifies these results. Overall, these data regarding cathepsin L verifies the utility of this new methodology and showcases that the readouts obtained are comparable to widely accepted in vivo data.…”

Section: Discussionsupporting

confidence: 67%

Bioprinting on Live Tissue for Investigating Cancer Cell Dynamics

Suarez‐Martinez

Sole-Gras

Dykes

et al. 2021

Tissue Engineering Part A

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A challenge in cancer research is the lack of physiologically responsive in vitro models that enable tracking of cancer cells in tissue-like environments. A model that enables real-time investigation of cancer cell migration, fate, and function during angiogenesis does not exist. Current models, such as 2D or 3D in vitro culturing, can contain multiple cell types, but they do not incorporate the complexity of intact microvascular networks. The objective of this study was to establish a tumor microvasculature model by demonstrating the feasibility of bioprinting cancer cells onto excised mouse tissue. Inkjet-printed DiI + breast cancer cells on mesometrium tissues from C57Bl/6 mice demonstrated cancer cells' motility and proliferation through time-lapse imaging. Colocalization of DAPI + nuclei confirmed that DiI + cancer cells remained intact postprinting. Printed DiI + 4T1 cells also remained viable after printing on Day 0 and after culture on Day 5. Time-lapse imaging over 5 days enabled tracking of cell migration and proliferation. The number of cells and cell area were significantly increased over time. After culture, cancer cell clusters were colocalized with angiogenic microvessels. The number of vascular islands, defined as disconnected endothelial cell segments, was increased for tissues with bioprinted cancer cells, which suggests that the early stages of angiogenesis were influenced by the presence of cancer cells. Bioprinting cathepsin L knockdown 4T1 cancer cells on wild-type tissues or nontarget 4T1 cells on NG2 knockout tissues served to validate the use of the model for probing tumor cell versus microenvironment changes. These results establish the potential for bioprinting cancer cells onto live mouse tissues to investigate cancer microvascular dynamics within a physiologically relevant microenvironment.

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Section: Discussionsupporting

confidence: 67%

Bioprinting on Live Tissue for Investigating Cancer Cell Dynamics

Suarez‐Martinez

Sole-Gras

Dykes

et al. 2021

Tissue Engineering Part A

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“…VEGFD, also known as c-fos-induced growth factor (FIGF), is the newest member of the VEGF family [ 19 ]. VEGFD can bind to the receptor VEGFR-2 on vascular endothelial cells, and the activation of VEGFR-2 promotes angiogenesis, tumor growth, and metastasis [ 20 ]. Several studies have proved that VEGFD contributes to the angiogenesis of gastric cancer [ 20 ], and VEGFD is a biomarker of disseminated disease in gastric cancer patients [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

LncRNA CRART16/miR-122-5p/FOS axis promotes angiogenesis of gastric cancer by upregulating VEGFD expression

Zhang

Pang

Lei

et al. 2022

Aging

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Background: We previously identified a novel lncRNA, CRART16, that could induce cetuximab resistance in colorectal cancer cells. This study explored the relationship of CRART16 expression to gastric cancer progression and the molecular mechanisms involved. Methods: We evaluated CRART16 expression in gastric cancer tissues and adjacent normal tissues from the TCGA database and our hospital. Besides, we assessed its relationship with the overall survival (OS) of patients with gastric cancer. The effects of CRART16 on gastric cancer angiogenesis were determined by endothelial tube formation assay, spheroid sprouting assay, HUVEC invasion assay, and chick embryo chorioallantoic membrane (CAM) assay. The involvement of the lncRNA CRART16/miR-122-5p/FOS axis was analyzed by western blotting and dual-luciferase reporter assay. The functions of CRART16 were confirmed in xenograft mouse models. Results: We found that CRART16 was substantially overexpressed in gastric cancer tissues compared with normal tissues, based on the TCGA database and our clinical samples. High expression of CRART16 correlated with more advanced tumor stages and poor prognosis. Overexpression of CRART16 in gastric cancer cells promoted proliferation, colony formation, angiogenesis, and bevacizumab resistance in vitro , and it promoted tumor growth and angiogenesis in vivo , and vice versa. CRART16 was found to downregulate miR-122-5p by acting as a sponge, upregulating the target oncogene FOS. Afterward, the increased FOS expression led to the upregulation of VEGFD. Conclusion: Our findings demonstrate that CRART16 promotes angiogenesis in vitro and in vivo , and CRART16 is a prognostic marker and therapeutic target in gastric cancer.

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“…In line with these findings, a poor prognosis for patients suffering from colorectal cancer with high levels of nuclear CTSL has been demonstrated [ 57 ]. Recently, a role for a CTSL‐CDP/Cux pathway has been suggested for induction of angiogenesis in gastric cancers [ 58 ]. In addition to CTSL, other cathepsins have also been implicated in cell cycle regulation.…”

Section: A Brief Account Of Cytosolic Cathepsins In Dying Cellsmentioning

confidence: 99%

Low‐level lysosomal membrane permeabilization for limited release and sublethal functions of cathepsin proteases in the cytosol and nucleus

Reinheckel

Tholen

2022

FEBS Open Bio

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For a long time, lysosomes were purely seen as organelles in charge of garbage disposal within the cell. They destroy any cargo delivered into their lumen with a plethora of highly potent hydrolytic enzymes, including various proteases. In case of damage to their limiting membranes, the lysosomes release their soluble content with detrimental outcomes for the cell. In recent years, however, this view of the lysosome changed towards acknowledging it as a platform for integration of manifold intracellular and extracellular signals. Even impaired lysosomal membrane integrity is no longer considered to be a one‐way street to cell death. Increasing evidence suggests that lysosomal enzymes, mainly cathepsin proteases, can be released in a spatially and temporarily restricted manner that is compatible with cellular survival. This way, cathepsins can act in the cytosol and the nucleus, where they affect important cellular processes such as cell division. Here, we review this evidence and discuss the routes and molecular mechanisms by which the cathepsins may reach their unusual destination.

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Cathepsin L promotes angiogenesis by regulating the CDP/Cux/VEGF-D pathway in human gastric cancer

Cited by 19 publications

References 35 publications

Bioprinting on Live Tissue for Investigating Cancer Cell Dynamics

Bioprinting on Live Tissue for Investigating Cancer Cell Dynamics

LncRNA CRART16/miR-122-5p/FOS axis promotes angiogenesis of gastric cancer by upregulating VEGFD expression

Low‐level lysosomal membrane permeabilization for limited release and sublethal functions of cathepsin proteases in the cytosol and nucleus

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