Activation of the VEGFC/VEGFR3 pathway induces cancer immune escape through tumor-associated lymphatic vessels and macrophages in colorectal cancer
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PROVIDER: PRJNA435506 | ENA |
REPOSITORIES: ENA
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Project description:Colorectal cancer (CRC) is one of the major causes of cancer-related death in Western countries and is associated with increased numbers of lymphatic vessels (LVs) and tumor-associated macrophages (TAMs). The VEGFC/VEGFR3 pathway is regarded as the principal inducer of lymphangiogenesis and it contributes to metastases; however, no data are available on its role during CRC development. We found that both VEGFC and VEGFR3 were upregulated in human non-metastatic CRC, with VEGFR3 localising on both LVs and TAMs. We further proved in different preclinical models of CRC, that VEGFC/VEGFR3 axis can shape both LECs and TAMs to synergically inhibit anti-tumor immunity and promote primary CRC growth. VEGFR3-directed therapy could be envisioned for the treatment of non-metastatic CRC.
2020-03-17 | GSE110990 | GEO
Project description:While colorectal cancer liver metastasis (CRCLM) is major cause of death of colorectal cancer, the mechanism of intrahepatic dissemination (trans-lymphatic metastasis) is not fully elucidated. Lymphangiogenesis can be the mechanism of the dissemination, but there are few evidences to prove it. In this study, we attempted to clarify the mechanism using syngeneic murine CRCLM model, especially focusing on vascular endothelial growth factor C (VEGFC), a promoter of lymphangiogenesis. We confirmed that 1) intrahepatic metastasis of CRCLM via lymphatic vessels was seen and lymphangiogenesis was upregulated in the CRCLM-bearing liver, 2) the degree of lymphangiogenesis and CRCLM was significantly correlated with the expression of VEGFC in colorectal cancer (CRC) cells and 3) macrophage inflammatory protein-1α (MIP-1α) was released from CRC cells under the stimulation of VEGFC and induced migration of immature bone marrow derived cells into the liver and differentiation into macrophage, which promoted dissemination of CRCLM. These findings suggest the possibility of therapeutic strategy targeting VEGFC / MIP-1α for diminishing CRCLM. In conclusion, VEGFC in CRC cells promoted trans-lymphatic metastasis of CRCLM by upregulation of lymphangiogenesis directly and indirectly via induction of macrophages derived from bone marrow cells.
2018-09-30 | GSE113235 | GEO
Project description:Lymphogenous metastasis is an important event in the progression of many human cancers, and is associated with expression of vascular endothelial growth factor-D (VEGF-D). Changes to the lymphatic vasculature can occur during metastasis, and may aid metastatic spread. We investigated the effect of tumour derived VEGFD on the endothelium of the collecting lymphatic vessels draining primary tumors. We used microarrays to detail the changes in gene expression in the collecting lymphatic endothelium of mice with 293EBNA xenografts compared to 293EBNA xenografts overexpressing VEGFD. Mice were injected with 293EBNA cells (transfected with either empty APEX vector, or vector containing VEGFD) and tumours were allowed to grow to size. Mice were sacrificed and collecting lymphatic vessels were dissected. The endothelial cell population was isolated and RNA was extracted and hybridized on Affymetrix microarrays.
2012-01-15 | E-GEOD-34135 | biostudies-arrayexpress
Project description:Lymphogenous metastasis is an important event in the progression of many human cancers, and is associated with expression of vascular endothelial growth factor-D (VEGF-D). Changes to the lymphatic vasculature can occur during metastasis, and may aid metastatic spread. We investigated the effect of tumour derived VEGFD on the endothelium of the collecting lymphatic vessels draining primary tumors. We used microarrays to detail the changes in gene expression in the collecting lymphatic endothelium of mice with 293EBNA xenografts compared to 293EBNA xenografts overexpressing VEGFD.
2012-01-15 | GSE34135 | GEO
Project description:The development of a differentiated and functional vasculature requires coordinated control of cell fate specification, lineage differentiation and vascular network growth. Cellular proliferation is spatiotemporally regulated in developing vessel networks but how this is achieved and differentially controlled in specific lineages is unknown. Using a zebrafish forward genetic screen for mutants that form blood vessels but fail to form lymphatic vessels, we uncovered a mutant for the RNA helicase Ddx21. Ddx21 cell-autonomously regulates the early development of lymphatic endothelial cells. Ddx21 is essential for Vegfc-Vegfr3 driven endothelial cell proliferation. Ddx21 is an established regulator of ribosomal RNA transcription and in the absence of Ddx21, mutant lymphatic endothelial cells show reduced ribosome biogenesis. Ultimately, loss of Ddx21 leads to a p53-p21 dependent cell cycle arrest that blocks embryonic lymphangiogenesis. Thus, the RNA helicase Ddx21 coordinates the endothelial cell proliferative response to Vegfc-Vegfr3 signalling by balancing ribosome biogenesis and p53-p21 signalling. This mechanism may have therapeutic potential in diseases of excessive lymphangiogenesis such as in cancer metastasis or lymphatic malformation.
2021-09-09 | GSE158566 | GEO
Project description:The development of a differentiated and functional vasculature requires coordinated control of cell fate specification, lineage differentiation and vascular network growth. Cellular proliferation is spatiotemporally regulated in developing vessel networks but how this is achieved and differentially controlled in specific lineages is unknown. Using a zebrafish forward genetic screen for mutants that form blood vessels but fail to form lymphatic vessels, we uncovered a mutant for the RNA helicase Ddx21. Ddx21 cell-autonomously regulates the early development of lymphatic endothelial cells. Ddx21 is essential for Vegfc-Vegfr3 driven endothelial cell proliferation. Ddx21 is an established regulator of ribosomal RNA transcription and in the absence of Ddx21, mutant lymphatic endothelial cells show reduced ribosome biogenesis. Ultimately, loss of Ddx21 leads to a p53-p21 dependent cell cycle arrest that blocks embryonic lymphangiogenesis. Thus, the RNA helicase Ddx21 coordinates the endothelial cell proliferative response to Vegfc-Vegfr3 signalling by balancing ribosome biogenesis and p53-p21 signalling. This mechanism may have therapeutic potential in diseases of excessive lymphangiogenesis such as in cancer metastasis or lymphatic malformation.
2021-09-09 | GSE179868 | GEO
Project description:Generation of specialized blood vessels via lymphatic transdifferentiation
| PRJNA809307 | ENA
Project description:Proteolytical processing of the growth factor VEGFC through the concerted activity of CCBE1 and ADAMTS3 is required for lymphatic development to occur. How these factors act together in time and space, and which cell types produce these factors is not understood. Here we assess the function of Adamts3 and the related protease Adamts14 during zebrafish lymphangiogenesis and show both proteins to be able to process Vegfc. Only the simultaneous loss of both protein functions results in lymphatic defects identical to vegfc loss-of-function situations. Cell transplantation experiments demonstrate neuronal structures and/or fibroblasts to constitute cellular sources not only for both proteases but also for Ccbe1 and Vegfc. We further show that it is the local restriction of Vegfc maturation which is needed to trigger normal lymphatic sprouting and directional migration. Our data provide a single-cell resolution model for establishing secretion and processing hubs for Vegfc during developmental lymphangiogenesis
2020-04-28 | GSE146923 | GEO
Project description:The lineage and developmental trajectory of a cell are key determinant s of cellular identity. In the vascular system, endothelial cells (ECs) of blood and lymphatic vessels (LVs) differentiate and diversify to cater the different physiological demands of each organ . While LVs are known to originate from multiple origins , lymphatic ECs (LECs) themselves are not known to generate other cell - types . Here, we u s e recurrent imaging and lineage - tracing of ECs in zebrafish anal fins (AF) from early development through adulthood , to uncover an unexpected mechanism of specialized blood vessel formation through transdifferentiation of LECs . Moreover, we demonstrate distinct functional implications for deriving AF vessels from either LECs or blood ECs, uncovering a link between cell ontogeny and functionality. We further use scRNA - seq to characterize the different cellular populations and transition states involved in the transdifferentiation process . Finally, we show that akin to its normal development, the vasculature is re - derived from lymphatics during AF regeneration, demonstr ating that LECs in adult fish retain both potency and plasticity for generating blood ECs . Overall, our work highlights a new innate mechanism of blood vess el formation through LEC trans differentiation, and provides in vivo evidence for a link between cell ontogeny and functionality in ECs
2022-05-19 | GSE197161 | GEO
Project description:Transcriptional profiling of mouse dural lymphatic endothelial cells (LECs) in comparing AAV-Controls with AAV-VEGFC treaded mice. Objective was to determine the effect of the VEGFC treatment on global gene expression of LECs.
2023-12-29 | GSE252115 | GEO