A New Antitumor Direction: Tumor-Specific Endothelial Cells

Liang, Jing; Wang, Shouqi; Zhang, Guowei; He, Baoyu; Bie, Qingli; Zhang, Bin

doi:10.3389/fonc.2021.756334

Cited by 8 publications

(5 citation statements)

References 147 publications

(141 reference statements)

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“…Endothelial barrier function is important in maintaining the proper functioning of the circulatory system and preventing the infiltration of harmful substances into tissues ( Mehta and Malik, 2006 ; Stan, 2007 ). It also plays a critical role in preventing cancer metastasis ( Chen et al, 2013 ; Wettschureck et al, 2019 ; Liang et al, 2021 ). EC barrier function is maintained by cellular junctions between adjacent ECs, which limit the movement of substances through the intercellular spaces ( Dejana et al, 2008 ).…”

Section: Resultsmentioning

confidence: 99%

Biomimetic on-chip assay reveals the anti-metastatic potential of a novel thienopyrimidine compound in triple-negative breast cancer cell lines

Sigdel,

Ofori-Kwafo,

Heizelman

et al. 2023

Front. Bioeng. Biotechnol.

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Introduction: This study presents a microfluidic tumor microenvironment (TME) model for evaluating the anti-metastatic efficacy of a novel thienopyrimidines analog with anti-cancer properties utilizing an existing commercial platform. The microfluidic device consists of a tissue compartment flanked by vascular channels, allowing for the co-culture of multiple cell types and providing a wide range of culturing conditions in one device.Methods: Human metastatic, drug-resistant triple-negative breast cancer (TNBC) cells (SUM159PTX) and primary human umbilical vein endothelial cells (HUVEC) were used to model the TME. A dynamic perfusion scheme was employed to facilitate EC physiological function and lumen formation.Results: The measured permeability of the EC barrier was comparable to observed microvessels permeability in vivo. The TNBC cells formed a 3D tumor, and co-culture with HUVEC negatively impacted EC barrier integrity. The microfluidic TME was then used to model the intravenous route of drug delivery. Paclitaxel (PTX) and a novel non-apoptotic agent TPH104c were introduced via the vascular channels and successfully reached the TNBC tumor, resulting in both time and concentration-dependent tumor growth inhibition. PTX treatment significantly reduced EC barrier integrity, highlighting the adverse effects of PTX on vascular ECs. TPH104c preserved EC barrier integrity and prevented TNBC intravasation.Discussion: In conclusion, this study demonstrates the potential of microfluidics for studying complex biological processes in a controlled environment and evaluating the efficacy and toxicity of chemotherapeutic agents in more physiologically relevant conditions. This model can be a valuable tool for screening potential anticancer drugs and developing personalized cancer treatment strategies.

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Section: Resultsmentioning

confidence: 99%

Biomimetic on-chip assay reveals the anti-metastatic potential of a novel thienopyrimidine compound in triple-negative breast cancer cell lines

Sigdel,

Ofori-Kwafo,

Heizelman

et al. 2023

Front. Bioeng. Biotechnol.

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“…Since stromal [7] and endothelial [30] cells, present in the BM, have previously been described to confer resistance to therapy, U937 cells were cultured on M-MΦ, fibroblasts (HS-5) or endothelial cell (EA.hy926) monolayers (Fig. 1D).…”

Section: Mif Inhibition Induces Aml Blast Apoptosis But Bm Cells Are ...mentioning

confidence: 99%

Macrophage migration inhibitory factor blockade reprograms macrophages and disrupts prosurvival signaling in acute myeloid leukemia

Spertini,

Bénéchet,

Birch

et al. 2024

Cell Death Discov.

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The malignant microenvironment plays a major role in the development of resistance to therapies and the occurrence of relapses in acute myeloid leukemia (AML). We previously showed that interactions of AML blasts with bone marrow macrophages (MΦ) shift their polarization towards a protumoral (M2-like) phenotype, promoting drug resistance; we demonstrated that inhibiting the colony-stimulating factor-1 receptor (CSF1R) repolarizes MΦ towards an antitumoral (M1-like) phenotype and that other factors may be involved. We investigated here macrophage migration inhibitory factor (MIF) as a target in AML blast survival and protumoral interactions with MΦ. We show that pharmacologically inhibiting MIF secreted by AML blasts results in their apoptosis. However, this effect is abrogated when blasts are co-cultured in close contact with M2-like MΦ. We next demonstrate that pharmacological inhibition of MIF secreted by MΦ, in the presence of granulocyte macrophage-colony stimulating factor (GM-CSF), efficiently reprograms MΦ to an M1-like phenotype that triggers apoptosis of interacting blasts. Furthermore, contact with reprogrammed MΦ relieves blast resistance to venetoclax and midostaurin acquired in contact with CD163+ protumoral MΦ. Using intravital imaging in mice, we also show that treatment with MIF inhibitor 4-IPP and GM-CSF profoundly affects the tumor microenvironment in vivo: it strikingly inhibits tumor vasculature, reduces protumoral MΦ, and slows down leukemia progression. Thus, our data demonstrate that MIF plays a crucial role in AML MΦ M2-like protumoral phenotype that can be reversed by inhibiting its activity and suggest the therapeutic targeting of MIF as an avenue towards improved AML treatment outcomes.

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“…Suprabasin, an upstream component of the AKT pathway, was substantially expressed in TECs compared to normal ECs and linked favourably with TECs’ capacity for migration and tube formation ( 75 ). On the other hand, microarray and immunohistochemical studies revealed that biglycan is a specific marker of TEC and an autocrine angiogenic factor of TECs ( 76 ). Because of the aggressive behaviour of tumor endothelial cells and their particular molecular, cytogenetic, and metabolic characteristics, the tumor microenvironment can therefore selectively draw in immune suppressive cells.…”

Section: Endothelial Cells In Tumors Are the “Switch Point” Aren’t They?mentioning

confidence: 99%

“…EndMT induced by TGF-β shows a decrease in the expression of endothelial markers such as VE-cadherin, claudin and zona-occludens 1 (ZO-1) and an elevation in EMT transcription factors such as Snail, Slug and ZEB-1 which marks metastasis. TGF-β promotes ECs to change into CAF-like cells, which results in the loss of endothelial adhesion molecules and remodelling of the endothelium cytoskeleton via the Rho and Rac-1 signalling pathway, which is the primary characteristic of EndMT ( 76 , 137 , 138 ). It has been found that hypoxia associated with inflammation or tissue damage can also cause EndEMT ( 139 ).…”

Section: Trans-endothelial Migrationmentioning

confidence: 99%

Enhancement of immune surveillance in breast cancer by targeting hypoxic tumor endothelium: Can it be an immunological switch point?

Thomas¹,

Moly²,

Xavier³

et al. 2023

Front. Oncol.

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Breast cancer ranks second among the causes of cancer-related deaths in women. In spite of the recent advances achieved in the diagnosis and treatment of breast cancer, further study is required to overcome the risk of cancer resistance to treatment and thereby improve the prognosis of individuals with advanced-stage breast cancer. The existence of a hypoxic microenvironment is a well-known event in the development of mutagenesis and rapid proliferation of cancer cells. Tumor cells, purposefully cause local hypoxia in order to induce angiogenesis and growth factors that promote tumor growth and metastatic characteristics, while healthy tissue surrounding the tumor suffers damage or mutate. It has been found that these settings with low oxygen levels cause immunosuppression and a lack of immune surveillance by reducing the activation and recruitment of tumor infiltrating leukocytes (TILs). The immune system is further suppressed by hypoxic tumor endothelium through a variety of ways, which creates an immunosuppressive milieu in the tumor microenvironment. Non responsiveness of tumor endothelium to inflammatory signals or endothelial anergy exclude effector T cells from the tumor milieu. Expression of endothelial specific antigens and immunoinhibitory molecules like Programmed death ligand 1,2 (PDL–1, 2) and T cell immunoglobulin and mucin-domain containing-3 (TIM-3) by tumor endothelium adds fuel to the fire by inhibiting T lymphocytes while promoting regulatory T cells. The hypoxic microenvironment in turn recruits Myeloid Derived Suppressor Cells (MDSCs), Tumor Associated Macrophages (TAMs) and T regulatory cells (Treg). The structure and function of newly generated blood vessels within tumors, on the other hand, are aberrant, lacking the specific organization of normal tissue vasculature. Vascular normalisation may work for a variety of tumour types and show to be an advantageous complement to immunotherapy for improving tumour access. By enhancing immune response in the hypoxic tumor microenvironment, via immune-herbal therapeutic and immune-nutraceuticals based approaches that leverage immunological evasion of tumor, will be briefly reviewed in this article. Whether these tactics may be the game changer for emerging immunological switch point to attenuate the breast cancer growth and prevent metastatic cell division, is the key concern of the current study.

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A New Antitumor Direction: Tumor-Specific Endothelial Cells

Cited by 8 publications

References 147 publications

Biomimetic on-chip assay reveals the anti-metastatic potential of a novel thienopyrimidine compound in triple-negative breast cancer cell lines

Biomimetic on-chip assay reveals the anti-metastatic potential of a novel thienopyrimidine compound in triple-negative breast cancer cell lines

Macrophage migration inhibitory factor blockade reprograms macrophages and disrupts prosurvival signaling in acute myeloid leukemia

Enhancement of immune surveillance in breast cancer by targeting hypoxic tumor endothelium: Can it be an immunological switch point?

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