Hexokinase 2-driven glycolysis in pericytes activates their contractility leading to tumor blood vessel abnormalities

Meng, Ya-Ming; Jiang, Xue; Zhao, Xu; Meng, Qiong; Wu, Sangqing; Chen, Yitian; Kong, Xiangbin; Qiu, Xiaoyi; Su, Lili; Huang, Cheng; Wang, Minghui; Liu, Chao; Wong, Ping-Pui

doi:10.1038/s41467-021-26259-y

Cited by 56 publications

(54 citation statements)

References 49 publications

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“…Pericytes play a role in tumor angiogenesis. They cover the surface of the basement membrane of vascular ECs and support and regulate vasoconstriction and relaxation under normal physiological conditions ( 42 , 43 ). In multiple solid malignant tumors, the number of infiltrated CD8+ T cells was shown to be related to patient prognosis and response rate to immunotherapy ( 44 – 47 ).…”

Section: Discussionmentioning

confidence: 99%

Endostatin induces normalization of blood vessels in colorectal cancer and promotes infiltration of CD8+ T cells to improve anti-PD-L1 immunotherapy

et al. 2022

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IntroductionThe purpose of this study was to evaluate recombinant human endostatin (rHE)-induced normalization of the tumor vasculature in colorectal cancer (CRC) and to evaluate the therapeutic effects of combined treatment with rHE and a programmed death ligand-1 (PD-L1) inhibitor.MethodsA mouse subcutaneous tumorigenesis model was established to evaluate the antitumor effects of endostatin combined with a PD-L1 inhibitor on CRC. Intravoxel incoherent motion diffusion-weighted magnetic resonance imaging (IVIM-DW MRI) was used to evaluate changes in the intratumor microcirculation in response to combined treatment with endostatin and a PD-L1 inhibitor. The infiltration density and function of CD8+ T cells in tumors were evaluated using flow cytometry. Finally, clinical specimens were used to evaluate the expression area of tumor vascular pericytes and CD8+ T cells in tumor tissues.ResultsThe antitumor effects of endostatin combined with a PD-L1 inhibitor were significantly greater than those of endostatin or a PD-L1 inhibitor alone. On the ninth day of intervention, the endostatin group showed significantly higher pseudo diffusion parameter (D*) and microvascular volume fraction (F) values in tumors than those in the control group or PD-L1 group. After 27 days of intervention, the endostatin groups showed significantly lower levels of vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β than those in the control group. Treatment of CD8+ T cells with endostatin for 24 h did not alter the expression levels of markers of reduced T-cell activity. However, endostatin reversed the VEGF-mediated inhibition of the secretion of interferon (IFN)-γ from T cells. The results in CRC clinical samples showed that treatment with endostatin induced significantly higher infiltration of CD8+ T cells compared with treatment that did not include endostatin. Furthermore, the expression area of pericytes was significantly positively related to the infiltration density of CD8+ T cells and overall survival time.ConclusionEndostatin improved the antitumor effects of PD-L1 inhibitors on CRC, significantly increased the activity of CD8+ T cells, and synergistically improved the tumor treatment effect of the two inhibitors.

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Section: Discussionmentioning

confidence: 99%

Endostatin induces normalization of blood vessels in colorectal cancer and promotes infiltration of CD8+ T cells to improve anti-PD-L1 immunotherapy

et al. 2022

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“…The human lung pericytes were isolated from an adjacent normal tissue in lung cancer patient as previously described [ 21 , 22 ]. Briefly, tissue was minced and digested in HBSS buffer containing collagenase I (300 U/ml) and dispase (5 U/ml).…”

Section: Methodsmentioning

confidence: 99%

ARHGEF37 overexpression promotes extravasation and metastasis of hepatocellular carcinoma via directly activating Cdc42

Zhang

Lang

et al. 2022

J Exp Clin Cancer Res

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Background The extravasation capability of hepatocellular carcinoma (HCC) cells plays a vital role in distant metastasis. However, the underlying mechanism of extravasation in HCC lung metastasis remains largely unclear. Methods The expression of ARHGEF37 in human HCC specimens and HCC cell lines was examined by quantitative RT-PCR, western blot, and immunohistochemistry (IHC) analyses. The biological roles and mechanisms of ARHGEF37/Cdc42 in promoting lung metastasis were investigated in vitro and in vivo using cell lines, patient samples, xenograft models. Results In the current study, we found that Rho guanine nucleotide exchange factor 37 (ARHGEF37) was upregulated in human HCC samples and was associated with tumor invasiveness, pulmonary metastasis and poor prognosis. Overexpressing ARHGEF37 significantly enhanced the extravasation and metastatic capability of HCC cells via facilitating tumor cell adhesion to endothelial cells and trans-endothelial migration. Mechanistically, ARHGEF37 directly interacted with and activated Cdc42 to promote the invadopodia formation in HCC cells, which consequently disrupted the interaction between endothelial cells and pericytes. Importantly, treatment with ZCL278, a specific inhibitor of Cdc42, dramatically inhibited the attachment of ARHGEF37-overexpressing HCC cells to endothelial cells, and the adherence and extravasation in the lung alveoli, resulting in suppression of lung metastasis in mice. Conclusion Our findings provide a new insight into the underlying mechanisms on the ARHGEF37 overexpression-mediated extravasation and pulmonary metastasis of HCC cells, and provided a potential therapeutic target for the prevention and treatment of HCC pulmonary metastasis.

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Section: Intrinsic Interactions Between Vascular Normalization and Im...mentioning

confidence: 99%

“…Moreover, Wong and co-workers elucidated that increased hexokinase 2 (HK2)-mediated pericyte glycolysis was capable of strengthening ROCK2-MLC2 axis-mediated contractility, thereby resulting in disrupted tumor vascular function ( 162 ). Treatment of a HK2 inhibitor (3BP) conferred the recruitment of pericytes, thereby facilitating tumor vasculature remodeling and further enhancing drug delivery into tumors ( 162 ). Additionally, genetic elimination of regulator of G-protein signaling 5 (RGS5) enabled immature PDGFR-β + pericytes to turn into mature αSMA + NG2 + pericytes without influencing their overall coverage onto the blood vessels ( 163 , 164 ).…”

Section: Intrinsic Interactions Between Vascular Normalization and Im...mentioning

confidence: 99%

Manipulation of the crosstalk between tumor angiogenesis and immunosuppression in the tumor microenvironment: Insight into the combination therapy of anti-angiogenesis and immune checkpoint blockade

et al. 2022

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Immunotherapy has been recognized as an effective and important therapeutic modality for multiple types of cancer. Nevertheless, it has been increasing recognized that clinical benefits of immunotherapy are less than expected as evidenced by the fact that only a small population of cancer patients respond favorably to immunotherapy. The structurally and functionally abnormal tumor vasculature is a hallmark of most solid tumors and contributes to an immunosuppressive microenvironment, which poses a major challenge to immunotherapy. In turn, multiple immune cell subsets have profound consequences on promoting neovascularization. Vascular normalization, a promising anti-angiogenic strategy, can enhance vascular perfusion and promote the infiltration of immune effector cells into tumors via correcting aberrant tumor blood vessels, resulting in the potentiation of immunotherapy. More interestingly, immunotherapies are prone to boost the efficacy of various anti-angiogenic therapies and/or promote the morphological and functional alterations in tumor vasculature. Therefore, immune reprograming and vascular normalization appear to be reciprocally regulated. In this review, we mainly summarize how tumor vasculature propels an immunosuppressive phenotype and how innate and adaptive immune cells modulate angiogenesis during tumor progression. We further highlight recent advances of anti-angiogenic immunotherapies in preclinical and clinical settings to solidify the concept that targeting both tumor blood vessels and immune suppressive cells provides an efficacious approach for the treatment of cancer.

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Hexokinase 2-driven glycolysis in pericytes activates their contractility leading to tumor blood vessel abnormalities

Cited by 56 publications

References 49 publications

Endostatin induces normalization of blood vessels in colorectal cancer and promotes infiltration of CD8+ T cells to improve anti-PD-L1 immunotherapy

Endostatin induces normalization of blood vessels in colorectal cancer and promotes infiltration of CD8+ T cells to improve anti-PD-L1 immunotherapy

ARHGEF37 overexpression promotes extravasation and metastasis of hepatocellular carcinoma via directly activating Cdc42

Manipulation of the crosstalk between tumor angiogenesis and immunosuppression in the tumor microenvironment: Insight into the combination therapy of anti-angiogenesis and immune checkpoint blockade

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