Hypoxic adaptation of leukemic cells infiltrating the CNS affords a therapeutic strategy targeting VEGFA

Kato, Ikunoshin; Nishinaka, Yoko; Nakamura, Masahiro; Akarca, Ayse U.; Niwa, Akira; Ozawa, Hiroki; Yoshida, Kenichi; Mori, Makiko; Wang, Dapeng; Morita, Maki; Ueno, Hikaru; Shiozawa, Yusuke; Shiraishi, Yuichi; Miyano, Satoru; Gupta, Rajeev; Umeda, Katsutsugu; Watanabe, Kenichiro; Koh, Katsuyoshi; Adachi, Souichi; Heike, Toshio; Saito, Megumu K.; Sanada, Masashi; Ogawa, Seishi; Marafioti, Teresa; Watanabe, Akira; Nakahata, Tatsutoshi; Enver, Tariq

doi:10.1182/blood-2016-06-721712

Cited by 24 publications

(42 citation statements)

References 12 publications

(14 reference statements)

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“…VEGF was one of the most upregulated genes in CNS leukemic cells. Similar findings were recently reported in Blood by Kato et al,4 who also confirmed the increased expression of VEGF in ALL cells isolated from the CSF of patients with CNS leukemia. These observations complement a previous report of high levels of VEGF in the CSF from patients with CNS leukemia.…”

supporting

confidence: 91%

“…6 VEGF may also promote the survival of cancer and leukemic cells. ) and the apoptosis observed by Kato et al in CNS leukemic cells after treatment with bevacizumab, 4 it is likely that VEGF supports the survival of ALL cells in the hypoxic growth inhibitory environment in the subarachnoid compartment. Indeed, this may be its more important function in CNS leukemia.…”

mentioning

confidence: 89%

“…These results contrast with murine gene ablation studies for the common pathway coagulation factors (F10, F5, and prothrombin), which demonstrate a mixture of embryonic lethality and fatal perinatal bleeding. [2][3][4][5] F10 deficiency in humans is a rare autosomal recessive bleeding disorder in which the majority of reported genetic defects are either homozygous or compound heterozygous …”

Section: T He F10mentioning

confidence: 99%

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Targeted therapy of CNS leukemia?

Izraeli

Eckert

2017

Blood

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supporting

confidence: 91%

mentioning

confidence: 89%

Section: T He F10mentioning

confidence: 99%

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Targeted therapy of CNS leukemia?

Izraeli

Eckert

2017

Blood

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“…Cytokine and chemokine‐mediated signaling play critical roles in the multistep processes by which immune cells can access to CNS under inflammatory conditions. There is intriguing evidence for the interplay between infiltrating immune cells that produce IL‐1β, TNF, or IL‐15 and other soluble factors, and the production of permeability factors (thymidine phosphorylase; TYMP, vascular endothelial growth factor‐A; VEGF‐A) by astrocytes and other resident brain cells . Also, the CXCR4 and CCR7 signaling pathways have been implicated in acute leukemia cell targeting to skull bone marrow and meningeal spaces .…”

Section: Introductionmentioning

confidence: 99%

“…There is intriguing evidence for the interplay between infiltrating immune cells that produce IL-1 , TNF, or IL-15 [19][20][21] and other soluble factors, and the production of permeability factors (thymidine phosphorylase; TYMP, vascular endothelial growth factor-A; VEGF-A) by astrocytes and other resident brain cells. [22][23][24] Also, the CXCR4 and CCR7 signaling pathways have been implicated in acute leukemia cell targeting to skull bone marrow and meningeal spaces. [25][26][27] Emerging evidence also suggests that membrane-bound carriers (extracellular vesicles, exosomes) released by cancer cells can mediate cell-cell communication via the delivery of their contents, proteins, mRNAs, and microRNAs [28][29][30] and potentially alter the microenvironment at extramedullary sites.…”

Section: Introductionmentioning

confidence: 99%

Leukemia-derived exosomes and cytokines pave the way for entry into the brain

Kinjyo

Bragin²,

Grattan

et al. 2019

Journal of Leukocyte Biology

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Infiltration of acute lymphoblastic leukemia (ALL) blasts into the CNS remains as a major clinical problem, with high risk for chemotherapy‐resistant relapse and treatment‐related morbidity. Despite the common inclusion of CNS prophylaxis treatments in therapy regimens, there are significant gaps in understanding the mechanisms that mediate leukemia cell entry into the CNS as well as roles for resident cells in the brain. In this study, we employ a xenograft model of human B cell precursor (BCP)‐ALL in immunocompromised mice. This model system recapitulates key pathological characteristics of leptomeningeal involvement seen in patients and provides insights into rare cases that involve parenchymal invasion. We examine the infiltration of engrafted leukemia blasts into brains of recipient mice and provide evidence that the interaction between blasts and brain resident cells causes aberrant activation of host cells in the brain microenvironment. BCP‐ALL blasts also release multiple cytokines and exosomes containing IL‐15 that bind and are internalized by astrocytes and brain vessel endothelial cells. Leukemic invasion is linked to production of VEGF‐AA by astrocytes and disruption of the blood‐brain‐barrier (BBB) integrity. Knockdown of either IL‐15 or IL‐15Rα in the NALM6 cell line decreases CNS infiltration in engrafted mice. These results provide important insights into the multiple mechanisms by which lymphoblasts modulate the brain microenvironment to breach the BBB for metastatic invasion.

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Hypoxia signaling in cancer: Implications for therapeutic interventions

Zhuang

Liu

et al. 2023

MedComm

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Hypoxia is a persistent physiological feature of many different solid tumors and a key driver of malignancy, and in recent years, it has been recognized as an important target for cancer therapy. Hypoxia occurs in the majority of solid tumors due to a poor vascular oxygen supply that is not sufficient to meet the needs of rapidly proliferating cancer cells. A hypoxic tumor microenvironment (TME) can reduce the effectiveness of other tumor therapies, such as radiotherapy, chemotherapy, and immunotherapy. In this review, we discuss the critical role of hypoxia in tumor development, including tumor metabolism, tumor immunity, and tumor angiogenesis. The treatment methods for hypoxic TME are summarized, including hypoxia‐targeted therapy and improving oxygenation by alleviating tumor hypoxia itself. Hyperoxia therapy can be used to improve tissue oxygen partial pressure and relieve tumor hypoxia. We focus on the underlying mechanisms of hyperoxia and their impact on current cancer therapies and discuss the prospects of hyperoxia therapy in cancer treatment.

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Hypoxic adaptation of leukemic cells infiltrating the CNS affords a therapeutic strategy targeting VEGFA

Cited by 24 publications

References 12 publications

Targeted therapy of CNS leukemia?

Targeted therapy of CNS leukemia?

Leukemia-derived exosomes and cytokines pave the way for entry into the brain

Hypoxia signaling in cancer: Implications for therapeutic interventions

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