Dynamic transition of the blood-brain barrier in the development of non-small cell lung cancer brain metastases

Uzunallı, Gözde; Dieterly, Alexandra M.; Kemet, Chinyere M; Weng, Hsin‐Yi; Soepriatna, Arvin H.; Goergen, Craig J.; Shinde, Aparna; Lyle, L. Tiffany

doi:10.18632/oncotarget.27274

Cited by 38 publications

(28 citation statements)

References 45 publications

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“…In fact, by using a BC mouse model, they demonstrated that the VEGF-receptor tyrosine kinase inhibitor PTK787/Z 222,584 significantly reduces CD31+ vessels in brain lesions, enhances apoptosis within the tumor mass, thereby decreasing the tumor burden in the brain [ 114 ]. This is in line with evidence showing that CD31 expression is often upregulated in endothelial cells of brain metastases of BCs, cervical carcinomas, and non-small cell lung cancers [ 115 , 116 ].…”

Section: Hallmarks Of Metastatic Bcmsupporting

confidence: 90%

Influence of Fibroblasts on Mammary Gland Development, Breast Cancer Microenvironment Remodeling, and Cancer Cell Dissemination

Avagliano

Fiume

Ruocco

et al. 2020

Cancers

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The stromal microenvironment regulates mammary gland development and tumorigenesis. In normal mammary glands, the stromal microenvironment encompasses the ducts and contains fibroblasts, the main regulators of branching morphogenesis. Understanding the way fibroblast signaling pathways regulate mammary gland development may offer insights into the mechanisms of breast cancer (BC) biology. In fact, the unregulated mammary fibroblast signaling pathways, associated with alterations in extracellular matrix (ECM) remodeling and branching morphogenesis, drive breast cancer microenvironment (BCM) remodeling and cancer growth. The BCM comprises a very heterogeneous tissue containing non-cancer stromal cells, namely, breast cancer-associated fibroblasts (BCAFs), which represent most of the tumor mass. Moreover, the different components of the BCM highly interact with cancer cells, thereby generating a tightly intertwined network. In particular, BC cells activate recruited normal fibroblasts in BCAFs, which, in turn, promote BCM remodeling and metastasis. Thus, comparing the roles of normal fibroblasts and BCAFs in the physiological and metastatic processes, could provide a deeper understanding of the signaling pathways regulating BC dissemination. Here, we review the latest literature describing the structure of the mammary gland and the BCM and summarize the influence of epithelial-mesenchymal transition (EpMT) and autophagy in BC dissemination. Finally, we discuss the roles of fibroblasts and BCAFs in mammary gland development and BCM remodeling, respectively.

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Section: Hallmarks Of Metastatic Bcmsupporting

confidence: 90%

Influence of Fibroblasts on Mammary Gland Development, Breast Cancer Microenvironment Remodeling, and Cancer Cell Dissemination

Avagliano

Fiume

Ruocco

et al. 2020

Cancers

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“…One of the major obstacles to the treatment of a brain tumor is the blood-brain barrier [ 44 ]. The transport analysis together with ex vivo, and in vivo data collectively provided multiple lines of evidence that the minimally invasive injection of CM is effective to deliver tumor-suppressing factors in the mouse model.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Growth of Breast Cancer-Associated Brain Tumors by the Osteocyte-Derived Conditioned Medium

Sano

Sun

Yuan

et al. 2021

Cancers

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The brain is a common site of metastasis from advanced breast cancer but few effective treatments are available. We examined a therapeutic option with a conditioned medium (CM), focusing on the role of Lrp5 and β-catenin in Wnt signaling, and IL1ra in osteocytes. Osteocytes presented the innate anti-tumor effect and the overexpression of the above genes strengthened their action. In a mouse model, the injection of their CM inhibited mammary tumors and tumor-driven osteolysis. Importantly, Lrp5- and/or IL1ra-overexpressing osteocytes or the local administration of β-catenin-overexpressing CM markedly inhibited brain tumors. In the transport analysis, tumor-suppressing factors in CM were shown to diffuse through the skull. Mechanistically, the CM with overexpression of the above genes downregulated oncogenic genes such as MMP9, Runx2, TGFβ, and Snail in breast cancer cells. Also, the CM with β-catenin overexpression downregulated CXCL1 and CXCL5 and upregulated tumor suppressors such as LIMA1, DSP, p53, and TRAIL in breast cancer cells. Notably, whole-genome proteomics revealed that histone H4 was enriched in CM and acted as an atypical tumor suppressor. Lrp5-overexpressing MSCs were also shown to act as anti-tumor agents. Collectively, this study demonstrated the therapeutic role of engineered CM in brain tumors and the tumor-suppressing action of extracellular histone H4. The result sheds light on the potential CM-based therapy for breast cancer-associated brain metastases in a minimally invasive manner.

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“…The majority of healthy CNS vessels express PDGFR-β protein [43,44]. Expression of other pericyte proteins is generally dependent upon the developmental stage or pathology [45][46][47][48]. Göritz et al reported increased pericyte proliferation after spinal cord injury in a mouse model.…”

Section: Discussionmentioning

confidence: 99%

Structural disruption of the blood–brain barrier in repetitive primary blast injury

Uzunallı

Herr

Dieterly

et al. 2021

Fluids Barriers CNS

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Background Blast-induced traumatic brain injury (bTBI) is a growing health concern due to the increased use of low-cost improvised explosive devices in modern warfare. Mild blast exposures are common amongst military personnel; however, these women and men typically do not have adequate recovery time from their injuries due to the transient nature of behavioral symptoms. bTBI has been linked to heterogeneous neuropathology, including brain edema, neuronal degeneration and cognitive abnormalities depending on the intensity of blast overpressure and frequency. Recent studies have reported heterogeneity in blood–brain barrier (BBB) permeability following blast injury. There still remains a limited understanding of the pathologic changes in the BBB following primary blast injuries. In this study, our goal was to elucidate the pathologic pattern of BBB damage through structural analysis following single and repetitive blast injury using a clinically relevant rat model of bTBI. Methods A validated, open-ended shock tube model was used to deliver single or repetitive primary blast waves. The pathology of the BBB was assessed using immunofluorescence and immunohistochemistry assays. All data were analyzed using the one-way ANOVA test. Results We have demonstrated that exposure to repetitive blast injury affects the desmin-positive and CD13-positive subpopulations of pericytes in the BBB. Changes in astrocytes and microglia were also detected. Conclusion This study provides analysis of the BBB components after repetitive blast injury. These results will be critical as preventative and therapeutic strategies are established for veterans recovering from blast-induced traumatic brain injury.

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Dynamic transition of the blood-brain barrier in the development of non-small cell lung cancer brain metastases

Cited by 38 publications

References 45 publications

Influence of Fibroblasts on Mammary Gland Development, Breast Cancer Microenvironment Remodeling, and Cancer Cell Dissemination

Influence of Fibroblasts on Mammary Gland Development, Breast Cancer Microenvironment Remodeling, and Cancer Cell Dissemination

Inhibition of the Growth of Breast Cancer-Associated Brain Tumors by the Osteocyte-Derived Conditioned Medium

Structural disruption of the blood–brain barrier in repetitive primary blast injury

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