Localization of claudin-3 in tight junctions of the blood-brain barrier is selectively lost during experimental autoimmune encephalomyelitis and human glioblastoma multiforme

Wolburg, Hartwig; Wolburg‐Buchholz, Karen; Kraus, Jörg; Rascher-Eggstein, Gesa; Liebner, Stefan; Hamm, Stefan; Duffner, Frank; Grote, Ernst-H.; Risau, Werner; Engelhardt, Britta

doi:10.1007/s00401-003-0688-z

Cited by 392 publications

(255 citation statements)

References 26 publications

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“…1,6,28 Previous studies have examined histological and immunohistochemical features of tight junctions associated with vascular endothelial cells of metastatic and primary tumors. Alterations in claudin expression at tight junctions have been demonstrated in tumors, as well as inflammatory disorders of the nervous system, 19,31,37 suggesting that the tight junctions are disrupted and are associated, at least in part, with BBB breakdown in a variety of CNS pathological states, including neoplasia.…”

Section: Discussionmentioning

confidence: 99%

“…11,19,31,37 Nevertheless, these changes do not explain many features of neoplastic BBB disruption, and further insight into the effects of the astrocytic contribution to the BBB in intracerebral neoplasia is needed. To gain deeper understanding into effects of the astrocytic contribution to the BBB in brain neoplasia, we systematically analyzed the vascular features of metastatic and primary brain tumors.…”

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confidence: 99%

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Characterization of the blood-brain barrier of metastatic and primary malignant neoplasms

Nduom

Yang

Merrill

et al. 2013

JNS

113

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Object The astrocytic contribution to the blood-brain barrier (BBB) in metastatic and primary malignant brain tumors is not well understood. To better understand the vascular properties associated with metastatic and primary malignant brain tumors, the authors systematically analyzed the astrocytic component of the BBB in brain neoplasms. Methods Twelve patients who underwent resection of metastatic or primary brain neoplasms (4 metastatic lesions, 2 low-grade astrocytomas, 2 anaplastic astrocytomas, and 4 glioblastoma multiforme) were included. Clinical, MRI, operative, histopathological and immunohistochemical (glial fibrillary acidic protein [GFAP], CD31, and aquaporin 4 [AQ4]) findings were analyzed. Results Intratumoral regions of MRI enhancement corresponded with breakdown of the normal astrocyte–endothelial cell relationship in the BBB in metastatic deposits and malignant gliomas. Metastases demonstrated lack of perivascular GFAP and AQ4 on CD31-positive intratumoral vessels. At the metastasis-brain interface, normalization of GFAP and AQ4 staining associated with intraparenchymal vessels was observed. Intratumoral vasculature in enhancing regions of high-grade gliomas revealed gaps in GFAP and AQ4 staining consistent with disintegration of the normal astrocyte–endothelial cell association in the BBB. Intratumoral vasculature in low-grade and nonenhancing regions of high-grade gliomas maintained the normal astrocyte–endothelial cell relationship seen in an intact BBB, with GFAP- and AQ4-positive glial processes that were uniformly associated with the CD31-positive vasculature. Conclusions Regions of MRI enhancement in metastatic and primary malignancies correspond to areas of breakdown of the physiological astrocyte–endothelial cell relationship of the BBB, including loss of normal perivascular astrocytic architecture on GFAP and AQ4 immunohistochemistry. Nonenhancing areas are associated with preservation of the normal astrocyte–endothelial cell relationship of the intact BBB.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Characterization of the blood-brain barrier of metastatic and primary malignant neoplasms

Nduom

Yang

Merrill

et al. 2013

JNS

113

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“…126 This finding implicated claudin-3 as an effector in the leakiness of glioblastoma vessels. There is further evidence implicating claudin-1 loss in tumor microvessels, as well as downregulation of claudin-5 and occludin in hyperplastic vasculature.…”

Section: Blood-brain Barrier and Tumor-associated Changesmentioning

confidence: 95%

Therapeutic strategies to improve drug delivery across the blood-brain barrier

Azad¹,

Pan²,

Connolly³

et al. 2015

FOC

106

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Resection of brain tumors is followed by chemotherapy and radiation to ablate remaining malignant cell populations. Targeting these populations stands to reduce tumor recurrence and offer the promise of more complete therapy. Thus, improving access to the tumor, while leaving normal brain tissue unscathed, is a critical pursuit. A central challenge in this endeavor lies in the limited delivery of therapeutics to the tumor itself. The blood-brain barrier (BBB) is responsible for much of this difficulty but also provides an essential separation from systemic circulation. Due to the BBB's physical and chemical constraints, many current therapies, from cytotoxic drugs to antibody-based proteins, cannot gain access to the tumor. This review describes the characteristics of the BBB and associated changes wrought by the presence of a tumor. Current strategies for enhancing the delivery of therapies across the BBB to the tumor will be discussed, with a distinction made between strategies that seek to disrupt the BBB and those that aim to circumvent it.

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“…Coexpression of Cld2 with Cld1 or Cld3 increases P-face association and strand continuity [13]. Coexpression of Cld5 with Cld3 correlates with high P-face association and tightness of brain endothelial cells [16, 17]. In summary, freeze fracture and functional data suggest that the combination and stoichiometry of claudin subtypes in heteropolymeric strands defines their P/E-face association and continuity as critical determinants of TJ barrier function.…”

Section: Introductionmentioning

confidence: 99%

Elucidating the principles of the molecular organization of heteropolymeric tight junction strands

Piontek

Fritzsche

Cording

et al. 2011

Cell. Mol. Life Sci.

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119

166

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Paracellular barrier properties of tissues are mainly determined by the composition of claudin hetero-polymers. To analyze the molecular organization of tight junctions (TJ), we investigated the ability of claudins (Cld) to form homo- and heteromers. Cld1, -2, -3, -5, and -12 expressed in cerebral barriers were investigated. TJ-strands were reconstituted by claudin-transfection of HEK293-cells. cis-Interactions and/or spatial proximity were analyzed by fluorescence resonance energy transfer inside and outside of strands and ranked: Cld5/Cld5 > Cld5/Cld1 > Cld3/Cld1 > Cld3/Cld3 > Cld3/Cld5, no Cld3/Cld2. Classic Cld1, -3, and -5 but not non-classic Cld12 showed homophilic trans-interaction. Freeze-fracture electron microscopy revealed that, in contrast to classic claudins, YFP-tagged Cld12 does not form homopolymers. Heterophilic trans-interactions were analyzed in cocultures of differently monotransfected cells. trans-Interaction of Cld3/Cld5 was less pronounced than that of Cld3/Cld1, Cld5/Cld1, Cld5/Cld5 or Cld3/Cld3. The barrier function of reconstituted TJ-strands was demonstrated by a novel imaging assay. A model of the molecular organization of TJ was generated.

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Localization of claudin-3 in tight junctions of the blood-brain barrier is selectively lost during experimental autoimmune encephalomyelitis and human glioblastoma multiforme

Cited by 392 publications

References 26 publications

Characterization of the blood-brain barrier of metastatic and primary malignant neoplasms

Characterization of the blood-brain barrier of metastatic and primary malignant neoplasms

Therapeutic strategies to improve drug delivery across the blood-brain barrier

Elucidating the principles of the molecular organization of heteropolymeric tight junction strands

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