MRI analysis to map interstitial flow in the brain tumor microenvironment

Kingsmore, Kathryn M.; Vaccari, Andrea; Abler, Daniel; Cui, Sophia; Epstein, Frederick H.; Rockne, Russell C.; Acton, Scott T.; Munson, Jennifer M.

doi:10.1063/1.5023503

Cited by 55 publications

(61 citation statements)

References 45 publications

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“…The pathological changes in conditions such as glioma or stroke can alter multiple aspects of the ISS, which may include changes in geometry, ECM and its components, the constituents of the ISF, and the transport of substances in the ISS [1,100,101]. In glioma, the uncontrolled growth of tumor cells disrupts the standard architecture of brain tissue.…”

Section: Status Of Iss In Neurological Disordersmentioning

confidence: 99%

The Interstitial System of the Brain in Health and Disease

Shetty

Zanirati

2020

Aging and disease

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The brain interstitial fluid (ISF) and the cerebrospinal fluid (CSF) cushion and support the brain cells. The ISF occupies the brain interstitial system (ISS), whereas the CSF fills the brain ventricles and the subarachnoid space. The brain ISS is an asymmetrical, tortuous, and exceptionally confined space between neural cells and the brain microvasculature. Recently, with a newly developed in vivo measuring technique, a series of discoveries have been made in the brain ISS and the drainage of ISF. The goal of this review is to confer recent advances in our understanding of the brain ISS, including its structure, function, and the various processes mediating or disrupting ISF drainage in physiological and pathological conditions. The brain ISF in the deep brain regions has recently been demonstrated to drain in a compartmentalized ISS instead of a highly connected system, together with the drainage of ISF into the cerebrospinal fluid (CSF) at the surface of the cerebral cortex and the transportation from CSF into cervical lymph nodes. Besides, accumulation of tau in the brain ISS in conditions such as Alzheimer's disease and its link to the sleep-wake cycle and sleep deprivation, clearance of ISF in a deep sleep via increased CSF flow, novel approaches to remove beta-amyloid from the brain ISS, and obstruction to the ISF drainage in neurological conditions are deliberated. Moreover, the role of ISS in the passage of extracellular vesicles (EVs) released from neural cells and the rapid targeting of therapeutic EVs into neural cells in the entire brain following an intranasal administration, and the promise and limitations of ISS based drug delivery approaches are discussed Key words: beta-amyloid, cerebrospinal fluid, extracellular matrix, extracellular vesicles, glymphatic system, interstitial fluid, phosphorylated tau contiguous glia, or the adjoining neurons and glia is also known as the extracellular space (ECS) [1-3].

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Section: Status Of Iss In Neurological Disordersmentioning

confidence: 99%

The Interstitial System of the Brain in Health and Disease

Shetty

Zanirati

2020

Aging and disease

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“…Regarding GBM, paths of brain tumor dissemination correlate with bulk fluid pathways 19 . Additionally, we now know that interstitial fluid flow pathways within GBM in mice are complex and heterogeneous, indicating a need for greater understanding of the impacts on cellular invasion 20 . Only recently we showed that interstitial flow indeed increases invasion of both murine and human glioma cells in vitro through the chemokine receptor-ligand pair CXCR4-CXCL12 6 , 7 .…”

Section: Discussionmentioning

confidence: 99%

Convective forces increase CXCR4-dependent glioblastoma cell invasion in GL261 murine model

Cornelison

Brennan

Kingsmore

et al. 2018

Sci Rep

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Glioblastoma is the most common and malignant form of brain cancer. Its invasive nature limits treatment efficacy and promotes inevitable recurrence. Previous in vitro studies showed that interstitial fluid flow, a factor characteristically increased in cancer, increases glioma cell invasion through CXCR4-CXCL12 signaling. It is currently unknown if these effects translate in vivo. We used the therapeutic technique of convection enhanced delivery (CED) to test if convective flow alters glioma invasion in a syngeneic GL261 mouse model of glioblastoma. The GL261 cell line was flow responsive in vitro, dependent upon CXCR4 and CXCL12. Additionally, transplanting GL261 intracranially increased the populations of CXCR4+ and double positive cells versus 3D culture. We showed that inducing convective flow within implanted tumors indeed increased invasion over untreated controls, and administering the CXCR4 antagonist AMD3100 (5 mg/kg) effectively eliminated this response. These data confirm that glioma invasion is stimulated by convective flow in vivo and depends on CXCR4 signaling. We also showed that expression of CXCR4 and CXCL12 is increased in patients having received standard therapy, when CED might be elected. Hence, targeting flow-stimulated invasion may prove beneficial as a second line of therapy, particularly in patients chosen to receive treatment by convection enhanced delivery.

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“…In the interstitium, a typical L is ~100 μm (approximate distance between microvessels) (Dewhirst and Secomb, 2017). A typical v interstitial is ~1 μm/s (Wiig and Swartz, 2012), although this value can be much lower or higher depending on the region of the tumor (Kingsmore et al, 2018). Finally, a representative value for D is ~10 −7 cm 2 /s (Chary and Jain, 1989) (reported for serum albumin in both normal and neoplastic tissues).…”

Section: Fundamentals Of Mass Transport In the Tumor Interstitiummentioning

confidence: 99%

Application of 3-D Microfluidic Models for Studying Mass Transport Properties of the Tumor Interstitial Matrix

Avendano

Cortes-Medina

Song

2019

Front. Bioeng. Biotechnol.

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The physical remodeling associated with cancer progression results in barriers to mass transport in the tumor interstitial space. This hindrance ultimately affects the distribution of macromolecules that govern cell fate and potency of cancer therapies. Therefore, knowing how specific extracellular matrix (ECM) and cellular components regulate transport in the tumor interstitium could lead to matrix normalizing strategies that improve patient outcome. Studies over the past decades have provided quantitative insights into interstitial transport in tumors by characterizing two governing parameters: (1) molecular diffusivity and (2) hydraulic conductivity. However, many of the conventional techniques used to measure these parameters are limited due to their inability to experimentally manipulate the physical and cellular environments of tumors. Here, we examine the application and future opportunities of microfluidic systems for identifying the physiochemical mediators of mass transport in the tumor ECM. Further advancement and adoption of microfluidic systems to quantify tumor transport parameters has potential to bridge basic science with translational research for advancing personalized medicine in oncology.

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MRI analysis to map interstitial flow in the brain tumor microenvironment

Cited by 55 publications

References 45 publications

The Interstitial System of the Brain in Health and Disease

The Interstitial System of the Brain in Health and Disease

Convective forces increase CXCR4-dependent glioblastoma cell invasion in GL261 murine model

Application of 3-D Microfluidic Models for Studying Mass Transport Properties of the Tumor Interstitial Matrix

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