Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

ACC 2024 Congress

Catch up on all the top stories and latest evidence in cardiology research with our ACC 2024 Congress hub page.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

Permeability changes and effect of chemotherapy in brain adjacent to tumor in an experimental model of metastatic brain tumor from breast cancer

Authors: Afroz S. Mohammad, Chris E. Adkins, Neal Shah, Rawaa Aljammal, Jessica I. G. Griffith, Rachel M. Tallman, Katherine L. Jarrell, Paul R. Lockman

Published in: BMC Cancer | Issue 1/2018

Login to get access

Abstract

Background

Brain tumor vasculature can be significantly compromised and leakier than that of normal brain blood vessels. Little is known if there are vascular permeability alterations in the brain adjacent to tumor (BAT). Changes in BAT permeability may also lead to increased drug permeation in the BAT, which may exert toxicity on cells of the central nervous system. Herein, we studied permeation changes in BAT using quantitative fluorescent microscopy and autoradiography, while the effect of chemotherapy within the BAT region was determined by staining for activated astrocytes.

Methods

Human metastatic breast cancer cells (MDA-MB-231Br) were injected into left ventricle of female NuNu mice. Metastases were allowed to grow for 28 days, after which animals were injected fluorescent tracers Texas Red (625 Da) or Texas Red dextran (3 kDa) or a chemotherapeutic agent 14C-paclitaxel. The accumulation of tracers and 14C-paclitaxel in BAT were determined by using quantitative fluorescent microscopy and autoradiography respectively. The effect of chemotherapy in BAT was determined by staining for activated astrocytes.

Results

The mean permeability of texas Red (625 Da) within BAT region increased 1.0 to 2.5-fold when compared to normal brain, whereas, Texas Red dextran (3 kDa) demonstrated mean permeability increase ranging from 1.0 to 1.8-fold compared to normal brain. The Kin values in the BAT for both Texas Red (625 Da) and Texas Red dextran (3 kDa) were found to be 4.32 ± 0.2 × 105 mL/s/g and 1.6 ± 1.4 × 105 mL/s/g respectively and found to be significantly higher than the normal brain. We also found that there is significant increase in accumulation of 14C-Paclitaxel in BAT compared to the normal brain. We also observed animals treated with chemotherapy (paclitaxel (10 mg/kg), erubilin (1.5 mg/kg) and docetaxel (10 mg/kg)) showed activated astrocytes in BAT.

Conclusions

Our data showed increased permeation of fluorescent tracers and 14C-paclitaxel in the BAT. This increased permeation lead to elevated levels of activated astrocytes in BAT region in the animals treated with chemotherapy.
Literature
1.
Platta CS, Khuntia D, Mehta MP, Suh JH. Current treatment strategies for brain metastasis and complications from therapeutic techniques: a review of current literature. Am J Clin Oncol. 2010;33(4):398–407.CrossRefPubMed
2.
Rivkin M, Kanoff RB. Metastatic brain tumors: current therapeutic options and historical perspective. The Journal of the American Osteopathic Association. 2013;113(5):418–23.PubMed
3.
Leone JP, Leone BA. Breast cancer brain metastases: the last frontier. Experimental Hematology & Oncology. 2015;4(1):33.CrossRef
4.
Frisk G, Svensson T, Bäcklund LM, Lidbrink E, Blomqvist P, Smedby KE. Incidence and time trends of brain metastases admissions among breast cancer patients in Sweden. Br J Cancer. 2012;106(11):1850–3.CrossRefPubMedPubMedCentral
5.
Adkins CE, Nounou MI, Mittapalli RK, Terrell-Hall TB, Mohammad AS, Jagannathan R, Lockman PR. A novel preclinical method to quantitatively evaluate early-stage metastatic events at the murine blood-brain barrier. Cancer prevention research (Philadelphia Pa). 2015;8(1):68–76.CrossRef
6.
Adkins CE, Mohammad AS, Terrell-Hall TB, Dolan EL, Shah N, Sechrest E, Griffith J, Lockman PR. Characterization of passive permeability at the blood–tumor barrier in five preclinical models of brain metastases of breast cancer. Clinical & Experimental Metastasis. 2016;33(4):373–83.CrossRef
7.
Lockman PR, Mittapalli RK, Taskar KS, Rudraraju V, Gril B, Bohn KA, Adkins CE, Roberts A, Thorsheim HR, Gaasch JA, et al. Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2010;16(23):5664–78.CrossRef
8.
Adkins CE, Nounou MI, Hye T, Mohammad AS, Terrell-Hall T, Mohan NK, Eldon MA, Hoch U, Lockman PR. NKTR-102 efficacy versus irinotecan in a mouse model of brain metastases of breast cancer. BMC Cancer. 2015;15:685.CrossRefPubMedPubMedCentral
9.
Guillaume DJ, Doolittle ND, Gahramanov S, Hedrick NA, Delashaw JB, Neuwelt EA. Intra-arterial chemotherapy with osmotic blood-brain barrier disruption for aggressive Oligodendroglial tumors: results of a phase I study. Neurosurgery. 2010;66(1):48–58.PubMed
10.
Konofagou EE, Tung Y-S, Choi J, Deffieux T, Baseri B, Vlachos F. Ultrasound-induced blood-brain barrier opening. Curr Pharm Biotechnol. 2012;13(7):1332–45.CrossRefPubMedPubMedCentral
11.
El-Habashy SE, Nazief AM, Adkins CE, Wen MM, El-Kamel AH, Hamdan AM, Hanafy AS, Terrell TO, Mohammad AS, Lockman PR, et al. Novel treatment strategies for brain tumors and metastases. Pharmaceutical patent analyst. 2014;3(3):279–96.CrossRefPubMed
12.
Mittapalli RK, Adkins CE, Bohn KA, Mohammad AS, Lockman JA, Lockman PR. Quantitative fluorescence microscopy measures vascular pore size in primary and metastatic brain tumors. Cancer Res. 2017;77(2):238–46.CrossRefPubMed
13.
Patlak CS, Blasberg RG, Fenstermacher JD. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab. 1983;3(1):1–7.CrossRefPubMed
14.
Asotra K, Ningaraj N, Black KL. Measurement of blood-brain and blood-tumor barrier permeabilities with [14C]-labeled tracers. Methods in molecular medicine. 2003;89:177–90.PubMed
15.
Blasberg RG, Shapiro WR, Molnar P, Patlak CS, Fenstermacher JD. Local blood-to-tissue transport in Walker 256 metastatic brain tumors. J Neuro-Oncol. 1984;2(3):205–18.
16.
Eng LF, Ghirnikar RS, Lee YL. Glial fibrillary acidic protein: GFAP-thirty-one years (1969–2000). Neurochem Res. 2000;25(9):1439–51.CrossRefPubMed
17.
Song L, Varma CA, Verhoeven JW, Tanke HJ. Influence of the triplet excited state on the photobleaching kinetics of fluorescein in microscopy. Biophys J. 1996;70(6):2959–68.CrossRefPubMedPubMedCentral
18.
Bohn KA, Adkins CE, Mittapalli RK, Terrell-Hall TB, Mohammad AS, Shah N, Dolan EL, Nounou MI, Lockman PR. Semi-automated rapid quantification of brain vessel density utilizing fluorescent microscopy. J Neurosci Methods. 2016;270:124–31.CrossRefPubMedPubMedCentral
19.
Knight RA, Karki K, Ewing JR, Divine GW, Fenstermacher JD, Patlak CS, Nagaraja TN. Estimating blood and brain concentrations and blood-to-brain influx by magnetic resonance imaging with step-down infusion of Gd-DTPA in focal transient cerebral ischemia and confirmation by quantitative autoradiography with Gd-[(14)C]DTPA. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2009;29(5):1048–58.CrossRef
20.
Knight RA, Nagaraja TN, Ewing JR, Nagesh V, Whitton PA, Bershad E, Fagan SC, Fenstermacher JD. Quantitation and localization of blood-to-brain influx by magnetic resonance imaging and quantitative autoradiography in a model of transient focal ischemia. Magn Reson Med. 2005;54(4):813–21.CrossRefPubMed
21.
van Tellingen O, Yetkin-Arik B, de Gooijer MC, Wesseling P, Wurdinger T, de Vries HE. Overcoming the blood-brain tumor barrier for effective glioblastoma treatment. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy. 2015;19:1–12.CrossRef
22.
23.
Fukumura D, Jain RK. Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization. Microvasc Res. 2007;74(2–3):72–84.CrossRefPubMedPubMedCentral
24.
Eilken HM, Adams RH. Dynamics of endothelial cell behavior in sprouting angiogenesis. Curr Opin Cell Biol. 2010;22(5):617–25.CrossRefPubMed
25.
Schmitt M, Horbach A, Kubitz R, Frilling A, Haussinger D. Disruption of hepatocellular tight junctions by vascular endothelial growth factor (VEGF): a novel mechanism for tumor invasion. J Hepatol. 2004;41(2):274–83.CrossRefPubMed
26.
27.
28.
Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods. 2000;44(1):235–49.CrossRefPubMed
29.
Levin VA. Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J Med Chem. 1980;23(6):682–4.CrossRefPubMed
30.
van de Waterbeemd H, Camenisch G, Folkers G, Chretien JR, Raevsky OA. Estimation of blood-brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors. J Drug Target. 1998;6(2):151–65.CrossRefPubMed
31.
Fischer H, Gottschlich R, Seelig A. Blood-brain barrier permeation: molecular parameters governing passive diffusion. J Membr Biol. 1998;165(3):201–11.CrossRefPubMed
32.
Uchida Y, Ohtsuki S, Katsukura Y, Ikeda C, Suzuki T, Kamiie J, Terasaki T. Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors. J Neurochem. 2011;117(2):333–45.CrossRefPubMed
33.
Sharom FJ. ABC multidrug transporters: structure, function and role in chemoresistance. Pharmacogenomics. 2008;9(1):105–27.CrossRefPubMed
34.
Hiesiger EM, Voorhies RM, Basler GA, Lipschutz LE, Posner JB, Shapiro WR. Opening the blood-brain and blood-tumor barriers in experimental rat brain tumors: the effect of intracarotid hyperosmolar mannitol on capillary permeability and blood flow. Ann Neurol. 1986;19(1):50–9.CrossRefPubMed
35.
Walker MD, Weiss HD. Chemotherapy in the treatment of malignant brain tumors. Adv Neurol. 1975;13:149–91.PubMed
36.
Blasberg RG, Gazendam J, Patlak CS, Shapiro WS, Fenstermacher JD. Changes in blood-brain transfer parameters induced by hyperosmolar intracarotid infusion and by metastatic tumor growth. Adv Exp Med Biol. 1980;131:307–19.CrossRefPubMed
37.
Fidler IJ, Yano S, Zhang RD, Fujimaki T, Bucana CD. The seed and soil hypothesis: vascularisation and brain metastases. The Lancet Oncology. 2002;3(1):53–7.CrossRefPubMed
38.
39.
Baba H, Nakahira K, Morita N, Tanaka F, Akita H, Ikenaka K. GFAP gene expression during development of astrocyte. Dev Neurosci. 1997;19(1):49–57.CrossRefPubMed
40.
Khurgel M, Ivy GO. Astrocytes in kindling: relevance to epileptogenesis. Epilepsy Res. 1996;26(1):163–75.CrossRefPubMed
41.
Yang Z, Wang KK. Glial fibrillary acidic protein: from intermediate filament assembly and gliosis to neurobiomarker. Trends Neurosci. 2015;38(6):364–74.CrossRefPubMedPubMedCentral
42.
Niranjan R, Nagarajan R, Hanif K, Nath C, Shukla R. LPS induces mediators of neuroinflammation, cell proliferation, and GFAP expression in human astrocytoma cells U373MG: the anti-inflammatory and anti-proliferative effect of guggulipid. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2014;35(3):409–14.CrossRef
43.
Hozumi I, Chiu FC, Norton WT. Biochemical and immunocytochemical changes in glial fibrillary acidic protein after stab wounds. Brain Res. 1990;524(1):64–71.CrossRefPubMed
44.
Tsuji T, Shimohama S, Kamiya S, Sazuka T, Ohara O. Analysis of brain proteins in Alzheimer's disease using high-resolution two-dimensional gel electrophoresis. J Neurol Sci. 1999;166(2):100–6.CrossRefPubMed
45.
Troost D, Sillevis Smitt PA, de Jong JM, Swaab DF. Neurofilament and glial alterations in the cerebral cortex in amyotrophic lateral sclerosis. Acta Neuropathol. 1992;84(6):664–73.CrossRefPubMed
46.
Banati RB, Daniel SE, Blunt SB. Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society. 1998;13(2):221–7.CrossRef
47.
Murayama S, Inoue K, Kawakami H, Bouldin TW, Suzuki K. A unique pattern of astrocytosis in the primary motor area in amyotrophic lateral sclerosis. Acta Neuropathol. 1991;82(6):456–61.CrossRefPubMed
48.
Laurence JA, Fatemi SH. Glial fibrillary acidic protein is elevated in superior frontal, parietal and cerebellar cortices of autistic subjects. Cerebellum (London, England). 2005;4(3):206–10.CrossRef
49.
Singh VK, Warren R, Averett R, Ghaziuddin M. Circulating autoantibodies to neuronal and glial filament proteins in autism. Pediatr Neurol. 1997;17(1):88–90.CrossRefPubMed
50.
Rosengren LE, Ahlsen G, Belfrage M, Gillberg C, Haglid KG, Hamberger A. A sensitive ELISA for glial fibrillary acidic protein: application in CSF of children. J Neurosci Methods. 1992;44(2–3):113–9.CrossRefPubMed
51.
Aurell A, Rosengren LE, Karlsson B, Olsson JE, Zbornikova V, Haglid KG. Determination of S-100 and glial fibrillary acidic protein concentrations in cerebrospinal fluid after brain infarction. Stroke. 1991;22(10):1254–8.CrossRefPubMed
52.
Hausmann R, Riess R, Fieguth A, Betz P. Immunohistochemical investigations on the course of astroglial GFAP expression following human brain injury. Int J Legal Med. 2000;113(2):70–5.CrossRefPubMed
53.
Johnston-Wilson NL, Sims CD, Hofmann JP, Anderson L, Shore AD, Torrey EF, Yolken RH. Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium. Molecular psychiatry. 2000;5(2):142–9.CrossRefPubMed
54.
Chumbalkar VC, Subhashini C, Dhople VM, Sundaram CS, Jagannadham MV, Kumar KN, Srinivas PN, Mythili R, Rao MK, Kulkarni MJ, et al. Differential protein expression in human gliomas and molecular insights. Proteomics. 2005;5(4):1167–77.CrossRefPubMed
55.
Kovalchuk A, Kolb B: Chemo brain: from discerning mechanisms to lifting the brain fog-an aging connection. Cell Cycle (Georgetown, Tex) 2017:1–5.
56.
Raffa RB. Is a picture worth a thousand (forgotten) words?: neuroimaging evidence for the cognitive deficits in 'chemo-fog'/'chemo-brain. J Clin Pharm Ther. 2010;35(1):1–9.CrossRefPubMed
57.
Castellon SA, Ganz PA, Bower JE, Petersen L, Abraham L, Greendale GA. Neurocognitive performance in breast cancer survivors exposed to adjuvant chemotherapy and tamoxifen. J Clin Exp Neuropsychol. 2004;26(7):955–69.CrossRefPubMed
58.
Schagen SB, van Dam FS, Muller MJ, Boogerd W, Lindeboom J, Bruning PF. Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer. 1999;85(3):640–50.CrossRefPubMed
59.
Ahles TA, Saykin AJ, Furstenberg CT, Cole B, Mott LA, Skalla K, Whedon MB, Bivens S, Mitchell T, Greenberg ER, et al. Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2002;20(2):485–93.CrossRef
60.
Kaiser J, Bledowski C, Dietrich J. Neural correlates of chemotherapy-related cognitive impairment. Cortex; a journal devoted to the study of the nervous system and behavior. 2014;54:33–50.CrossRefPubMed
61.
Seigers R, Fardell JE. Neurobiological basis of chemotherapy-induced cognitive impairment: a review of rodent research. Neurosci Biobehav Rev. 2011;35(3):729–41.CrossRefPubMed
62.
Seigers R, Loos M, Van Tellingen O, Boogerd W, Smit AB, Schagen SB. Cognitive impact of cytotoxic agents in mice. Psychopharmacology. 2015;232(1):17–37.CrossRefPubMed
63.
Seigers R, Pourtau L, Schagen SB, van Dam FS, Koolhaas JM, Konsman JP, Buwalda B. Inhibition of hippocampal cell proliferation by methotrexate in rats is not potentiated by the presence of a tumor. Brain Res Bull. 2010;81(4–5):472–6.CrossRefPubMed
64.
Seigers R, Timmermans J, van der Horn HJ, de Vries EF, Dierckx RA, Visser L, Schagen SB, van Dam FS, Koolhaas JM, Buwalda B. Methotrexate reduces hippocampal blood vessel density and activates microglia in rats but does not elevate central cytokine release. Behav Brain Res. 2010;207(2):265–72.CrossRefPubMed
Metadata
Title
Permeability changes and effect of chemotherapy in brain adjacent to tumor in an experimental model of metastatic brain tumor from breast cancer
Authors
Afroz S. Mohammad
Chris E. Adkins
Neal Shah
Rawaa Aljammal
Jessica I. G. Griffith
Rachel M. Tallman
Katherine L. Jarrell
Paul R. Lockman
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-5115-x

Other articles of this Issue 1/2018

BMC Cancer 1/2018 Go to the issue

Research article

TIPE3 differentially modulates proliferation and migration of human non-small-cell lung cancer cells via distinct subcellular location

Case report

Successfully treatment by eribulin in visceral crisis: a case of lymphangitic carcinomatosis from metastatic breast cancer

Study protocol

Study protocol: a randomized control trial of African American families fighting parental cancer together

Research article

An inflammation-related nomogram for predicting the survival of patients with non-small cell lung cancer after pulmonary lobectomy

Case report

Mixed response on regorafenib treatment for GIST (gastro-intestinal stromal tumor) according to 18F–FDG-PET/CT

Research article

Overall survival and time trends in breast and cervical cancer incidence and mortality in the Regional Health District (RHD) of Barretos, São Paulo, Brazil
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits