Microglia promote colonization of brain tissue by breast cancer cells in a Wnt‐dependent way

Pukrop, Tobias; Dehghani, Faramarz; Chuang, Han-Ning; Lohaus, Raphaela; Bayanga, Kathrin; Heermann, Stephan; Regen, Tommy; Rossum, Denise van; Klemm, Florian; Schulz, Matthias; Siam, Laila; Hoffmann, Anja; Trümper, Lorenz; Stadelmann, Christine; Bechmann, Ingo; Hanisch, Uwe‐Karsten; Binder, Claudia R.

doi:10.1002/glia.21022

Cited by 185 publications

(220 citation statements)

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“…Consequently, the invading breast cancer cells exhibit specific neural characteristics which enable them to penetrate into the brain tissue; thereby, highly activated GABA expression increases their proliferative capacity, particularly within the pre-metastatic niches as the preferable microenvironment. In this context, an active communication between invading cancer cells, astrocytes and microglia in the Bhosting^brain parenchyma has been identified representing an essential part of the successful cancer cell nesting and metastatic process [49][50][51][52].…”

Section: Molecular and Genetic Biomarkers Other Than Hormone And Her2mentioning

confidence: 99%

Mystery of the brain metastatic disease in breast cancer patients: improved patient stratification, disease prediction and targeted prevention on the horizon?

et al. 2017

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The breast cancer (BC) diagnosis currently experiences the epidemic evolution with more than half of million deaths each year. Despite screening programmes applied and treatments available, breast cancer patients frequently develop distant metastases. The brain is one of the predominant sites of the metastatic spread recorded for more than 20% of BC patients, in contrast to the general population, where brain tumours are rarely diagnosed. Although highly clinically relevant, the brain tumour mystery in the cohort of breast cancer patients has not been yet adequately explained. This review summarises currently available information on the risk factors predicting brain metastases in BC patients to motivate the relevant scientific areas to explore the data/facts available and elucidate disease-specific mechanisms that are of a great clinical utility.

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Section: Molecular and Genetic Biomarkers Other Than Hormone And Her2mentioning

confidence: 99%

Mystery of the brain metastatic disease in breast cancer patients: improved patient stratification, disease prediction and targeted prevention on the horizon?

et al. 2017

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“…Additionally, this is the first time, to our knowledge, microglia were found to actively transport carcinoma cells 23 .…”

Section: Discussionmentioning

confidence: 58%

Coculture System with an Organotypic Brain Slice and 3D Spheroid of Carcinoma Cells

Chuang

Lohaus

Hanisch

et al. 2013

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Patients with cerebral metastasis of carcinomas have a poor prognosis. However, the process at the metastatic site has barely been investigated, in particular the role of the resident (stromal) cells. Studies in primary carcinomas demonstrate the influence of the microenvironment on metastasis, even on prognosis 1,2 . Especially the tumor associated macrophages (TAM) support migration, invasion and proliferation 3 . Interestingly, the major target sites of metastasis possess tissue-specific macrophages, such as Kupffer cells in the liver or microglia in the CNS. Moreover, the metastatic sites also possess other tissue-specific cells, like astrocytes. Recently, astrocytes were demonstrated to foster proliferation and persistence of cancer cells 4,5 . Therefore, functions of these tissue-specific cell types seem to be very important in the process of brain metastasis 6,7 . Despite these observations, however, up to now there is no suitable in vivo/in vitro model available to directly visualize glial reactions during cerebral metastasis formation, in particular by bright field microscopy. Recent in vivo live imaging of carcinoma cells demonstrated their cerebral colonization behavior 8 . However, this method is very laborious, costly and technically complex. In addition, these kinds of animal experiments are restricted to small series and come with a substantial stress for the animals (by implantation of the glass plate, injection of tumor cells, repetitive anaesthesia and long-term fixation). For these reasons, we established a coculture system consisting of an organotypic mouse brain slice and epithelial cells embedded in matrigel (3D cell sphere). The 3D carcinoma cell spheres were placed directly next to the brain slice edge in order to investigate the invasion of the neighboring brain tissue. This enables us to visualize morphological changes and interactions between the glial cells and carcinoma cells by fluorescence and even by bright field microscopy. After the coculture experiment, the brain tissue or the 3D cell spheroids can be collected and used for further molecular analyses (e.g. qRT-PCR, IHC, or immunoblot) as well as for investigations by confocal microscopy. This method can be applied to monitor the events within a living brain tissue for days without deleterious effects to the brain slices. The model also allows selective suppression and replacement of resident cells by cells from a donor tissue to determine the distinct impact of a given genotype. Finally, the coculture model is a practicable alternative to in vivo approaches when testing targeted pharmacological manipulations. Video LinkThe video component of this article can be found at https://www.jove.com/video/50881/ ProtocolThis new model is an adaptation of a previously published organotypic hippocampal brain slice approach [9][10][11][12] . Modifications and additions were introduced to optimize the cancer cell-brain tissue interactions and to guarantee reproducibility. The study was reviewed and approved by the local ethics commi...

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“…These findings indicate that glioma cells stimulate microglial cells to increase breakdown of extracellular matrix by induction of MMP-2 and thereby promote tumour invasiveness (Markovic, Glass, Synowitz, Rooijen, & Kettenmann, 2005). In consistency, it was reported that microglia promote brain colonisation of MCF-7 cells in a Wnt-dependent manner (Pukrop et al, 2010).…”

Section: Discussionmentioning

confidence: 62%

“…Microglia, the resident macrophages of the central nervous system, play central roles in neurodegenerative and neuroinflammatory responses (Pukrop et al, 2010). There is 75 compelling evidence that microglia contribute to cerebral malignancies (Pukrop et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

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Heregulin (Neuregulin)/HER3 signalling increases invasive behaviour of HER2-positive breast cancer cells

Momeny¹

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Breast cancer is a heterogeneous disease with distinct histological and molecular subtypes differing in prognosis, response to therapy and metastatic behaviour. Like most cancers, poor outcome in breast cancer is related to tumour cell spread and colonisation of distant organs, which ultimately disrupts local and systemic physiological processes to the demise of the patient. Colonisation of the brain is arguably the most aggressive manifestation of metastatic disease. Brain metastasis is a growing public health problem associated with a high degree of morbidity and virtually 100% mortality. The current treatments for these patients are surgery, radiotherapy and chemotherapy, but their outcome remains poor. In this regard, the management of brain metastases is an unmet medical need for which establishment of more effective preventive and therapeutic treatment strategies is of paramount importance. In order to achieve that, we need to deepen our knowledge and insights about the molecular mechanisms and signal transduction pathways underlying initiation and progression of brain metastases.Invasion of breast tumour cells across the basement membrane and endothelium to gain entry to the blood stream and lymphovascular system is a critical early requirement for metastasis.Disseminated cells must then undergo extravasation at distant tissue sites. In the case of brain metastases, cells must breach the highly specialised and impermeable blood-brain-barrier.Improving our understanding of the molecular mechanisms underlying these processes may reveal new drug targets to prevent development or suppress growth of these lethal tumours.Of all the breast cancer subtypes, patients with HER2-positive disease (amplification and/or overexpression of the ERBB2 receptor tyrosine kinase) exhibit the highest frequency of brain metastases. Both HER2 and its obligate dimerisation partner, HER3 (ERBB3), are associated with development of brain metastases, though a mechanistic link has not yet been established.The main goal of this project was to elucidate the molecular mechanisms by which the HER2/HER3 heterodimer promotes metastatic progression and more specifically, development of brain metastases. In order to achieve this, activation of the HER2/HER3 iv

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Microglia promote colonization of brain tissue by breast cancer cells in a Wnt‐dependent way

Cited by 185 publications

References 58 publications

Mystery of the brain metastatic disease in breast cancer patients: improved patient stratification, disease prediction and targeted prevention on the horizon?

Mystery of the brain metastatic disease in breast cancer patients: improved patient stratification, disease prediction and targeted prevention on the horizon?

Coculture System with an Organotypic Brain Slice and 3D Spheroid of Carcinoma Cells

Heregulin (Neuregulin)/HER3 signalling increases invasive behaviour of HER2-positive breast cancer cells

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