Perspectives on the role of brain cellular players in cancer-associated brain metastasis: translational approach to understand molecular mechanism of tumor progression

Raza, Masoom; Prasad, Peeyush; Gupta, Purva; Kumar, Naveen; Sharma, Taruna; Rana, Mandeep; Goldman, Aaron; Sehrawat, Seema

doi:10.1007/s10555-018-9766-5

Cited by 20 publications

(13 citation statements)

References 100 publications

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“…The pathogenic mechanisms underlying brain metastasis from CC remain unclear. It has been reported that the interaction between tumor cells and brain cells within the brain microenvironment results in the release of various cytokines that subsequently promote tumor growth [21–24]. Another significant bottleneck in understanding the pathogenesis of brain metastasis is the limited availability of nutrients in the brain.…”

Section: Discussionmentioning

confidence: 99%

Pathologically confirmed brain metastases from primary uterine cervical tumors: two cases and a literature review

2019

World J Surg Onc

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BackgroundPathologically confirmed brain metastasis from primary cervical cancer is extremely rare. Herein, we report two cases of intracranial metastasis from cervical cancer that were histopathologically confirmed after surgical excision. In addition, we conducted a literature review to characterize the clinical manifestation, pathogenesis, and treatment of these patients.Case summaryAmong the 1800 patients with primary cervical cancer who received therapy at our center from 2010 to 2018, two patients (0.1%) had definite histopathological evidence of brain metastasis. A 46-year-old female who had a history of poorly differentiated stage IIB cervical cancer with neuroendocrine differentiation presented with a solitary mass in the right occipital lobe 26 months after the initial diagnosis. She underwent surgery and chemotherapy but died of disease progression 9 months later. Another 55-year-old female diagnosed with poorly differentiated stage IVB cervical squamous cancer presented with a solitary mass in the right frontal lobe 16 months after simple hysterectomy. Twelve months later, multiple lesions were observed in the bilateral frontal-parietal lobe. The lesions were treated by surgery and stereotactic radiosurgery. The patient died of multiple organ failure 14 months later.ConclusionThe pathogenesis and best management of brain metastasis from cervical cancer are not clear. Highly invasive subtypes or advanced cancer stages may be the key clinicopathological factors of brain metastasis. Surgical treatment is warranted in patients with a good health status and without metastasis to other sites.

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Section: Discussionmentioning

confidence: 99%

Pathologically confirmed brain metastases from primary uterine cervical tumors: two cases and a literature review

2019

World J Surg Onc

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“…Microglia interact with metastatic breast cancer cells in a heterogeneous fashion in mouse models, adopting multiple morphological states related to diverse functional contributions to tumour progression [20]. The spectrum of activated microglial phenotypes in brain tumours ranges from "classical" M1 proinflammatory cells capable of releasing proinflammatory cytokines and eliciting a T cell response, to "alternative" M2 anti-inflammatory cells which promote tumour growth, angiogenesis and invasion [21][22][23][24][25]. Thus, targeting the anti-inflammatory microglial population [26][27][28], and/or enhancing the activity of the proinflammatory population [29], may provide a new treatment approach for brain metastases.…”

Section: Introductionmentioning

confidence: 99%

Metastatic breast cancer cells induce altered microglial morphology and electrical excitability in vivo

Simon

Yang

Marrison

et al. 2020

J Neuroinflammation

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Background: An emerging problem in the treatment of breast cancer is the increasing incidence of metastases to the brain. Metastatic brain tumours are incurable and can cause epileptic seizures and cognitive impairment, so better understanding of this niche, and the cellular mechanisms, is urgently required. Microglia are the resident brain macrophage population, becoming "activated" by neuronal injury, eliciting an inflammatory response. Microglia promote proliferation, angiogenesis and invasion in brain tumours and metastases. However, the mechanisms underlying microglial involvement appear complex and better models are required to improve understanding of function. Methods: Here, we sought to address this need by developing a model to study metastatic breast cancer cellmicroglial interactions using intravital imaging combined with ex vivo electrophysiology. We implanted an optical window on the parietal bone to facilitate observation of cellular behaviour in situ in the outer cortex of heterozygous Cx3cr1 GFP/+ mice. Results: We detected GFP-expressing microglia in Cx3cr1 GFP/+ mice up to 350 μm below the window without significant loss of resolution. When DsRed-expressing metastatic MDA-MB-231 breast cancer cells were implanted in Matrigel under the optical window, significant accumulation of activated microglia around invading tumour cells could be observed. This inflammatory response resulted in significant cortical disorganisation and aberrant spontaneously-occurring local field potential spike events around the metastatic site. Conclusions: These data suggest that peritumoral microglial activation and accumulation may play a critical role in local tissue changes underpinning aberrant cortical activity, which offers a possible mechanism for the disrupted cognitive performance and seizures seen in patients with metastatic breast cancer.

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“…Survival and seeding to a new niche in CNS are supported by several mechanisms in which different brain cells take part, with a prominent role of microglia (and potentially non-parenchymal macrophages). Cancer cells take-over several mechanisms and polarize microglia and infiltrating peripheral macrophages, which in turn increases proliferation and survival of cancer cells (109). Growing evidence points to a significant and unexplored role of microglia and non-parenchymal macrophages in CNS metastases.…”

Section: Discussionmentioning

confidence: 99%

Immune Microenvironment of Brain Metastases—Are Microglia and Other Brain Macrophages Little Helpers?

2019

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Brain metastases are common intracranial neoplasms and their frequency increases with prolonged survival of cancer patients. New pharmaceuticals targeting oncogenic kinases and immune checkpoint inhibitors augment both overall and progression-free survival in patients with brain metastases, but are not fully successful in reducing metastatic burden and still a majority of oncologic patients die due to dissemination of the disease. Despite therapy advancements, median survival of patients with brain metastases is several months, although it may vary in different types or subtypes of cancer. Contribution of the innate immune system to cancer progression is well established. Tumor-associated macrophages (TAMs), instead of launching antitumor responses, promote extracellular matrix degradation, secrete immunosuppressive cytokines, promote neoangiogenesis and tumor growth. While their roles as pro-tumorigenic cells facilitating tissue remodeling, invasion and metastasis is well documented, much less is known about the immune microenvironment of brain metastases and roles of specific immune cells in those processes. The central nervous system (CNS) is armed in resident myeloid cells: microglia and perivascular macrophages which colonize CNS in early development and maintain homeostasis in brain parenchyma and at brain-blood vessels interfaces. In this study we discuss available data on the immune composition of most common brain metastases, focusing on interactions between metastatic cancer cells and microglia, perivascular and meningeal macrophages. Cancer cells ‘highjack’ several CNS protective mechanisms and may employ microglia and CNS-border associated macrophages into helping cancer cells to colonize a pre-metastatic niche. We describe emerging molecular insights into mechanisms governing communication between microglia and metastatic cancer cells that culminate in activation of CNS resident microglia and trafficking of monocytic cells from the periphery. We present mechanisms controlling those processes in brain metastases and hypothesize on potential therapeutic approaches. In summary, microglia and non-parenchymal brain macrophages are involved in multiple stages of a metastatic disease and, unlike tumor cells, are genetically stable and predictable, which makes them an attractive target for anticancer therapies.

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Perspectives on the role of brain cellular players in cancer-associated brain metastasis: translational approach to understand molecular mechanism of tumor progression

Cited by 20 publications

References 100 publications

Pathologically confirmed brain metastases from primary uterine cervical tumors: two cases and a literature review

Pathologically confirmed brain metastases from primary uterine cervical tumors: two cases and a literature review

Metastatic breast cancer cells induce altered microglial morphology and electrical excitability in vivo

Immune Microenvironment of Brain Metastases—Are Microglia and Other Brain Macrophages Little Helpers?

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