CCR4 is a determinant of melanoma brain metastasis

Klein, Anat; Sagi‐Assif, Orit; Meshel, Tsipi; Telerman, Alona; Izraely, Sivan; Ben-Menachem, Shlomit; Bayry, Jagadeesh; Marzese, Diego M.; Ohe, Shuichi; Hoon, Dave S. B.; Erez, Neta

doi:10.18632/oncotarget.16076

Cited by 63 publications

(63 citation statements)

References 40 publications

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“…The specific organ microenvironment plays a significant (positive or negative) role in the development of metastasis in that organ . Previous results from our lab showed that brain microenvironmental cells and their molecular products are involved in the progression of melanoma toward brain metastasis …”

Section: Discussionmentioning

confidence: 89%

“…In our study, we used the brain metastatic variant DP.CB2. Immortalized human microglia‐SV40 cell line (ABM, Milton, ON, Canada) was maintained as described previously . Immortalized human brain microvascular endothelial cells (hCMEC/D3) were kindly provided by Clara Nahmias and Pierre‐Olivier Couraud (Inserm, U1016, Institute Cochin, Paris, France) and were maintained as described previously .…”

Section: Methodsmentioning

confidence: 99%

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The metastatic microenvironment: Melanoma–microglia cross‐talk promotes the malignant phenotype of melanoma cells

Izraely

Ben-Menachem

Sagi‐Assif

et al. 2018

Intl Journal of Cancer

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Melanoma has the highest propensity to metastasize to the brain compared to other cancers, as brain metastases are found frequently high in patients who have prolonged survival with visceral metastasis. Once disseminated in the brain, melanoma cells communicate with brain resident cells that include astrocytes and microglia. Microglia cells are the resident macrophages of the brain and are the main immunological cells in the CNS involved in neuroinflammation. Data on the interactions between brain metastatic melanoma cells and microglia and on the role of microglia-mediated neuroinflammation in facilitating melanoma brain metastasis are lacking. To elucidate the role of microglia in melanoma brain metastasis progression, we examined the bidirectional interactions between microglia and melanoma cells in the tumor microenvironment. We identified the molecular and functional modifications occurring in brain-metastasizing melanoma cells and microglia cells after the treatment of each cell type with supernatants of the counter cell type. Both cells induced alteration in gene expression programs, cell signaling, and cytokine secretion in the counter cell type. Moreover, melanoma cells exerted significant morphological changes on microglia cells, enhanced proliferation, induced matrix metalloproteinase-2 (MMP-2) activation, and cell migration. Microglia cells induced phenotypic changes in melanoma cells increasing their malignant phenotype: increased melanoma proliferation, MMP-2 activity, cell migration, brain endothelial penetration, and tumor cells ability to grow as spheroids in 3D cultures. Our work provides a novel insight into the bidirectional interactions between melanoma and micoglia cells, suggesting the contribution of microglia to melanoma brain metastasis formation.

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Section: Discussionmentioning

confidence: 89%

Section: Methodsmentioning

confidence: 99%

The metastatic microenvironment: Melanoma–microglia cross‐talk promotes the malignant phenotype of melanoma cells

Izraely

Ben-Menachem

Sagi‐Assif

et al. 2018

Intl Journal of Cancer

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“…Astrocytic exosome inhibition can prevent BM (41). A multicentre study on 318 patients with breast cancer (84 with BM) highlighted that fibroblast growth factor-inducible protein 14 (FN14) and GRP94 are prediction/prognosis markers that can be used as therapeutic targets in BM patients (42). However, this study was performed in breast cancer patients and the results should be carefully extrapolated in BM from melanoma due to the specific molecular signature of the melanoma cells.…”

Section: Biomarkers In Melanoma Brain Metastasis Predictionmentioning

confidence: 98%

Molecular and cellular stratagem of brain metastases associated with melanoma (Review)

et al. 2019

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Tumors of the central nervous system are the most prevalent complications of melanoma, especially in the late stage of disease. Melanoma, lung and breast cancer are the leading cause of secondary tumors in the brain, the majority of them having a poor outcome. Brain dissemination is developed in half of stage IV melanomas and these cases can increase up to 75%, having a major impact on the quality of life. This review will focus on recent findings that provide new ways to potentially prevent brain metastases in malignant melanoma. The key of these findings is based on the heterogeneity of the melanoma and of the brain metastases at genetic levels. This new era of technologies provides new tools in understanding the dissemination mechanisms of malignant cells. The cellular and molecular changes, the immune status of the patient and the blood-brain barrier permeability are key regulators of cancer cell dissemination. Understanding these mechanisms can render new hope in preventing brain metastases by focusing on melanoma and new pharmacologic approaches. Contents

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“…During this process, the role of chemokines and their cognate receptors cannot be ignored 91. Izraely discovered that brain‐metastasizing melanoma cells expressed really higher level of C‐C motif chemokine receptor 4 (CCR4).…”

Section: The Mechanism Of Brain Metastasismentioning

confidence: 99%

Emerging findings into molecular mechanism of brain metastasis

Chen

2018

Cancer Medicine

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Brain metastasis is an important cause of morbidity and mortality in cancer patients. Hence, the need to develop improved therapies to prevent and treat metastasis to the brain is becoming urgent. Recent studies in this area are bringing about some advanced progress on brain metastasis. It was concluded that the occurrence and poor prognosis of brain metastasis have been mostly attributed to the exclusion of anticancer drugs from the brain by the blood‐brain barrier. And several highly potent new generation targeted drugs with enhanced CNS distribution have been developed constantly. However, the noted “seed and soil” hypothesis also suggests that the outcome of metastasis depends on the relationship between unique tumor cells and the specific organ microenvironment. Moreover, increasing studies in multiple tumor types demonstrated that brain metastasis has great molecular differences between primary tumors and extracranial metastasis to a large extent. Here, the authors summarized the most common malignancies that could lead to brain metastasis—lung cancer, breast cancer and melanoma and their related mutated factors. Only by comprehending a deeper understanding of the molecular mechanisms, more effective brain‐specific therapies will be developed for brain metastasis.

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CCR4 is a determinant of melanoma brain metastasis

Cited by 63 publications

References 40 publications

The metastatic microenvironment: Melanoma–microglia cross‐talk promotes the malignant phenotype of melanoma cells

The metastatic microenvironment: Melanoma–microglia cross‐talk promotes the malignant phenotype of melanoma cells

Molecular and cellular stratagem of brain metastases associated with melanoma (Review)

Emerging findings into molecular mechanism of brain metastasis

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