Preclinical approaches to study the biology and treatment of brain metastases

Cruz‐Muñoz, William; Kerbel, Robert S.

doi:10.1016/j.semcancer.2010.12.001

Cited by 46 publications

(29 citation statements)

References 80 publications

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“…Reproducible models of brain metastasis that recapitulate the multistep process of metastases have been a major challenge for several decades (11,31,32). We have established a clinically relevant murine model of spontaneous melanoma brain metastasis in immunocompetent mice that provides a unique platform to study the pathophysiology of brain metastasis.…”

Section: Discussionmentioning

confidence: 99%

Incipient Melanoma Brain Metastases Instigate Astrogliosis and Neuroinflammation

et al. 2016

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Malignant melanoma is the deadliest of skin cancers. Melanoma frequently metastasizes to the brain, resulting in dismal survival. Nevertheless, mechanisms that govern early metastatic growth and the interactions of disseminated metastatic cells with the brain microenvironment are largely unknown. To study the hallmarks of brain metastatic niche formation, we established a transplantable model of spontaneous melanoma brain metastasis in immunocompetent mice and developed molecular tools for quantitative detection of brain micrometastases. Here we demonstrate that micrometastases are associated with instigation of astrogliosis, neuroinflammation, and hyperpermeability of the blood-brain barrier. Furthermore, we show a functional role for astrocytes in facilitating initial growth of melanoma cells. Our findings suggest that astrogliosis, physiologically instigated as a brain tissue damage response, is hijacked by tumor cells to support metastatic growth. Studying spontaneous melanoma brain metastasis in a clinically relevant setting is the key to developing therapeutic approaches that may prevent brain metastatic relapse.

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Section: Discussionmentioning

confidence: 99%

Incipient Melanoma Brain Metastases Instigate Astrogliosis and Neuroinflammation

et al. 2016

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“…Studies of HER2-positive breast cancer metastasis to the brain have been severely hampered by the lack of clinically relevant laboratory models (11,(32)(33)(34). We describe here a metastatic model that faithfully replicates the clinical response to treatment: failure of a HER2-dependent tumor growing in the brain to respond to anti-HER2 therapy.…”

Section: Discussionmentioning

confidence: 99%

Combined targeting of HER2 and VEGFR2 for effective treatment ofHER2-amplified breast cancer brain metastases

Kodack¹,

Chung

Yamashita³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

139

106

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Brain metastases are a serious obstacle in the treatment of patients with human epidermal growth factor receptor-2 (HER2)-amplified breast cancer. Although extracranial disease is controlled with HER2 inhibitors in the majority of patients, brain metastases often develop. Because these brain metastases do not respond to therapy, they are frequently the reason for treatment failure. We developed a mouse model of HER2-amplified breast cancer brain metastasis using an orthotopic xenograft of BT474 cells. As seen in patients, the HER2 inhibitors trastuzumab and lapatinib controlled tumor progression in the breast but failed to contain tumor growth in the brain. We observed that the combination of a HER2 inhibitor with an anti-VEGF receptor-2 (VEGFR2) antibody significantly slows tumor growth in the brain, resulting in a striking survival benefit. This benefit appears largely due to an enhanced antiangiogenic effect: Combination therapy reduced both the total and functional microvascular density in the brain xenografts. In addition, the combination therapy led to a marked increase in necrosis of the brain lesions. Moreover, we observed even better antitumor activity after combining both trastuzumab and lapatinib with the anti-VEGFR2 antibody. This triple-drug combination prolonged the median overall survival fivefold compared with the control-treated group and twofold compared with either two-drug regimen. These findings support the clinical development of this three-drug regimen for the treatment of HER2-amplified breast cancer brain metastases.treatment resistance | tumor-stroma interaction | targeted therapy | tumor microenvironment | antiangiogenesis

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“…By western blot analysis, we found that ZEB2 expression was decreased in brain metastatic adenocarcinoma cells, compared to their parental cell lines. Currently, there is no animal model for studying brain metastatic gastric cancer (31,32). Although we did not prepare a stable, spontaneous metastatic cell line, we were able to generate 2 'transient' brain metastatic gastric cancer cell lines by intracardiac injection.…”

Section: Increased Mirna Ratiomentioning

confidence: 94%

MicroRNA-200 family members and ZEB2 are associated with brain metastasis in gastric adenocarcinoma

Minn

Lee

Hyung

et al. 2014

International Journal of Oncology

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Abstract. Although the incidence of brain metastasis in gastric cancer is relatively low, its prevalence may increase with improved therapy and longer survival tumors. The molecular mechanisms underlying brain metastases are not well understood. To gain insight into the mechanism of brain metastasis, we studied differences in microRNA (miRNA) expression levels in 8 cases of matched primary gastric adenocarcinoma and brain metastatic adenocarcinoma using the Illumina microRNA microarray chip. We identified 6 upregulated and 2 downregulated miRNAs in all 8 cases simultaneously. Interestingly, 2 out of 8 miRNAs (hsa-miR-141-3p and hsa-miR-200b-3p) belonged to the miR-200 family. Online microRNA database searching revealed that ZEB2 is the topranked target gene for hsa-miR141-3p and hsa-miR-200b-3p, prompting us to focus ZEB2 expression in brain metastatic adenocarcinoma. We confirmed that ZEB2 expression was markedly downregulated in some brain metastatic samples. In addition, decreased ZEB2 expression was noted by western blot analysis of 2 metastatic gastric adenocarcinoma cell types that were derived by in vivo selection following intracardiac injection of gastric cancer cell lines. In conclusion, we demonstrate that expression of miRNA-200 family members and ZEB2 are associated with brain metastases of gastric adenocarcinoma, not only in matched patient samples, but also in metastatic cell lines that were derived by in vivo selection. IntroductionAlthough the incidence of gastric cancer has been declining since 1950, gastric cancer remains the 4th most common cancer worldwide (1). The prevalence of gastric cancer shows wide geographic variations, with the highest rates found in Eastern Asia (including China, Japan and Korea), Eastern Europe, and Central and Latin America (1). In a recent report by the World Health Organization, gastric cancer was classified into 5 main types of adenocarcinomas and rare variants (2). In contrast to the better prognoses associated with early gastric cancers, advanced gastric cancers generally have poor prognoses, with known prognostic factors including stage and the number of lymph node metastases (2). Unlike lung or breast cancer, the brain metastases of gastric cancer are very rare and have been reported in <1% of clinical cases (3,4), most cases of which were reported as leptomeningeal carcinomatosis (5-7).Prolonged survival in gastric cancer patients accompanying improvements in systematic approaches and overall patient care has increased the likelihood of patients developing central nervous system metastases (8). Similarly, the incidence of brain metastasis in non-small cell lung cancer patients has increased in recent years (9), likely resulting from improved therapy, diagnostic modalities, and screening programs for early detection. In addition, evidence suggests that improved targeted therapy in patients with HER-2-positive breast cancer may increase the incidence of brain metastases (10,11). Although there is no established targeted therapy for treating gastric cancer,...

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Preclinical approaches to study the biology and treatment of brain metastases

Cited by 46 publications

References 80 publications

Incipient Melanoma Brain Metastases Instigate Astrogliosis and Neuroinflammation

Incipient Melanoma Brain Metastases Instigate Astrogliosis and Neuroinflammation

Combined targeting of HER2 and VEGFR2 for effective treatment ofHER2-amplified breast cancer brain metastases

MicroRNA-200 family members and ZEB2 are associated with brain metastasis in gastric adenocarcinoma

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