Molecular insights into melanoma brain metastases

Westphal, Dana; Niessner, Heike

doi:10.1002/cncr.30594

Cited by 36 publications

(37 citation statements)

References 117 publications

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“…Our understanding of the brain‐homing process has been rather limited because research focused on brain dissemination has been restricted by the paucity of available preclinical models and human specimens annotated for development of cerebral lesions. The emergence of newer studies of key molecules involved in brain metastasis has added some new insights to our current understanding of the pathogenesis of disease while providing new opportunities for developing brain metastasis–specific therapies …”

Section: Introductionmentioning

confidence: 99%

“…The emergence of newer studies of key molecules involved in brain metastasis has added some new insights to our current understanding of the pathogenesis of disease while providing new opportunities for developing brain metastasis-specific therapies. [8][9][10][11][12][13][14][15][16] Using an integrated clinical and bench-based approach, we previously showed that melanomas that tend to spread, survive, and proliferate in the central nervous system (brain-tropic) display distinct molecular features. 13 Our study identified PLEKHA5, a gene involved in normal brain development, as a likely mediator of melanoma brain dissemination.…”

Section: Introductionmentioning

confidence: 99%

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PLEKHA5 regulates tumor growth in metastatic melanoma

Zhang

Zhu

Deng

et al. 2019

Cancer

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Background PLEKHA5 has previously been identified as a novel molecule implicated in melanoma brain metastasis, a disease that continues to portend a poor prognosis. The aim of this study was to further investigate the functional role of PLEKHA5 in disseminated melanoma. Methods The impact of PLEKHA5 on proliferation and tumor growth was examined in vitro and in melanoma xenograft models, including brain‐tropic melanomas (melanomas tending to disseminate to the brain). In vitro loss‐ and gain‐of‐function studies were used to explore the underlying mechanisms of PLEKHA5‐mediated tumor growth and the crosstalk between PLEKHA5 and PI3K/AKT/mTOR or MAPK/ERK signaling. The clinical relevance of PLEKHA5 dysregulation was further investigated in a cohort of matched cranial and extracranial melanoma metastases. Results PLEKHA5 stable knockdown negatively regulated cell proliferation by inhibiting the G1‐to‐S cell cycle transition, which coincided with upregulation of the cell cycle regulator PDCD4. Conversely, ectopic PLEKHA5 expression exhibited the inverse effect. PLEKHA5 knockdown significantly inhibited tumor growth, whereas its overexpression upregulated the growth of tumors, which was induced by cranial and subcutaneous inoculation of cells in nude mice. PLEKHA5 modulation affected PDCD4 protein stability and was coupled with changes in PI3K/AKT/mTOR pathway signaling. High PDCD4 expression in cerebral specimens was associated with better overall survival. Conclusions This study further supports the role of PLEKHA5 as a regulator of melanoma growth at distant sites, including the brain. Furthermore, the results highlight the significance of PDCD4 dysregulation in disseminated melanoma and implicate PDCD4 as a possible causal link between PLEKHA5 and cell proliferation and growth.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PLEKHA5 regulates tumor growth in metastatic melanoma

Zhang

Zhu

Deng

et al. 2019

Cancer

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“…It is well accepted that advanced melanoma patients with brain metastases generally have a dismal prognosis, with limited benefit to therapeutic interventions other than surgery or radiotherapy. This can be at least partially explained by a very unique microenvironment, distinguished by the presence of a functional blood–brain barrier that limits the passage of molecular and cellular elements . Similarly, nonvisceral metastases are associated with a better survival relative to visceral metastases, and metastases in certain organs such as adrenal glands and lungs can be more responsive to treatment than others .…”

Section: Disrupting Cancer Immune Escapementioning

confidence: 99%

The good, the (not so) bad and the ugly of immune homeostasis in melanoma

et al. 2018

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Within the immune system multiple mechanisms balance the need for efficient pathogen recognition and destruction with the prevention of tissue damage by excessive, inappropriate or even self-targeting (auto)immune reactions. This immune homeostasis is a tightly regulated system which fails during tumor development, often due to the hijacking of its essential self-regulatory mechanisms by cancer cells. It is facilitated not only by tumor intrinsic properties, but also by the microbiome, host genetics and other factors. In certain ways many cancers can therefore be considered a rare failure of immune control rather than an uncommon or rare disease of the tissue of origin, as the acquisition of potentially oncogenic traits through mutation occurs constantly in most tissues during proliferation. Normally, aberrant cells are well-controlled by cell intrinsic (repair or apoptosis) and extrinsic (immune) mechanisms. However, occasionally oncogenic cells survive and escape control. Melanoma is one of the first cancer types where treatments aimed at restoring and enhancing an immune response to regain control over the tumor have been used with various success rates. With the advent of "modern" immunotherapeutics such as anti-CTLA-4 or anti-PD-1 antibodies that both target negative immune-regulatory pathways on immune cells resulting in durable responses in a proportion of patients, the importance of the interplay between the immune system and cancer has been established beyond doubt.

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“…A majority of these patients show multiple brain lesions and/or meningeal involvement, and these factors are associated with particularly poor prognosis [2,5]. While current treatment options for patients with a limited number of brain parenchymal lesions include surgical resection and stereotactic radiosurgery, the treatment options for patients with multifocal disease and meningeal involvement are mainly palliative and include whole-brain radiotherapy and chemotherapy [1,7,8]. Recently, the introduction of molecularly targeted therapies and immunotherapy has given hope to patients with advanced melanoma [9,10], and several trials are evaluating the effect of BRAF inhibitors and immune checkpoint inhibitors in patients with brain metastases [1,11].…”

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confidence: 99%

Bevacizumab treatment of meningeal melanoma metastases

2020

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Background: Melanoma patients with metastatic growth in the meninges have poor prognosis and few treatment options. Although treatment with BRAF inhibitors or immune checkpoint inhibitors has provided promising results, most patients with advanced melanoma are resistant to these treatments and develop severe side effects. Novel treatment strategies are needed for patients with meningeal melanoma metastases, and the potential of antiangiogenic therapy was investigated in this preclinical study. Methods: Two GFP-transfected melanoma models (A-07 and D-12) differing substantially in VEGF-A expression were included in the study, and the anti-VEGF-A antibody bevacizumab was used as therapeutic agent. Meningeal metastases were initiated in BALB/c nu/nu mice by intracranial inoculation of melanoma cells, and bevacizumab treatment was given twice a week in i.p. doses of 10 mg/kg until the mice became moribund. Therapeutic effects were evaluated by determining tumor host survival time, assessing tumor growth and angiogenic activity by quantitative analyses of histological preparations, and measuring the expression of angiogenesis-related genes by quantitative PCR. Results: Meningeal A-07 melanomas showed higher expression of VEGF-A than meningeal D-12 melanomas, whereas the expression of ANGPT2 and IL8, two important angiogenesis drivers in melanoma, was much higher in D-12 than in A-07 tumors. Bevacizumab treatment inhibited tumor angiogenesis and prolonged host survival in mice with A-07 tumors but not in mice with D-12 tumors. Meningeal A-07 tumors in bevacizumab-treated mice compensated for the reduced VEGF-A activity by up-regulating a large number of angiogenesis-related genes, including ANGPT2 and its receptors TIE1 and TIE2. Melanoma cells migrated from meningeal tumors into the cerebrum, where they initiated metastatic growth by vessel co-option. In the A-07 model, the density of cerebral micrometastases was higher in bevacizumab-treated than in untreated mice, either because bevacizumab treatment increased mouse survival or induced increased tumor gene expression. Conclusions: The development of antiangiogenic strategies for the treatment of meningeal melanoma metastases is a challenging task because the outcome of treatment will depend on the angiogenic signature of the tumor tissue, treatment-induced alterations of the angiogenic signature, and the treatment sensitivity of metastatic lesions in other intracranial sites.

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Molecular insights into melanoma brain metastases

Cited by 36 publications

References 117 publications

PLEKHA5 regulates tumor growth in metastatic melanoma

PLEKHA5 regulates tumor growth in metastatic melanoma

The good, the (not so) bad and the ugly of immune homeostasis in melanoma

Bevacizumab treatment of meningeal melanoma metastases

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