Transforming Growth Factor-β2 Is a Molecular Determinant for Site-Specific Melanoma Metastasis in the Brain

Zhang, Chenyu; Zhang, Fahao; Tsan, Rachel; Fidler, Isaiah J.

doi:10.1158/0008-5472.can-08-2588

Cited by 79 publications

(60 citation statements)

References 31 publications

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“…These parameters are known to affect neurogenesis and impact melanoma brain metastasis. 7,35,67 Our results demonstrate that in addition to these locationspecific diversities, the invasion of brain tissue by individual cancer cells induces a variety of glial responses that add to the uniqueness of each local microenvironment. Distinct glial responses may help explain why cancer cells that arrested in the microvasculature can have different fates, even if they are located within the same brain area.…”

Section: Discussionmentioning

confidence: 72%

“…[3][4][5] The brain provides a unique environment with paracrine growth factors that differ from most other organs. 6,7 The involvement of brain-resident cells including brain endothelial cells, microglia, and astrocytes in the pathology of primary and metastatic brain tumors is only partially understood. Brain endothelial cells are the first host cell type that circulating cancer cells encounter when they arrest within the brain microvasculature.…”

mentioning

confidence: 99%

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Capturing Changes in the Brain Microenvironment during Initial Steps of Breast Cancer Brain Metastasis

Lorger

Felding-Habermann

2010

The American Journal of Pathology

284

302

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Brain metastases are diagnosed in 10 to 40% of all cancer patients, and the incidence is rising as patients live longer due to improved treatments for extracranial metastases.1,2 Brain lesions are most frequently associated with lung cancer, breast cancer, and melanoma. 1,2 Unfortunately, brain metastases are still very difficult to treat and the mechanisms underlying their establishment and progression are poorly understood. Thus, information in this direction and models for analysis are a prerequisite for the development of new, efficient therapies.The essential role of the tumor microenvironment in cancer progression has been well documented for extracranial malignancies, and recent findings indicate that the tumor microenvironment might be a suitable target in anticancer therapies, as well as a valuable biomarker for prognostic purposes.3-5 The brain provides a unique environment with paracrine growth factors that differ from most other organs. 6,7 The involvement of brain-resident cells including brain endothelial cells, microglia, and astrocytes in the pathology of primary and metastatic brain tumors is only partially understood. Brain endothelial cells are the first host cell type that circulating cancer cells encounter when they arrest within the brain microvasculature. In addition to posing the initial barrier for brain invasion, endothelial cells and their basement membrane seem to play important roles in supporting the growth of brain metastases as well as brain tumor stem cells. 8 -10

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Section: Discussionmentioning

confidence: 72%

mentioning

confidence: 99%

Capturing Changes in the Brain Microenvironment during Initial Steps of Breast Cancer Brain Metastasis

Lorger

Felding-Habermann

2010

The American Journal of Pathology

284

302

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“…Re-expressing phospho-Twist1 notably rescued TGF-β2 expression, demonstrating a link between Twist1 phosphorylation and TGF-β2 expression in vivo. In addition, knockdown of TGF-β2 in melanoma significantly inhibited brain metastasis (39), and a TGF-β2 inhibitor has shown positive responses against malignant tumors in phase I/II clinical trials (40). Nevertheless, it should also be noted that the inhibition of the lung metastases upon knockdown of TGF-β2 is not comparable with knockdown of Twist1, indicating that other yet-unknown downstream targets of Twist1 synergistically contribute to cancer cell invasion.…”

Section: March 2012 Cancer Discovery | 255mentioning

confidence: 99%

Akt/PKB-Mediated Phosphorylation of Twist1 Promotes Tumor Metastasis via Mediating Cross-Talk between PI3K/Akt and TGF-β Signaling Axes

et al. 2012

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MARCH 2012 CANCER DISCOVERY | 249The BATTLE Trial: Personalizing Therapy for Lung Cancer RESEARCH ARTICLE efficiently induces EMT. In a clinically relevant orthotopic breast cancer mouse model, Twist1 expression is essential for the formation of lung metastasis (5). In hepatocelluar carcinomas, overexpression of Twist1 correlates with EMTassociated changes and metastasis (6). Twist1 expression can also negatively regulate programmed cell death (7) and overcome oncogene-induced senescence (4).These studies indicate that Twist1 plays multiple roles in the regulation of antiapoptosis and metastasis during tumor progression. Active Akt directly phosphorylates Twist1 on serine 42 (S42) and protects cells from apoptosis induced by DNA damage (8). Twist1 promotes crucial prometastatic roles in tumor development and is frequently associated with aberrant hyperactivation of phosphoinositide 3-kinase (PI3K)/Akt. This prompted us to explore whether phosphorylation of Twist1 by Akt is part of a molecular mechanism contributing to Twist1 activity in cancer and particularly in metastasis.We analyzed Twist1 phosphorylation in human cancer cell lines (with different genetic backgrounds) and invasive human breast tumors and addressed its functional importance in a mouse model of spontaneous breast tumor metastasis. We show that Twist1 is ubiquitously phosphorylated in invasive human breast tumors and is required for breast cancer lung metastasis in vivo. Twist1 phosphorylation supports metastasis by transcriptionally upregulating TGF-β2, leading to enhanced activation of TGF-βR/Smad2 signaling, and these effects could be significantly suppressed by the knockdown of TGF-β2 expression. These data suggest that Twist1 phosphorylation not only mediates a feedback loop allowing cross-talk with TGF-β to maintain hyperactivation of PI3K/Akt but can also potentiate cancer metastasis, at least in part, through enhanced TGF-β signaling in cancer cells. Collectively, our data uncover a novel mechanism Metastatic breast tumor cells display an epithelial-mesenchymal transition (EMT) that increases cell motility, invasion, and dissemination. Although the transcription factor Twist1 has been shown to contribute to EMT and cancer metastasis, the signaling pathways regulating Twist1 activity are poorly understood. Here, we show that Twist1 is ubiquitously phosphorylated in 90% of 1,532 invasive human breast tumors. Akt/protein kinase B (PKB)-mediated Twist1 phosphorylation promotes EMT and breast cancer metastasis by modulating its transcriptional target TGF-β2, leading to enhanced TGF-β receptor signaling, which in turn maintains hyperactive phosphoinositide 3-kinase (PI3K)/Akt signaling. Preventing phosphorylation of Twist1, as well as depletion of TGF-β2, significantly impaired the metastatic potential of cancer cells in vivo, indicating a key role of phosphorylated Twist1 (phospho-Twist1) in mediating cross-talk between the PI3K/Akt and TGF-β/Smad signaling axes that supports metastatic tumor development. Our results describe a novel signalin...

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“…The fact that HER2+ and claudin-low breast tumour subtypes compared to the other molecular subtypes have a high tendency to establish BM might suggest that BM formation in breast cancer occurs on the basis of the "seed" and "soil" theory (Ramakrishna & Rostomily, 2013). This is in agreement with the findings that brain has a unique microenvironment with paracrine growth factors that can attract brain-seeking tumour cells (Nicolson et al, 1996;C. Zhang, Zhang, Tsan, & Fidler, 2009).…”

Section: Discussionsupporting

confidence: 80%

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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Transforming Growth Factor-β2 Is a Molecular Determinant for Site-Specific Melanoma Metastasis in the Brain

Cited by 79 publications

References 31 publications

Capturing Changes in the Brain Microenvironment during Initial Steps of Breast Cancer Brain Metastasis

Capturing Changes in the Brain Microenvironment during Initial Steps of Breast Cancer Brain Metastasis

Akt/PKB-Mediated Phosphorylation of Twist1 Promotes Tumor Metastasis via Mediating Cross-Talk between PI3K/Akt and TGF-β Signaling Axes

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

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