Margit A. Huber

NF-κB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression

The transcription factor NF-κB is activated in a range of human cancers and is thought to promote tumorigenesis, mainly due to its ability to protect transformed cells from apoptosis. To investigate the role of NF-κB in epithelial plasticity and metastasis, we utilized a well-characterized in vitro/in vivo model of mammary carcinogenesis that depends on the collaboration of the Ha-Ras oncoprotein and TGF-β. We show here that the IKK-2/IκBα/NF-κB pathway is required for the induction and maintenance of epithelial-mesenchymal transition (EMT). Inhibition of NF-κB signaling prevented EMT in Ras-transformed epithelial cells, while activation of this pathway promoted the transition to a mesenchymal phenotype even in the absence of TGF-β. Furthermore, inhibition of NF-κB activity in mesenchymal cells caused a reversal of EMT, suggesting that NF-κB is essential for both the induction and maintenance of EMT. In line with the importance of EMT for invasion, blocking of NF-κB activity abrogated the metastatic potential of mammary epithelial cells in a mouse model system. Collectively, these data provide evidence of an essential role for NF-κB during distinct steps of breast cancer progression and suggest that the cooperation of Ras- and TGF-β–dependent signaling pathways in late-stage tumorigenesis depends critically on NF-κB activity.

NF-κB promotes epithelial–mesenchymal transition, migration and invasion of pancreatic carcinoma cells

The transcription factor NF-kappaB is constitutively active in pancreatic adenocarcinoma. Here we explore the contribution of NF-kappaB to the malignant phenotype of pancreatic cancer cells in addition to its anti-apoptotic role. Block of NF-kappaB signalling by non-destructible IkappaBalpha rendered cells resistant to TGF-beta-induced epithelial-mesenchymal transition (EMT). In contrast, NF-kappaB activation by TNF-alpha or expression of constitutively active IKK2 induced an EMT-phenotype with up-regulation of vimentin and ZEB1, and down-regulation of E-cadherin. EMT could also be induced in cells with defective TGF-beta signalling. Functional assays demonstrated reduced or strongly enhanced migration and invasion upon NF-kappaB inhibition or activation, respectively.

Epithelial-Mesenchymal Transition: NF-κB Takes Center Stage

Activation of the transcription factor NF-?B occurs in many human tumors, and studies have shown that NF-κB can promote cell proliferation and oncogenesis, possibly by protecting cells from apoptosis. Little is known, however, about whether NF-κB is involved in tumor progression including epithelial-mesenchymal transition (EMT), a central process governing both morphogenesis and carcinoma progression in multicellular organisms. In a combined in vitro/in vivo model of mammary carcinogenesis, NF-κB was essential both for the induction and maintenance of EMT and for in vivo metastasis. NF-κB and the signaling pathways that are involved in its activation should therefore receive attention as potential targets for the development of novel anti-metastatic cancer treatments.

Expression of stromal cell markers in distinct compartments of human skin cancers

Background:  The importance of changes in the supporting tumor stroma for cancer initiation and progression is well established. The characteristics of an activated tumor stroma, however, are not completely understood. In an effort to better characterize the desmoplastic response to human skin tumors, we evaluated the expression pattern of three stromal cell markers, fibroblast‐activation protein (FAP), endoglyx‐1, and endosialin, in a series of melanocytic and epithelial skin tumors.

Management of Refractory Early-Stage Cutaneous T-Cell Lymphoma

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of non-Hodgkin’s lymphomas that manifest primarily in the skin. Mycosis fungoides is recognized as the most common type of CTCL. Patients with early-stage CTCL usually have a benign and chronic disease course. However, although there is a wide array of therapeutic options for early-stage CTCL, not all patients respond to these individual therapies, resulting in refractory cutaneous disease over time. Refractory early-stage CTCL poses an important therapeutic challenge, as one of the principal treatment goals is to keep the disease confined to the skin, thereby preventing disease progression.Much of the focus of current research has been on the evaluation of already available skin-directed therapies and biologic response modifiers and combination regimens thereof, such as the combination of psoralen and UVA (PUVA) with interferon-α or retinoids. Recent novel developments include oral bexarotene, a retinoid X receptor-selective retinoid that has activity in all stages of CTCL and has been shown to be effective in patients with refractory early-stage disease as well as advanced-stage disease. Likewise, the topical gel formulation of bexarotene has proved to be an important therapeutic option in patients with refractory or relapsed lesions. Oral bexarotene and topical bexarotene have been approved by the US FDA for the treatment of refractory CTCL. Systemic chemotherapy is typically reserved for advanced-stage CTCL and is usually not recommended for early-stage, skin-limited disease. However, recent exploratory studies indicate that low-dose methotrexate may represent an overall well tolerated therapy in a subset of patients with refractory early-stage CTCL, as may pegylated liposomal doxorubicin, which is currently being investigated in this specific clinical setting. Another recently FDA-approved therapy is the interleukin-2 fusion toxin denileukin diftitox, which is now well established to play a role in the treatment of refractory CTCL, including early-stage extensive plaque disease. The value of other agents, such as topical tazarotene, topical methotrexate, and topical imiquimod, and of novel immunomodulatory approaches including monoclonal antibodies, still needs to be assessed for refractory early-stage CTCL.

BI 5700, a Selective Chemical Inhibitor of IκB Kinase 2, Specifically Suppresses Epithelial-Mesenchymal Transition and Metastasis in Mouse Models of Tumor Progression

Increasing evidence suggests that processes termed epithelial-mesenchymal transitions (EMTs) play a key role in therapeutic resistance, tumor recurrence, and metastatic progression. NF-κB signaling has been previously identified as an important pathway in the regulation of EMT in a mouse model of tumor progression. However, it remains unclear whether there is a broad requirement for this pathway to govern EMT and what the relative contribution of IKK family members acting as upstream NF-κB activators is toward promoting EMT and metastasis. To address this question, we have used a novel, small-molecule inhibitor of IκB kinase 2 (IKK2/IKKβ), termed BI 5700. We investigated the role of IKK2 in a number of mouse models of EMT, including TGFβ-induced EMT in the mammary epithelial cell line EpRas, CT26 colon carcinoma cells, and 4T1 mammary carcinoma cells. The latter model was also used to evaluate in vivo activities of BI 5700.We found that BI 5700 inhibits IKK2 with an IC(50) of 9 nM and was highly selective as compared to other IKK family members (IKK1, IKKε, and TBK1) and other kinases. BI 5700 effectively blocks NF-κB activity in EpRas cells and prevents TGFβ-induced EMT. In addition, BI 5700 reverts EMT in mesenchymal CT26 cells and prevents EMT in the 4T1 model. Oral application of BI 5700 significantly interferes with metastasis after mammary fat-pad injection of 4T1 cells, yielding fewer, smaller, and more differentiated metastases as compared to vehicle-treated control animals. We conclude that IKK2 is a key regulator of both the induction and maintenance of EMT in a panel of mouse tumor progression models and that the IKK2 inhibitor BI 5700 constitutes a promising candidate for the treatment of metastatic cancers.

Intermittent vemurafenib therapy in malignant melanoma: Correspondence

Herein, we report on three female patients with inoperable stage IIIC and IV, BRAF V600E-mutant melanoma treated with intermittent dosing of the BRAF inhibitor vemurafenib. Common to all three patients, enrollment in a study was neither feasible nor requested, and – due to drug toxicity – continuous treatment (even following dose reduction in order to manage side effects) was not tolerated, either. On intermittent therapy, consisting of four weeks of the maximum tolerable vemurafenib dose followed by a two-week treatment-free interval, all three patients showed stable disease for at least 24 months.

Key drivers of biomedical innovation in cancer drug discovery

Discovery and translational research has led to the identification of a series of “cancer drivers”—genes that, when mutated or otherwise misregulated, can drive malignancy. An increasing number of drugs that directly target such drivers have demonstrated activity in clinical trials and are shaping a new landscape for molecularly targeted cancer therapies. Such therapies rely on molecular and genetic diagnostic tests to detect the presence of a biomarker that predicts response. Here, we highlight some of the key discoveries bringing precision oncology to cancer patients. Large‐scale “omics” approaches as well as modern, hypothesis‐driven science in both academic and industry settings have significantly contributed to the field. Based on these insights, we discuss current challenges and how to foster future biomedical innovation in cancer drug discovery and development.

Intervalltherapie mit Vemurafenib beim malignen Melanom: Correspondence

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Letter to the Editor The BRAF V600E Mutation is Not Present in All Cells of the Primary Melanoma and May Not Be Detected in All Metastatic Sites

The invention of targeted therapy for advanced stage melanoma has made it necessary to perform a mutation analysis of each melanoma case in order to detect the BRAF V600E mutation required for the prescription of selective BRAF inhibitors. In this new clinical context it is important to realize that the tumour seeds may come from different tumour clones and thus not all carry the mutation. We present an illustrative case that shows this phenomenon and discuss the consequences for clinical management in case of possible false negative mutation testing.