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1.
Ther Umsch ; 76(4): 187-194, 2019 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-31498037

RESUMO

Immunotherapies - Overview, mode of action and clinical implications Abstract. The introduction of immunotherapies has led to major advances in the treatment of cancer patients. The mainstays of immunotherapies in clinical routine are immune checkpoint inhibitors. Immune checkpoints like CTLA-4 or the PD-1 / PD-L1 axis are important contributors to the immune homeostasis by preventing overshooting immune responses against pathogens and thus preventing collateral damage to normal tissue, or by preventing autoimmunity. However, immune checkpoints can impede the development of an efficient anti-tumor immune response. Thus, therapeutic monoclonal antibodies against CTLA-4 and PD-1 or PD-L1 displayed remarkable clinical activity such as complete sustained clinical remission even in patients bearing multiple metastases. Malignant melanoma, non-small cell lung cancer or Hodgkin's lymphoma are examples of cancer entities with especially well clinical responses to immune checkpoint inhibitors. This fast-developing field is rapidly expanding the indications for immune checkpoint inhibitors and combinations with other therapeutic strategies like vessel-modulating agents or classical chemotherapy are in preclinical and clinical testing. In this article, the mechanistic principles of immune checkpoint inhibition and their clinical applications are illustrated.


Assuntos
Imunoterapia , Neoplasias/terapia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno CTLA-4/antagonistas & inibidores , Humanos , Imunoterapia/métodos
2.
Artigo em Inglês | MEDLINE | ID: mdl-30209717

RESUMO

Genetically engineered mouse models have become an indispensable tool for breast cancer research. Combination of multiple site-specific recombination systems such as Cre/loxP and Flippase (Flp)/Frt allows for engineering of sophisticated, multi-layered conditional mouse models. Here, we report the generation and characterization of a novel transgenic mouse line expressing a mouse codon-optimized Flp under the control of the mouse mammary tumor virus (MMTV) promoter. These mice show robust Flp-mediated recombination in luminal mammary gland and breast cancer cells but no Flp activity in non-mammary tissues, with the exception of limited activity in salivary glands. These mice provide a unique tool for studying mammary gland biology and carcinogenesis in mice.

3.
Oncogenesis ; 7(9): 73, 2018 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-30237500

RESUMO

Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that regulates a plethora of downstream signaling pathways essential for cell migration, proliferation and death, processes that are exploited by cancer cells during malignant progression. These well-established tumorigenic activities, together with its high expression and activity in different cancer types, highlight FAK as an attractive target for cancer therapy. We have assessed and characterized the therapeutic potential and the biological effects of BI 853520, a novel small chemical inhibitor of FAK, in several preclinical mouse models of breast cancer. Treatment with BI 853520 elicits a significant reduction in primary tumor growth caused by an anti-proliferative activity by BI 853520. In contrast, BI 853520 exerts effects with varying degrees of robustness on the different stages of the metastatic cascade. Together, the data demonstrate that the repression of FAK activity by the specific FAK inhibitor BI 853520 offers a promising anti-proliferative approach for cancer therapy.

5.
Mol Cancer Ther ; 16(11): 2502-2515, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28729403

RESUMO

Increasing the efficacy of approved systemic treatments in metastasized pancreatic neuroendocrine tumors (PanNET) is an unmet medical need. The antiangiogenic tyrosine kinase inhibitor sunitinib is approved for PanNET treatment. In addition, sunitinib is a lysosomotropic drug and such drugs can induce lysosomal membrane permeabilization as well as autophagy. We investigated sunitinib-induced autophagy as a possible mechanism of PanNET therapy resistance. Sunitinib accumulated in lysosomes and induced autophagy in PanNET cell lines. Adding the autophagy inhibitor chloroquine reduced cell viability in cell lines and in primary cells isolated from PanNET patients. The same treatment combination reduced tumor burden in the Rip1Tag2 transgenic PanNET mouse model. The combination of sunitinib and chloroquine reduced recovery and induced apoptosis in vitro, whereas single treatments did not. Knockdown of key autophagy proteins in combination with sunitinib showed similar effect as chloroquine. Sunitinib also induced lysosomal membrane permeabilization, which further increased in the presence of chloroquine or knockdown of lysosome-associated membrane protein (LAMP2). Both combinations led to cell death. Our data indicate that chloroquine increases sunitinib efficacy in PanNET treatment via autophagy inhibition and lysosomal membrane permeabilization. We suggest that adding chloroquine to sunitinib treatment will increase efficacy of PanNET treatment and that such patients should be included in respective ongoing clinical trials. Mol Cancer Ther; 16(11); 2502-15. ©2017 AACR.


Assuntos
Indóis/administração & dosagem , Proteína 2 de Membrana Associada ao Lisossomo/genética , Neovascularização Patológica/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Pirróis/administração & dosagem , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/química , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Técnicas de Silenciamento de Genes , Humanos , Indóis/química , Lisossomos/química , Camundongos , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Pirróis/química , Sunitinibe
6.
Methods Mol Biol ; 1464: 151-161, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27858364

RESUMO

The Rip1Tag2 transgenic mouse model of ß-cell carcinogenesis has been instrumental in studying various aspects of tumor angiogenesis and in investigating the response to anti-angiogenic therapeutics. Thereby, the in-depth assessment of blood and lymphatic vessel phenotypes and functionality represents key experimental analyses. In this chapter, we describe basic protocols to assess tumor blood vessel morphology (pericyte coverage), functionality (perfusion, leakiness, and hypoxia), lymphatic tumor coverage, and tumor cell proliferation and apoptosis based on immunofluorescence microscopy analysis.


Assuntos
Carcinoma Neuroendócrino/genética , Insulinoma/genética , Neovascularização Patológica/patologia , Neoplasias Pancreáticas/genética , Animais , Antígenos Virais de Tumores/genética , Apoptose , Carcinoma Neuroendócrino/irrigação sanguínea , Carcinoma Neuroendócrino/patologia , Proliferação de Células , Insulina/genética , Insulinoma/irrigação sanguínea , Insulinoma/patologia , Camundongos , Camundongos Transgênicos , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/genética , Neovascularização Patológica/genética , Neoplasias Pancreáticas/irrigação sanguínea , Neoplasias Pancreáticas/patologia , Regiões Promotoras Genéticas
7.
Cell Rep ; 15(6): 1161-74, 2016 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-27134168

RESUMO

Despite the approval of several anti-angiogenic therapies, clinical results remain unsatisfactory, and transient benefits are followed by rapid tumor recurrence. Here, we demonstrate potent anti-angiogenic efficacy of the multi-kinase inhibitors nintedanib and sunitinib in a mouse model of breast cancer. However, after an initial regression, tumors resume growth in the absence of active tumor angiogenesis. Gene expression profiling of tumor cells reveals metabolic reprogramming toward anaerobic glycolysis. Indeed, combinatorial treatment with a glycolysis inhibitor (3PO) efficiently inhibits tumor growth. Moreover, tumors establish metabolic symbiosis, illustrated by the differential expression of MCT1 and MCT4, monocarboxylate transporters active in lactate exchange in glycolytic tumors. Accordingly, genetic ablation of MCT4 expression overcomes adaptive resistance against anti-angiogenic therapy. Hence, targeting metabolic symbiosis may be an attractive avenue to avoid resistance development to anti-angiogenic therapy in patients.


Assuntos
Inibidores da Angiogênese/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Mamárias Animais/metabolismo , Neovascularização Patológica/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Animais , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Glicólise/efeitos dos fármacos , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Neoplasias Mamárias Animais/irrigação sanguínea , Neoplasias Mamárias Animais/tratamento farmacológico , Neoplasias Mamárias Animais/patologia , Camundongos , Modelos Biológicos , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/metabolismo , Neovascularização Patológica/patologia
8.
Angiogenesis ; 19(3): 339-58, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27038485

RESUMO

UNLABELLED: Viral VEGF-E (ovVEGF-E), a homolog of VEGF-A, was discovered in the genome of Orf virus. Together with VEGF-A, B, C, D, placental growth factor (PlGF) and snake venom VEGF (svVEGF), ovVEGF-E is a member of the VEGF family of potent angiogenesis factors with a bioactivity similar to VEGF-A: it induces proliferation, migration and sprouting of cultured vascular endothelial cells and proliferative lesions in the skin of sheep, goat and man that are characterized by massive capillary proliferation and dilation. These biological functions are mediated exclusively via its interaction with VEGF receptor-2 (VEGFR-2). Here, we have generated transgenic mice specifically expressing ovVEGF-E in ß-cells of the endocrine pancreas (Rip1VEGF-E; RVE). RVE mice show an increase in number and size of the islets of Langerhans and a distorted organization of insulin and glucagon-expressing cells. Islet endothelial cells of RVE mice hyper-proliferate and form increased numbers of functional blood vessels. In addition, the formation of disorganized lymphatic vessels and increased immune cell infiltration is observed. Upon crossing RVE single-transgenic mice with Rip1Tag2 (RT2) transgenic mice, a well-studied model of pancreatic ß-cell carcinogenesis, double-transgenic mice (RT2;RVE) display hyper-proliferation of endothelial cells resulting in the formation of hemangioma-like lesions. In addition, RT2;RVE mice exhibit activated lymphangiogenesis at the tumor periphery and increased neutrophil and macrophage tumor infiltration and micro-metastasis to lymph nodes and lungs. These phenotypes markedly differ from the phenotypes observed with the transgenic expression of the other VEGF family members in ß-cells of normal mice and of RT2 mice.


Assuntos
Hemangioma/etiologia , Neoplasias Pancreáticas/etiologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteínas Virais/metabolismo , Animais , Proliferação de Células , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Cabras , Hemangioma/metabolismo , Hemangioma/patologia , Humanos , Células Secretoras de Insulina/metabolismo , Linfangiogênese/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Ovinos , Transdução de Sinais , Proteínas Virais/genética
9.
Oncotarget ; 7(18): 25983-6002, 2016 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-27036020

RESUMO

An epithelial to mesenchymal transition (EMT) enables epithelial tumor cells to break out of the primary tumor mass and to metastasize. Understanding the molecular mechanisms driving EMT in more detail will provide important tools to interfere with the metastatic process. To identify pharmacological modulators and druggable targets of EMT, we have established a novel multi-parameter, high-content, microscopy-based assay and screened chemical compounds with activities against known targets. Out of 3423 compounds, we have identified 19 drugs that block transforming growth factor beta (TGFß)-induced EMT in normal murine mammary gland epithelial cells (NMuMG). The active compounds include inhibitors against TGFß receptors (TGFBR), Rho-associated protein kinases (ROCK), myosin II, SRC kinase and uridine analogues. Among the EMT-repressing compounds, we identified a group of inhibitors targeting multiple receptor tyrosine kinases, and biochemical profiling of these multi-kinase inhibitors reveals TGFBR as a thus far unknown target of their inhibitory spectrum. These findings demonstrate the feasibility of a multi-parameter, high-content microscopy screen to identify modulators and druggable targets of EMT. Moreover, the newly discovered "off-target" effects of several receptor tyrosine kinase inhibitors have important consequences for in vitro and in vivo studies and might beneficially contribute to the therapeutic effects observed in vivo.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Ensaios de Triagem em Larga Escala/métodos , Neoplasias Mamárias Animais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Proliferação de Células/efeitos dos fármacos , Feminino , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/patologia , Camundongos , Receptores Proteína Tirosina Quinases , Receptor do Fator de Crescimento Transformador beta Tipo II , Fator de Crescimento Transformador beta/metabolismo , Células Tumorais Cultivadas
10.
Clin Cancer Res ; 21(21): 4856-67, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26206868

RESUMO

PURPOSE: Pancreatic neuroendocrine tumors (PNET) represent a rare but challenging heterogeneous group of cancers with an increasing incidence over the last number of decades. Herein, we report an in-depth evaluation of the new antiangiogenic small-molecule tyrosine kinase inhibitor (TKI) nintedanib in the preclinical Rip1Tag2 transgenic mouse model of neuroendocrine carcinoma of the pancreas (insulinoma). EXPERIMENTAL DESIGN: We have assessed the antiangiogenic and antitumor activity of nintedanib, in comparison with other antiangiogenic TKI, by treating Rip1Tag2 transgenic mice with different treatment schedules complemented with histopathologic, cell biologic, and biochemical analyses. RESULTS: Prolonged nintedanib treatment of Rip1Tag2 mice has led to a strong suppression of angiogenesis, accompanied by a reduced tumor burden, which translated into a significant prolongation of survival. Despite nintedanib's inhibitory action on perivascular cells, the blood vessels remaining after therapy displayed a considerably mature phenotype with tight perivascular cell coverage and preserved perfusion. Nintedanib treatment did not increase local tumor invasiveness or metastasis to the liver and pancreatic lymph nodes--a phenomenon that has been observed with antiangiogenic treatments of Rip1Tag2 transgenic mice in other laboratories. In contrast with the strong reduction in blood microvessel densities, nintedanib did not have any impact on tumor lymphangiogenesis. CONCLUSIONS: Based on our findings, we propose the clinical evaluation of the antiangiogenic drug nintedanib as a new treatment modality for PNET patients, notably in a direct comparison with already established therapeutic regimens, such as sunitinib.


Assuntos
Antígenos Transformantes de Poliomavirus/genética , Antineoplásicos/farmacologia , Carcinoma Neuroendócrino/genética , Indóis/farmacologia , Insulina/genética , Neoplasias Pancreáticas/genética , Regiões Promotoras Genéticas , Animais , Apoptose/efeitos dos fármacos , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/patologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Camundongos , Camundongos Transgênicos , Metástase Neoplásica , Estadiamento de Neoplasias , Neovascularização Patológica/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Carga Tumoral , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo
11.
Angiogenesis ; 18(3): 327-45, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26021306

RESUMO

Tumor growth depends on the formation of new blood vessels (tumor angiogenesis) either from preexisting vessels or by the recruitment of bone marrow-derived cells. Despite encouraging results obtained with preclinical cancer models, the therapeutic targeting of tumor angiogenesis has thus far failed to deliver an enduring clinical response in cancer patients. One major obstacle for improving anti-angiogenic therapy is the lack of validated biomarkers, which allow patient stratification for suitable treatment and a rapid assessment of therapy response. Toward these goals, we have employed several mouse models of tumor angiogenesis to identify cell populations circulating in their blood that correlated with the extent of tumor angiogenesis and therapy response. Flow cytometry analyses of different combinations of cell surface markers that define subsets of bone marrow-derived cells were performed on peripheral blood mononuclear cells from tumor-bearing and healthy mice. We identified one cell population, CD45(dim)VEGFR1(-)CD31(low), that was increased in levels during active tumor angiogenesis in a variety of transgenic and syngeneic transplantation mouse models of cancer. Treatment with various anti-angiogenic drugs did not affect CD45(dim)VEGFR1(-)CD31(low) cells in healthy mice, whereas in tumor-bearing mice, a consistent reduction in their levels was observed. Gene expression profiling of CD45(dim)VEGFR1(-)CD31(low) cells characterized these cells as an immature B cell population. These immature B cells were then directly validated as surrogate marker for tumor angiogenesis and of pharmacologic responses to anti-angiogenic therapies in various mouse models of cancer.


Assuntos
Linfócitos B/imunologia , Biomarcadores/metabolismo , Neoplasias/patologia , Neovascularização Patológica , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Membrana Celular/metabolismo , Técnicas de Cocultura , Biologia Computacional , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , Antígenos Comuns de Leucócito/metabolismo , Leucócitos Mononucleares/citologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
12.
FEBS Lett ; 589(14): 1577-87, 2015 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-25979173

RESUMO

Although major progress has been achieved in treating breast cancer patients, metastatic breast cancer still remains a deadly disease. A full understanding of the process of systemic cancer cell dissemination is therefore critical to develop next generation therapies. A plethora of experimental data points toward a central role of an epithelial to mesenchymal transition (EMT) in the multistep cascade of metastasis formation. However, in patients the data are based on correlative studies which often, but not always, tie the expression of EMT markers to cancer invasion, metastasis and poor clinical outcome. Moreover, the notion that cancer cells are able to switch between different modes of migration asks for a thorough review of the actual relevance of EMT in cancer metastasis.


Assuntos
Neoplasias da Mama/patologia , Transição Epitelial-Mesenquimal , Metástase Neoplásica , Animais , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Invasividade Neoplásica
13.
J Neuroimmunol ; 232(1-2): 207-8, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21051092

RESUMO

The adhesion molecule P-selectin glycoprotein ligand (PSGL)-1 has been suggested to be involved in the immunopathogenesis of multiple sclerosis (MS). However, in C57BL/6 mice PSGL-1 was found to be dispensible for the development of MOG(aa35-55)-induced experimental autoimmune encephalomyelitis (EAE), an animal model for MS. To study, if involvement of PSGL-1 to EAE pathogenesis can be observed in another common mouse model, we backcrossed PSGL-1(-/-) mice for at least 12 generations into the SJL/J background and compared PLP(aa139-151) induced EAE in PSGL-1(-/-) SJL/J mice versus wild-type SJL/J mice. Here, we demonstrate that PSGL-1(-/-) SJL/J mice exhibited EAE pathogenesis indistinguishable from wild-type SJL/J mice. Our present study underscores and emphasizes previous observations that PSGL-1 is dispensible for EAE pathogenesis.


Assuntos
Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Animais , Camundongos , Camundongos Knockout
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