RESUMO
Mantle cell lymphoma and other lymphoma subtypes often spread to the bone marrow, and stromal interactions mediated by focal adhesion kinase frequently enhance survival and drug resistance of the lymphoma cells. To study the role of focal adhesion kinase in mantle cell lymphoma, immunohistochemistry of primary cases and functional analysis of mantle cell lymphoma cell lines and primary mantle cell lymphoma cells co-cultured with bone marrow stromal cells (BMSC) using small molecule inhibitors and RNAi-based focal adhesion kinase silencing was performed. We showed that focal adhesion kinase is highly expressed in bone marrow infiltrates of mantle cell lymphoma and in mantle cell lymphoma cell lines. Stroma-mediated activation of focal adhesion kinase led to activation of multiple kinases (AKT, p42/44 and NF-κB), that are important for prosurvival and proliferation signaling. Interestingly, RNAi-based focal adhesion kinase silencing or inhibition with small molecule inhibitors (FAKi) resulted in blockage of targeted cell invasion and induced apoptosis by inactivation of multiple signaling cascades, including the classic and alternative NF-κB pathway. In addition, the combined treatment of ibrutinib and FAKi was highly synergistic, and ibrutinib resistance of mantle cell lymphoma could be overcome. These data demonstrate that focal adhesion kinase is important for stroma-mediated survival and drug resistance in mantle cell lymphoma, providing indications for a targeted therapeutic strategy.
Assuntos
Medula Óssea/metabolismo , Medula Óssea/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Proteína-Tirosina Quinases de Adesão Focal/genética , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Microambiente Tumoral/genética , Adenina/análogos & derivados , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Feminino , Quinase 1 de Adesão Focal/genética , Quinase 1 de Adesão Focal/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Expressão Gênica , Humanos , Imuno-Histoquímica , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/metabolismo , Masculino , NF-kappa B/metabolismo , Piperidinas , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacosRESUMO
Telepathology facilitates histological diagnoses through sharing expertise between pathologists. However, the associated costs are high and frequently prohibitive, especially in low-resource settings, where telepathology would paradoxically be of paramount importance due to a paucity of pathologists.We have constructed a telepathology system (TelePi) with a budget of < 120 using the small, single-board computer Raspberry Pi Zero and its High-Quality Camera Module in conjunction with a standard microscope and open-source software. The system requires no maintenance costs or service contracts, has a small footprint, can be moved and shared across several microscopes, and is independent from other computer operating systems. TelePi uses a responsive and high-resolution web-based live stream which allows remote consultation between two or more locations. TelePi can serve as a telepathology system for remote diagnostics of frozen sections. Additionally, it can be used as a standard microscope camera for teaching of medical students and for basic research. The quality of the TelePi system compared favorable to a commercially available telepathology system that exceed its cost by more than 125-fold. Additionally, still images are of publication quality equal to that of a whole slide scanner that costs 800 times more.In summary, TelePi is an affordable, versatile, and inexpensive camera system that potentially enables telepathology in low-resource settings without sacrificing image quality.