RESUMO
The failure of therapies targeting tumor angiogenesis may be caused by anti-angiogenic resistance mechanisms induced by VEGF and non-VEGF pathways alterations. Anti-angiogenic therapy failure is also attributed to immune system, acting by tumor-associated macrophages that release pro-angiogenic factors and a consequent increase of blood vessels. Recently, in a study by Rheal et al., a new angiogenic receptor, epidermal growth factor, latrophilin, and 7 trans-membrane domain-containing protein 1 on chromosome 1(ELTD1) has been identified as a promising glioma biomarker. In this study we aim to analyse whether this receptor may be used as a target molecule in glioblastoma therapy. Our results showed that small interfering RNA silencing ELTD1 caused cytotoxicity in glioblastoma cells. We also found that PDGFR, VEGFR, and their common PI3K/mTOR intracellular pathway inactivation-induced cytotoxicity in glioblastoma cells. Further, we found high percent of cytotoxicity in a low passage glioblastoma cell line after BEZ235 (a dual inhibitor of PI3K/mTOR pathway) treatment at nanomolar concentrations, compared to AG1433 (a PDGFR inhibitor) and SU1498 (a VEGFR inhibitor) that were only cytotoxic at micromolar ranges. In the future, these could prove as attractive therapeutic targets in single therapy or coupled with classic therapeutic approaches such as chemotherapy of radiotherapy.
Assuntos
Fator de Crescimento Epidérmico/deficiência , Inativação Gênica , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , RNA Interferente Pequeno/genética , Receptores Acoplados a Proteínas G/deficiência , Receptores de Peptídeos/deficiência , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/deficiência , Biomarcadores Tumorais/genética , Morte Celular/efeitos dos fármacos , Fator de Crescimento Epidérmico/biossíntese , Fator de Crescimento Epidérmico/genética , Inativação Gênica/efeitos dos fármacos , Glioblastoma/genética , Humanos , RNA Interferente Pequeno/farmacologia , Receptores Acoplados a Proteínas G/biossíntese , Receptores Acoplados a Proteínas G/genética , Receptores de Peptídeos/biossíntese , Receptores de Peptídeos/genéticaRESUMO
Almost all tumors are composed of a heterogeneous cell population, making them difficult to treat. A small cancer stem cell population with a low proliferation rate and a high tumorigenic potential is thought to be responsible for cancer development, metastasis and resistance to therapy. Stem cells were reported to be involved in both normal development and carcinogenesis, some molecular mechanisms being common in both processes. No less controversial, stem cells are considered to be important in treatment of malignant diseases both as targets and drug carriers. The efforts to understand the role of different signalling in cancer stem cells requires in depth knowledge about the mechanisms that control their self-renewal, differentiation and malignant potential. The aim of this paper is to discuss insights into cancer stem cells historical background and to provide a brief review of the new therapeutic strategies for targeting cancer stem cells.
Assuntos
Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Humanos , Terapia de Alvo Molecular/métodos , Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
ABSTRACT: The development and function of the nervous system is dependent on many growth factors and their signaling. Tropomyosin-receptor-kinase receptor family controls synaptic strength and plasticity in the mammalian nervous system. Dysregulation of Tropomyosin-receptor-kinase receptors signaling can lead to neural developmental disorders and has been reported in certain diseases of the nervous system. Apart from their role in the nervous system, these tyrosine kinase receptors are also involved in cancer biology. Tropomyosin-receptor-kinases and their ligands, neurotrophins, are also involved in neural precursor stem cells differentiation. This review focuses on Tropomyosin-receptor-kinases, the most abundant receptors in mammalian nervous system.
