ABSTRACT
Melanoma cells express the platelet-activating factor receptor (PAFR) and, thus, respond to PAF, a bioactive lipid produced by both tumour cells and those in the tumour microenvironment such as macrophages. Here, we show that treatment of a human melanoma SKmel37 cell line with cisplatin led to increased expression of PAFR and its accumulation. In the presence of exogenous PAF, melanoma cells were significantly more resistant to cisplatin-induced cell death. Inhibition of PAFR-dependent signalling pathways by a PAFR antagonist (WEB2086) showed chemosensitisation of melanoma cells in vitro. Nude mice were inoculated with SKmel37 cells and treated with cisplatin and WEB2086. Animals treated with both agents showed significantly decreased tumour growth compared to the control group and groups treated with only one agent. PAFR accumulation and signalling are part of a prosurvival program of melanoma cells, therefore constituting a promising target for combination therapy for melanomas.
Subject(s)
Antineoplastic Agents/pharmacology , Azepines/pharmacology , Gene Expression Regulation, Neoplastic , Melanoma/metabolism , Platelet Membrane Glycoproteins/biosynthesis , Receptors, G-Protein-Coupled/biosynthesis , Triazoles/pharmacology , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Azepines/administration & dosage , Cell Line, Tumor , Cell Survival , Cisplatin/administration & dosage , Cisplatin/pharmacology , Female , Humans , Macrophages/metabolism , Mice , Mice, Nude , Neoplasm Transplantation , Signal Transduction , Triazoles/administration & dosageABSTRACT
Antes tido como um conjunto de células alteradas em proliferação, hoje o cânceré mais bem entendido como um microambiente, em que as interações entre os elementos celulares e moleculares que o compõem são determinantes na progressão tumoral. Como resultado, a compreensão do evento neoplásico ganha complexidade crescente. A dinâmica das células tumorais passa a ser avaliada como parte de um verdadeiro tecido tumoral, sujeita a condições de vascularização, de oxigenação, de pressão intersticial e de necrose tecidual, que influenciam na cinética tumoral. Estão sendo identificados novos componentes deste nicho tumoral e as suas respectivas atuações. Entre esses integrantes, encontram-se os elementos da imunidade, cuja modulação tem sido demonstrada por uma série de pesquisas aqui revisadas, tanto no sentido da vigilância imunológica, como pressão seletiva negativa, quanto nofavorecimento da progressão tumoral. Esta revisão analisará a neoplasia do ponto de vista de um microambiente tumoral, focando na participação imunológica e na cinética tumoral, expondo as principais idéias e descobertas que criaram e estão aperfeiçoando o conceito de câncer.
Formerly referred to as a group of altered cells in proliferation, today cancer is better understood as a microenvironment, in which the interactions between the cellular andmolecular elements are determinative in tumor progression. As a result, the comprehension of a neoplasic event gains increasing complexity. The dynamics of the tumor cells are nowanalyzed as part of a true tumoral tissue, subject to conditions of vascularization, oxygenation, interstitial pressure and tissue necrosis, which influence tumor kinetics. New components of this tumoral niche and their respective actions are being identified. Among these constituentsare the elements of the immune system which, as a series of experiments have shown, are involved in the aspect of immunosurveillance, as negative selective pressure, as well as inmechanisms of tumor progression. This review will analyze neoplasia as a tumor microenvironment, focusing on immunological participation and on tumor kinetics, and exposing the mainideas and discoveries that created and are improving the concept of cancer.
