RESUMO
Lung carcinoma is still the most common malignancy worldwide. One of the major subtypes of non-small cell lung cancer (NSCLC) is adenocarcinoma (AC). As driver mutations and hence therapies differ in AC subtypes, we theorized that the expression and function of ABC drug transporters important in multidrug resistance (MDR) would correlate with characteristic driver mutations KRAS or EGFR. Cisplatin resistance (CR) was generated in A549 (KRAS) and PC9 (EGFR) cell lines and gene expression was tested. In three-dimensional (3D) multicellular aggregate cultures, both ABCB1 and ABCG2 transporters, as well as the WNT microenvironment, were investigated. ABCB1 and ABCG2 gene expression levels were different in primary AC samples and correlated with specific driver mutations. The drug transporter expression pattern of parental A549 and PC9, as well as A549-CR and PC9-CR, cell lines differed. Increased mRNA levels of ABCB1 and ABCG2 were detected in A549-CR cells, compared to parental A549, while the trend observed in the case of PC9 cells was different. Dominant alterations were observed in LEF1, RHOU and DACT1 genes of the WNT signalling pathway in a mutation-dependent manner. The study confirmed that, in lung AC-s, KRAS and EGFR driver mutations differentially affect both drug transporter expression and the cisplatin-induced WNT signalling microenvironment.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/genética , Mutação/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Células A549 , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular , Linhagem Celular Tumoral , Cisplatino/farmacologia , Receptores ErbB/genética , Feminino , Expressão Gênica/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Microambiente Tumoral/genéticaRESUMO
In spite of intensive research, the survival rates of patients diagnosed with tumors of the central nervous system (CNS) have not improved significantly in the last decade. Immunotherapy as novel and efficacious treatment option in several other malignancies has failed in neuro-oncology likely due to the immunosuppressive property of the brain tissues. Glioblastoma (GBM) is the most aggressive malignant CNS neoplasm, while meningioma (MNG) is a mainly low grade or benign brain tumor originating from the non-glial tissues of the CNS. The aim of the current preliminary study is to compare the immune microenvironment of MNG and GBM as potential target in immunotherapy. Interestingly, the immune microenvironment of MNG and GBM have proved to be similar. In both tumors types the immune suppressive elements including regulatory T cells (Treg), tumor-associated macrophages (TAM) were highly elevated. The cytokine environment supporting Treg differentiation and the presence of indoleamine 2,3-dioxygenase 1 (IDO1) have also increased the immunosuppressive microenvironment. The results of the present study show an immune suppressive microenvironment in both brain tumor types. In a follow-up study with a larger patient cohort can provide detailed background information on the immune status of individual patients and aid selection of the best immune checkpoint inhibitor or other immune modulatory therapy. Immune modulatory treatments in combination with IDO1 inhibitors might even become alternative therapy for relapsed, multiple and/or malignant MNG or chemo-resistant GBM.
