RESUMEN
BACKGROUND: The predominant metastatic site of lung cancer (LC) is the brain. Although outdated, conventional cisplatin treatment is still the main therapeutic approach for patients with advanced non-small cell lung cancer (NSCLC), since targeted therapy that offers better tumor control is not always possible. In the present study brain metastasis associated cytokine expression was investigated in primary NSCLC adenocarcinoma (AC) tissues with known oncogenic mutations in the presence or absence of platina based and tyrosine kinase inhibitor (TKI) drugs. METHODS: Primary lung tumor samples were isolated, DNA was sequenced and then the samples were grouped based on mutation. Experiments were also performed using KRAS mutant A549 and EGFR mutant PC-9 cells. Drug response was analyzed in three dimensional (3D) tissue cultures. We assessed drug response and IL-6 and IL-8 cytokine expression in relation to cellular invasion using ATP dependent cell viability, qRT-PCR analysis, cytokine bead array, and migration assay. RESULTS: In 3D co-cultures, primary NSCLC derived cells harboring EGFR mutation responded better to erlotinib treatment than KRAS mutant or KRAS/EGFR wild type (WT) cancer cells. In contrast, under the same culture conditions KRAS/EGFR WT or KRAS mutant cancer cells are more sensitive to cisplatin than EGFR mutant cells. Drug response and pro-inflammatory cytokine production varied depending on the driver mutations. Cisplatin but not erlotinib increased both IL-6 and IL-8 secretion and only IL-6 increased cellular migration and proliferation. CONCLUSION: In vitro assays are available to determine the response to planned therapeutic approach of lung cancer subtypes. The sequence of administration of therapeutic drugs determines cytokine production and therefore therapeutic response.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Cisplatino/uso terapéutico , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Neoplasias Pulmonares/metabolismo , Mutación/fisiología , Células A549 , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Cisplatino/farmacología , Humanos , Interleucina-6/genética , Interleucina-8/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación/efectos de los fármacosRESUMEN
The majority of lung cancers (LC) belong to the non-small cell lung carcinoma (NSCLC) type. The two main NSCLC sub-types, namely adenocarcinoma (AC) and squamous cell carcinoma (SCC), respond differently to therapy. Whereas the link between cigarette smoke and lung cancer risk is well established, the relevance of non-canonical Wnt pathway up-regulation detected in SCC remains poorly understood. The present study was undertaken to investigate further the molecular events in canonical and non-canonical Wnt signalling during SCC development. A total of 20 SCC and AC samples with matched non-cancerous controls were obtained after surgery. TaqMan array analysis confirmed up-regulation of non-canonical Wnt5a and Wnt11 and identified down-regulation of canonical Wnt signalling in SCC samples. The molecular changes were tested in primary small airway epithelial cells (SAEC) and various lung cancer cell lines (e.g. A549, H157, etc). Our studies identified Wnt11 and Wnt5a as regulators of cadherin expression and potentiated relocation of ß-catenin to the nucleus as an important step in decreased cellular adhesion. The presented data identifies additional details in the regulation of SCC that can aid identification of therapeutic drug targets in the future.
Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Transformación Celular Neoplásica/metabolismo , Neoplasias Pulmonares/metabolismo , Vía de Señalización Wnt , Carcinoma de Células Escamosas/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Transporte de Proteínas , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Proteína Wnt-5a , beta Catenina/metabolismoRESUMEN
McCune-Albright syndrome is characterized by polyostotic fibrous dysplasia, cafe au lait pigmentation of the skin, and multiple endocrinopathies. The authors report a history of a 30-years-old man who had a pathologic humerus fracture at the age of 14 years. The diagnosis of polyostotic fibrous dysplasia was established by radiologic examinations and bone biopsy. Fourteen years thereafter, active acromegaly due to a pituitary microadenoma was diagnosed using hormone measurements and pituitary magnetic resonance imaging. Pituitary surgery was refused because of an extensive skull involvement caused by the fibrous dysplasia. After an unsuccessful therapy with bromocriptine lasting three months, long-acting octreotide (Sandostatin LAR, Novartis) treatment was started. After a 12-months course of treatment, serum growth hormone levels markedly decreased, clinical symptoms improved, but serum insulin-like growth factor I levels remained unchanged. These observations that serum insulin-like growth factor I levels failed to reflect the decrease of serum growth hormone concentrations after long-acting octreotide treatment suggest that the increased production of insulin-like growth factor I in patients with acromegaly due to McCune-Albright syndrome may involve mechanism(s) other than increased growth hormone levels.