RESUMEN
Increasing evidence indicates that the inflammatory tumor microenvironment can lead to cancer cell metastasis. Shikonin, which is extracted from the Chinese herb Zicao (the dried root of Lithospermum erythrorhizon), possesses various pharmacological effects, but its effect on tumor metastasis in the inflammatory microenvironment remains unknown. In the present study, we aimed to investigate the potential effect of shikonin on tumor metastasis in an inflammatory microenvironment as well as the underlying molecular mechanisms. It was found that, in the inflammatory microenvironment simulated by THP1 cell conditioned medium (THP1CM) in vitro, shikonin significantly inhibited the epithelialmesenchymal transition (EMT), migration and invasion of human lung adenocarcinoma cell lines A549 and H1299. In addition, we found that interleukin6 (IL6), which is expressed in THP1CM, promoted the EMT of lung adenocarcinoma cells, and shikonin markedly inhibited IL6induced EMT and cell motility. Moreover, shikonin inhibited IL6induced phosphorylation of signal transducer and activator of transcription 3 (STAT3), prevented phosphorylated STAT3 (pSTAT3) translocation into the nucleus, and suppressed pSTAT3 transactivation activity. Additionally, it was found that shikonin inhibited lung metastasis, EMT and expression of pSTAT3 of A549 cells in vivo. Furthermore, IL6 levels in human lung adenocarcinoma tissues were significantly associated with tumornodemetastasis stage and lymph node metastasis, and its expression was correlated with tumorassociated macrophage (TAM) infiltration. Together, these results suggest that shikonin suppresses the migration and invasion of human lung adenocarcinoma cells in an inflammatory microenvironment involving the IL6/STAT3 signaling pathway.
Asunto(s)
Adenocarcinoma del Pulmón/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Metástasis Linfática/tratamiento farmacológico , Naftoquinonas/farmacología , Células A549 , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/secundario , Movimiento Celular/efectos de los fármacos , Movimiento Celular/inmunología , Medicamentos Herbarios Chinos/uso terapéutico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/inmunología , Femenino , Humanos , Interleucina-6/análisis , Interleucina-6/metabolismo , Pulmón/inmunología , Pulmón/patología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Metástasis Linfática/inmunología , Masculino , Persona de Mediana Edad , Naftoquinonas/uso terapéutico , Invasividad Neoplásica/inmunología , Invasividad Neoplásica/prevención & control , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Células THP-1 , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Macrófagos Asociados a Tumores/efectos de los fármacos , Macrófagos Asociados a Tumores/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Diagnosis and treatment of primary lung adenocarcinoma in children remains challenging given its rarity. Here we highlight the clinical history, pathological evaluation, genomic findings, and management of a very young patient with metastatic lung adenocarcinoma. CASE PRESENTATION: A 10-year-old white girl presented with brain metastases due to primary pulmonary adenocarcinoma. Next generation sequencing analysis with "Comprehensive Cancer Panel" highlighted the presence of multiple non-targetable mutations in the FLT4, UBR5, ATM, TAF1, and GUCY1A2 genes. She was treated aggressively with chemotherapy, surgery, and radiation therapy for local and distant recurrence. Eventually, therapy with nivolumab was started compassionately, and she died 23 months after diagnosis. CONCLUSIONS: Extremely rare cancers in children such as lung adenocarcinoma need accurate and specific diagnosis in order to develop an optimal plan of treatment. It is also necessary to underline that "children are not little adults," thus implying that an adult-type cancer in the pediatric population might have a different etiopathogenesis. Diagnostic confirmation and primary treatment of such rare conditions should be centralized in reference centers, collaborative networks, or both, with multidisciplinary approaches and very specific expertise.