RESUMEN
PROBLEM: Development of platinum resistance in ovarian cancer is mediated by both cancer cells and tumor microenvironment. Activation of epithelial-mesenchymal transition program in cancer cells may lead to enrichment for resistant clones. These processes can be affected by tumor-associated macrophages, a highly plastic population of cells that participate in tumor progression and response to treatment by shaping the microenvironment. We aimed to study how platinum resistance influences the crosstalk between macrophages and ovarian cancer cells. METHOD OF STUDY: Using cisplatin-sensitive ovarian cancer cell line A2780, we developed and characterized cisplatin-resistant A2780Cis and cisplatin and doxorubicin co-resistant A2780Dox cell lines. Next, we set up an indirect coculture system with THP-1 cell line-derived M0-type-, M1-type- and M2-type-like polarized macrophages. We monitored the expression of genes associated with cellular stemness, multidrug resistance, and epithelial-mesenchymal transition in cancer cells, and expression profile of M1/M2 markers in macrophages. RESULTS: Development of drug resistance in ovarian cancer cell lines was accompanied by increased migration, clonogenicity, and upregulated expression of transcription factors, associated with cellular stemness and epithelial-mesenchymal transition. Upon coculture, we noted that the most relevant changes in gene expression profile occurred in A2780 cells. Moreover, M0- and M1-type macrophages, but not M2-type macrophages, showed significant transcriptional alterations. CONCLUSION: Our results provide the evidence for bidirectional interplay between cancer cells and macrophages. Independent of platinum resistance status, ovarian cancer cells polarize macrophages toward M2-like type, whereas macrophages induce epithelial-mesenchymal transition and stemness-related gene expression profile in cisplatin-sensitive, but not cisplatin-resistant cancer cells.
Asunto(s)
Adenocarcinoma/inmunología , Cisplatino/uso terapéutico , Macrófagos/inmunología , Neoplasias Ováricas/inmunología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Diferenciación Celular , Línea Celular Tumoral , Movimiento Celular , Técnicas de Cocultivo , Citocinas/metabolismo , Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunomodulación , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Células Th2/inmunología , Escape del Tumor , Microambiente TumoralRESUMEN
Genetic linkage analysis previously suggested that GKAP, a scaffold protein of the N-methyl-D-aspartate receptor (NMDAR), was a potential modifier of invasion in a mouse model of pancreatic neuroendocrine tumor (PanNET). Here, we establish that GKAP governs invasive growth and treatment response to NMDAR inhibitors of PanNET via its pivotal role in regulating NMDAR pathway activity. Combining genetic knockdown of GKAP and pharmacological inhibition of NMDAR, we implicate as downstream effectors FMRP and HSF1, which along with GKAP demonstrably support invasiveness of PanNET and pancreatic ductal adenocarcinoma cancer cells. Furthermore, we distilled genome-wide expression profiles orchestrated by the NMDAR-GKAP signaling axis, identifying transcriptome signatures in tumors with low/inhibited NMDAR activity that significantly associate with favorable patient prognosis in several cancer types.
Asunto(s)
Carcinoma Neuroendocrino/genética , Carcinoma Ductal Pancreático/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Factores de Transcripción del Choque Térmico/genética , Neoplasias Pancreáticas/genética , Proteínas Asociadas a SAP90-PSD95/genética , Transducción de Señal , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinoma Neuroendocrino/tratamiento farmacológico , Carcinoma Neuroendocrino/metabolismo , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Línea Celular Tumoral , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Invasividad Neoplásica , Trasplante de Neoplasias , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Pronóstico , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Análisis de Secuencia de ARN/métodos , Transducción de Señal/efectos de los fármacos , Análisis de SupervivenciaRESUMEN
Therapeutic targeting of tumor angiogenesis with VEGF inhibitors results in demonstrable, but transitory efficacy in certain human tumors and mouse models of cancer, limited by unconventional forms of adaptive/evasive resistance. In one such mouse model, potent angiogenesis inhibitors elicit compartmental reorganization of cancer cells around remaining blood vessels. The glucose and lactate transporters GLUT1 and MCT4 are induced in distal hypoxic cells in a HIF1α-dependent fashion, indicative of glycolysis. Tumor cells proximal to blood vessels instead express the lactate transporter MCT1, and p-S6, the latter reflecting mTOR signaling. Normoxic cancer cells import and metabolize lactate, resulting in upregulation of mTOR signaling via glutamine metabolism enhanced by lactate catabolism. Thus, metabolic symbiosis is established in the face of angiogenesis inhibition, whereby hypoxic cancer cells import glucose and export lactate, while normoxic cells import and catabolize lactate. mTOR signaling inhibition disrupts this metabolic symbiosis, associated with upregulation of the glucose transporter GLUT2.
