RESUMEN
Personalized treatment approaches for patients with limited liver metastases from colorectal cancer are critically needed. By leveraging three large, independent cohorts of patients with colorectal liver metastases (n = 336), we found that a proliferative subtype associated with elevated CIN70 scores is linked to immune exclusion, increased metastatic proclivity, and inferior overall survival in colorectal liver metastases; however, high CIN70 scores generate a therapeutic vulnerability to DNA-damaging therapies leading to improved treatment responses. We propose CIN70 as a candidate biomarker to personalize systemic treatment options for patients with metastatic colorectal cancer. These findings are potentially broadly applicable to other human cancers.
RESUMEN
Metastasis suppressor 1 (MTSS1) has been shown to be a metastasis suppressor in a number of cancers. However, its role in lung adenocarcinoma is largely unknown. To evaluate the significance of MTSS1 expression on lung adenocarcinoma metastatic properties, the gain or loss of MTSS1 in in vivo and in vitro experiments were employed. Using an in vivo orthotopic mouse xenograft model mimicking human disease progression, stable overexpression of MTSS1 in lung adenocarcinoma cells resulted in a significant decrease in metastatic burden. Stable overexpression of MTSS1 in NCI-H1299 decreased in vitro lung adenocarcinoma invasion and migration while knockdown of MTSS1 in A549 resulted in a significant increase in cell invasion and migration. Using The Cancer Genome Atlas dataset of over 500 patient lung adenocarcinoma specimens, we demonstrated a 20% increase in 5-year survival associated with preserved intratumoral MTSS expression. MTSS1 expression in lung adenocarcinoma is associated with decreased metastatic burden, as assessed by an in vivo orthotopic model, and correlates with a 20% survival advantage at 5 years following diagnosis. In vitro data suggests MTSS1 regulates lung adenocarcinoma through augmentation of cell invasion and migration.
Asunto(s)
Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteínas de Microfilamentos/genética , Proteínas de Neoplasias/genética , Animales , Línea Celular Tumoral , Conjuntos de Datos como Asunto , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Regulación hacia Abajo , Técnicas de Silenciamiento del Gen , Xenoinjertos , Humanos , Ratones , Invasividad Neoplásica , Metástasis de la Neoplasia/genética , Tasa de SupervivenciaRESUMEN
Hepatocellular carcinoma is one of the most common malignancies worldwide and evidence suggests that Ras signaling regulates various hallmarks of cancer via regulating several effector pathways such as ERK and PI3K. The aim of the present study is to understand the efficacy of a flavonoid myricetin for the first time in inhibiting the downstream target p21 activated kinase 1 (PAK1) of Ras signaling pathway in hepatocellular carcinoma. The analysis of gene expression revealed that myricetin inhibits PAK1 by abrogating the Ras-mediated signaling by decelerating Wnt signaling, the downstream of Erk/Akt, thereby inducing intrinsic caspase-mediated mitochondrial apoptosis by downregulating the expression of anti-apoptotic Bcl-2 and survivin and upregulating pro-apoptotic Bax. The results also provide striking evidence that the myricetin inhibits the development of HCC by inhibiting PAK1 via coordinate abrogation of MAPK/ERK and PI3K/AKT and their downstream signaling Wnt/ß-catenin pathway, thus being a promising candidate for cancer prevention and therapy.
Asunto(s)
Analgésicos/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Flavonoides/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Quinasas p21 Activadas/genética , Quinasas p21 Activadas/metabolismo , Analgésicos/farmacología , Animales , Apoptosis , Carcinoma Hepatocelular/enzimología , Carcinoma Hepatocelular/patología , Proliferación Celular/efectos de los fármacos , Flavonoides/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/patología , Masculino , Ratas , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Hepatic stellate cells (HSCs), a specialized stromal cytotype have a great impact on the biological behaviors of liver diseases. Despite this fact, the underlying mechanism that regulates HSC still remains poorly understood. The aim of the present study was to understand the role of TRPC6 signaling in regulating the molecular mechanism of HSCs in response to hypoxia. In the present study we showed that under hypoxia condition, the upregulated Hypoxia Inducible Factor 1α (HIF1α) increases NICD activation, which in turn induces the expression of transient receptor potential channel 6 (TRPC6) in HSC line lx-2. TRPC6 causes a sustained elevation of intracellular calcium which is coupled with the activation of the calcineurin-nuclear factor of activated T-cell (NFAT) pathway which activates the synthesis of extracellular matrix proteins. TRPC6 also activates SMAD2/3 dependent TGF-ß signaling in facilitating upregulated expression of αSMA and collagen. As activated HSCs may be a suitable target for HCC therapy and targeting these cells rather than the HCC cells may result in a greater response. Collectively, our studies indicate for the first time the detailed mechanism of activation of HSC through TRPC6 signaling and thus being a promising therapeutic target.
