https://www.um.es/biomybiotec/web/Seminarios/2010/papers/Cano_2.pdf

Epithelial-Mesenchymal Transitions in Development and Disease

The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.

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The basics of epithelial-mesenchymal transition

Hepatocellular Carcinoma: Epidemiology and Molecular Carcinogenesis

Pathology and genetics of tumors of soft tissue and bone

Cells continually experience stress and damage from exogenous and endogenous sources, and their responses range from complete recovery to cell death. Proliferating cells can initiate an additional response by adopting a state of permanent cell-cycle arrest that is termed cellular senescence. Understanding the causes and consequences of cellular senescence has provided novel insights into how cells react to stress, especially genotoxic stress, and how this cellular response can affect complex organismal processes such as the development of cancer and ageing.

Cellular senescence: when bad things happen to good cells

Low-dose radiotherapy (LDRT) given in 2 × 2 Gy is a highly effective and safe treatment for palliation of indolent lymphomas Otherwise, very little regarding the use of LDRT for diffuse large B-cell lymphoma (DLBCL) has been investigated We designed a phase 2 trial of LDRT in patients with DLBCL with indication for palliative radiation Low-dose radiotherapy was administered on symptomatic areas only Clinical response was assessed 21 days after LDRT and defined as reduction >50% of maximum diameter of the radiated lesions Quality of life was scored by the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire Tumor subtype (germinal center B-cell type versus activated B-cell type) and the presence of TP53 mutations in pathologic specimens of the target lesion were also evaluated Twenty-three of twenty-five radiated patients were evaluable for response, and 2 died of disease before the visit at 21 days The overall response rate was 70% (16 of 23 patients), with 7 complete responses and 9 partial responses (mean duration of response, 6 months; range, 1-39 months) Fifteen patients answered to the QLQ-C30 questionnaires, and an improved quality of life was documented in 9 cases TP53 mutations were detected in 2 of 6 (33%) nonresponders and in none of the responders (P = 12) Germinal center B-cell type responded better than activated B-cell type (response rate was 83% and 29%, respectively, P = 01) These findings indicate that LDRT is effective for palliation in patients with DLBCL

Low-dose radiotherapy in diffuse large B-cell lymphoma

The targeting of the Mitogen-Activated Protein Kinase (MAPK) signalling pathway in melanoma improves the prognosis of patients harbouring the V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF) mutation. However, a fraction of these patients may experience tumour progression due to resistance to targeted therapy. Mutations affecting the Phosphoinositol-3-Kinase (PI3K)–Akt pathway may favour the onset of drug resistance, suggesting the existence of a crosstalk between the MAPK and PI3K–Akt pathways. We hypothesized that the inhibition of both pathways may be a therapeutic option in resistant melanoma. However, conflicting data have been generated in this context. In this study, three different A375 cell melanoma models either overexpressing or not expressing the wild-type or mutated form of the PhosphatidylInositol-4,5-bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) gene were used to clarify the therapeutic response of melanoma to BRAF, Mitogen-Activated Protein Kinase Kinase 1 (MEK), and PI3K inhibitors in the presence of the PIK3CA H1047R mutation. Our data strongly support the notion that the crosstalk between the MAPK and PI3K–Akt pathways is one of the main mechanisms associated with melanoma development and progression and that the combination of MAPK and PI3K inhibitors may sensitize melanoma cells to therapy.

/pdf/the-pik3ca-h1047r-mutation-confers-resistance-to-braf-and-3okycqrk.pdf

The PIK3CA H1047R Mutation Confers Resistance to BRAF and MEK Inhibitors in A375 Melanoma Cells through the Cross-Activation of MAPK and PI3K–Akt Pathways

Interference of p53:Twist1 interaction through competing nanobodies

Mink cell focus-forming viruses (MCF) are slow-transforming retroviruses that are able to accelerate the appearance of T-cell lymphomas when injected in newborn AKR mice. Activation of proto-oncogenes by proviral insertion is thought to be the major mechanism by which these viruses exert their oncogenic potential. However, molecular phenomena not strictly virus-determined, such as mutations in cellular oncogenes/tumor suppressor genes or chromosome aberrations, have been hypothesized to contribute to the achievement of the fully neoplastic phenotype in MCF-infected mice. To evaluate the role of spontaneous mutagenesis phenomena in murine virus-induced lymphomagenesis, we analyzed a series of 18 MCF247-induced thymic lymphomas and derived cell lines for the presence of p53 and c-ras gene mutations. Only 1 mutation at the p53 gene and 1 mutation at the ki-ras gene were detected in our study. Our results suggest that spontaneous mutagenesis plays a minor role in virus-induced lymphomagenesis and support the notion that multiple proviral insertions could be the prevalent mechanism of transformation in this experimental system.

Sara Piccinin

Papers

Low-dose radiotherapy in diffuse large B-cell lymphoma

The PIK3CA H1047R Mutation Confers Resistance to BRAF and MEK Inhibitors in A375 Melanoma Cells through the Cross-Activation of MAPK and PI3K–Akt Pathways

Interference of p53:Twist1 interaction through competing nanobodies

Spontaneous mutation of cell oncogenes plays a minor role in neoplastic transformation of virus-induced murine T-cell lymphomas.