The Journal of pathology
-
The Journal of pathology · Apr 2016
Multicenter StudyMicroglandular adenosis associated with triple-negative breast cancer is a neoplastic lesion of triple-negative phenotype harbouring TP53 somatic mutations.
Microglandular adenosis (MGA) is a rare proliferative lesion of the breast composed of small glands lacking myoepithelial cells and lined by S100-positive, oestrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative epithelial cells. There is evidence to suggest that MGA may constitute a non-obligate precursor of triple-negative breast cancer (TNBC). We sought to define the genomic landscape of pure MGA and of MGA, atypical MGA (AMGA) and associated TNBCs, and to determine whether synchronous MGA, AMGA, and TNBCs would be clonally related. ⋯ In the MGA/AMGA associated with TNBC lacking TP53 mutations, somatic mutations affecting PI3K pathway-related genes (eg PTEN, PIK3CA, and INPP4B) and tyrosine kinase receptor signalling-related genes (eg ERBB3 and FGFR2) were identified. At diagnosis, MGAs associated with TNBC were found to display subclonal populations, and clonal shifts in the progression from MGA to AMGA and/or to TNBC were observed. Our results demonstrate the heterogeneity of MGAs, and that MGAs associated with TNBC, but not necessarily pure MGAs, are genetically advanced, clonal, and neoplastic lesions harbouring recurrent mutations in TP53 and/or other cancer genes, supporting the notion that a subset of MGAs and AMGAs may constitute non-obligate precursors of TNBCs.
-
The Journal of pathology · Dec 2015
TH17 predominant T-cell responses in radiation-induced bowel disease are modulated by treatment with adipose-derived mesenchymal stromal cells.
Radiation proctitis is an insidious disease associated with substantial morbidity and mortality. It may develop following the treatment of several cancers by radiotherapy when normal colorectal tissues are present in the irradiation field. There is no unified approach for the assessment and treatment of this disease, partly due to insufficient knowledge about the mechanism involved in the development of radiation proctitis. ⋯ Additionally, we demonstrated in vitro that IL17 acts directly on colonic smooth muscle cells to induce expression of pro-inflammatory genes that could participate in the development of radiation-induced injury. Our data demonstrate that the TH17 population is specifically induced during development of radiation-induced side effects in the colon. Moreover, Ad-MSC treatment modulates the TH17 population and reduces the extracellular matrix remodelling process induced following irradiation.
-
The Journal of pathology · Nov 2015
Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance.
Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome- and RNA-sequencing. ⋯ The HER3 ligands NRG1/2 were barely detectable by RNAseq, with NRG1 (8p12) genomic loss in 63.6% breast cancer-BMs, suggesting a microenvironmental source of ligand. In summary, this is the first study to characterize the genomic landscapes of BM. The data revealed novel candidates, potential clinical applications for genomic profiling of resectable BMs, and highlighted the possibility of therapeutically targeting HER3, which is broadly over-expressed and activated in BMs, independent of primary site and systemic therapy.
-
The Journal of pathology · Mar 2015
Characterization of the cell of origin and propagation potential of the fibroblast growth factor 9-induced mouse model of lung adenocarcinoma.
Fibroblast growth factor 9 (FGF9) is essential for lung development and is highly expressed in a subset of human lung adenocarcinomas. We recently described a mouse model in which FGF9 expression in the lung epithelium caused proliferation of the airway epithelium at the terminal bronchioles and led to rapid development of adenocarcinoma. Here, we used this model to characterize the effects of prolonged FGF9 induction on the proximal and distal lung epithelia, and examined the propagation potential of FGF9-induced lung tumours. ⋯ Activation of an alternative FGF-FGFR axis and the interaction with tumour stromal cells is likely to be responsible for the development of this independence. This study demonstrates the complex role of FGF-FGFR signalling in the initiation, growth and propagation of lung cancer. Our findings suggest that analysing the expressions of FGF-FGFRs in human lung cancer will be a useful tool for guiding customized therapy.
-
The Journal of pathology · Jan 2015
ReviewPathogenesis of Middle East respiratory syndrome coronavirus.
Human coronaviruses (CoVs) mostly cause a common cold that is mild and self-limiting. Zoonotic transmission of CoVs such as the recently identified Middle East respiratory syndrome (MERS)-CoV and severe acute respiratory syndrome (SARS)-CoV, on the other hand, may be associated with severe lower respiratory tract infection. ⋯ These findings are in line with differences in the induction of cytopathological changes, induction of host gene responses and sensitivity to the antiviral effect of interferons in vitro when comparing both MERS-CoV and SARS-CoV. The challenge will be to translate these findings into an integrated picture of MERS pathogenesis in humans and to develop intervention strategies that will eventually allow the effective control of this newly emerging infectious disease.