27 research outputs found
The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase
Tumour metastasis is a complex process involving reciprocal interplay
between cancer cells and host stroma at both primary and secondary
sites, and is strongly influenced by microenvironmental
factors such as hypoxia. Tumour-secreted proteins play a crucial role
in these interactions and present strategic therapeutic potential.
Metastasis of breast cancer to the bone affects approximately 85%
of patients with advanced disease and renders them largely untreatable. Specifically, osteolytic bone lesions, where bone is destroyed,
lead to debilitating skeletal complications and increased patient morbidity
and mortality. The molecular interactions governing the
early events of osteolytic lesion formation are currently unclear.
Here we show hypoxia to be specifically associated with bone relapse
in patients with oestrogen-receptor negative breast cancer. Global
quantitative analysis of the hypoxic secretome identified lysyl oxidase
(LOX) as significantly associated with bone-tropism and relapse.
High expression of LOX in primary breast tumours or systemic delivery
of LOX leads to osteolytic lesion formation whereas silencing or
inhibition of LOX activity abrogates tumour-driven osteolytic lesion
formation. We identify LOX as a novel regulator of NFATc1-driven
osteoclastogenesis,independent of RANK ligand, which disrupts normal
bone homeostasisleading to the formation of focal pre-metastatic
lesions. We show that these lesions subsequently provide a platform
for circulating tumour cells to colonize and form bone metastases.
Our study identifies a novel mechanism of regulation of bone homeostasis
and metastasis, opening up opportunities for novel therapeutic
intervention with important clinical implications
Transcriptional patterns in peritoneal tissue of encapsulating peritoneal sclerosis, a complication of chronic peritoneal dialysis
Encapsulating peritoneal sclerosis (EPS) is a devastating complication of peritoneal dialysis (PD), characterized by marked inflammation and severe fibrosis of the peritoneum, and associated with high morbidity and mortality. EPS can occur years after termination of PD and, in severe cases, leads to intestinal obstruction and ileus requiring surgical intervention. Despite ongoing research, the pathogenesis of EPS remains unclear. We performed a global transcriptome analysis of peritoneal tissue specimens from EPS patients, PD patients without EPS, and uremic patients without history of PD or EPS (Uremic). Unsupervised and supervised bioinformatics analysis revealed distinct transcriptional patterns that discriminated these three clinical groups. The analysis identified a signature of 219 genes expressed differentially in EPS as compared to PD and Uremic groups. Canonical pathway analysis of differentially expressed genes showed enrichment in several pathways, including antigen presentation, dendritic cell maturation, B cell development, chemokine signaling and humoral and cellular immunity (P value<0.05). Further interactive network analysis depicted effects of EPS-associated genes on networks linked to inflammation, immunological response, and cell proliferation. Gene expression changes were confirmed by qRT-PCR for a subset of the differentially expressed genes. EPS patient tissues exhibited elevated expression of genes encoding sulfatase1, thrombospondin 1, fibronectin 1 and alpha smooth muscle actin, among many others, while in EPS and PD tissues mRNAs encoding leptin and retinol-binding protein 4 were markedly down-regulated, compared to Uremic group patients. Immunolocalization of Collagen 1 alpha 1 revealed that Col1a1 protein was predominantly expressed in the submesothelial compact zone of EPS patient peritoneal samples, whereas PD patient peritoneal samples exhibited homogenous Col1a1 staining throughout the tissue samples. The results are compatible with the hypothesis that encapsulating peritoneal sclerosis is a distinct pathological process from the simple peritoneal fibrosis that accompanies all PD treatment