Epigenetic silencing of CXCL12 increases the metastatic potential of mammary carcinoma cells.

Expression of the chemokine receptor CXCR4 has been linked with increased metastasis and decreased clinical prognosis in breast cancer. The current paradigm dictates that CXCR4 fosters carcinoma cell metastasis along a chemotactic gradient to organs expressing the ligand CXCL12. The present study asked if alterations in autocrine CXCR4 signaling via dysregulation of CXCL12 in mammary carcinoma cells modulated their metastatic potential. While CXCR4 was consistently detected, expression of CXCL12 characteristic of human mammary epithelium was silenced by promoter hypermethylation in breast cancer cell lines and primary mammary tumors. Stable re-expression of functional CXCL12 in ligand null cells increased orthotopic primary tumor growth in the mammary fat-pad model of tumorigenesis. Those data parallel increased carcinoma cell proliferation measured in vitro with little-to-no-impact on apoptosis. Moreover, re-expression of autocrine CXCL12 markedly reduced metastatic lung invasion assessed using in vivo bioluminescence imaging following tail vein injection. Consistent with those data, decreased metastasis reflected diminished intracellular calcium signaling and chemotactic migration in response to exogenous CXCL12 independent of changes in CXCR4 expression. Together these data suggest that an elevated migratory signaling response to ectopic CXCL12 contributes to the metastatic potential of CXCR4-expressing mammary carcinoma cells, subsequent to epigenetic silencing of autocrine CXCL12.

A rare complication of pneumonectomy: diagnosis made by a literature search.

This case describes platypnoea-orthodeoxia syndrome in a patient 2 months after a right pneumonectomy for adenocarcinoma of the lung. The patient complained of platypnoea (breathlessness in the upright position) and was noted to have orthodeoxia (arterial desaturation on standing) on clinical examination. This was due to anatomical changes after the pneumonectomy that resulted in direct blood flow from the inferior vena cava through a previously unrecognised atrial septal defect into the left atrium. The closure of this right to left shunt with an Amplatzer occluder produced immediate and striking symptomatic relief in the patient. The authors had no previous experience of this very rare complication of pneumonectomy. The diagnosis was made after a literature search using PubMed/Medline, underlining the direct clinical benefit provided by these databases.