Chemokine (C-C motif) ligand 2 mediates the prometastatic effect of dysadherin in human breast cancer cells.

Dysadherin, a cancer-associated membrane glycoprotein, down-regulates E-cadherin and promotes cancer metastasis. This study examined the role of dysadherin in breast cancer progression. Expression of dysadherin was found to be highest in breast cancer cell lines and tumors that lacked the estrogen receptor (ER). Knockdown of dysadherin caused increased association of E-cadherin with the actin cytoskeleton in breast cancer cell lines that expressed E-cadherin. However, knockdown of dysadherin could still suppress cell invasiveness in cells that had no functional E-cadherin, suggesting the existence of a novel mechanism of action. Global gene expression analysis identified chemokine (C-C motif) ligand 2 (CCL2) as the transcript most affected by dysadherin knockdown in MDA-MB-231 cells, and dysadherin was shown to regulate CCL2 expression in part through activation of the nuclear factor-kappaB pathway. The ability of dysadherin to promote tumor cell invasion in vitro was dependent on the establishment of a CCL2 autocrine loop, and CCL2 secreted by dysadherin-positive tumor cells also promoted endothelial cell migration in a paracrine fashion. Finally, experimental suppression of CCL2 in MDA-MB-231 cells reduced their ability to metastasize in vivo. This study shows that dysadherin has prometastatic effects that are independent of E-cadherin expression and that CCL2 could play an important role in mediating the prometastatic effect of dysadherin in ER-negative breast cancer.

Bone sialoprotein mediates the tumor cell-targeted prometastatic activity of transforming growth factor beta in a mouse model of breast cancer.

Transforming growth factor betas (TGF-beta) play a dual role in carcinogenesis, functioning as tumor suppressors early in the process, and then switching to act as prometastatic factors in late-stage disease. We have previously shown that high molecular weight TGF-beta antagonists can suppress metastasis without the predicted toxicities. To address the underlying mechanisms, we have used the 4T1 syngeneic mouse model of metastatic breast cancer. Treatment of mice with a monoclonal anti-TGF-beta antibody (1D11) significantly suppressed metastasis of 4T1 cells to the lungs. When metastatic 4T1 cells were recovered from lungs of 1D11-treated and control mice, the most differentially expressed gene was found to be bone sialoprotein (Bsp). Immunostaining confirmed the loss of Bsp protein in 1D11-treated lung metastases, and TGF-beta was shown to regulate and correlate with Bsp expression in vitro. Functionally, knockdown of Bsp in 4T1 cells reduced the ability of TGF-beta to induce local collagen degradation and invasion in vitro, and treatment with recombinant Bsp protected 4T1 cells from complement-mediated lysis. Finally, suppression of Bsp in 4T1 cells reduced metastasis in vivo. We conclude that Bsp is a plausible mediator of at least some of the tumor cell-targeted prometastatic activity of TGF-beta in this model and that Bsp expression in metastases can be successfully suppressed by systemic treatment with anti-TGF-beta antibodies.

Ready for the frontline: is early thoracoscopic decortication the new standard of care for advanced pneumonia with empyema?

Video-assisted thoracoscopic decortication (VATD) has been established as an effective and potentially less morbid alternative to open thoracotomy for the management of empyema. However, the timing and role of VATD for advanced pneumonia with empyema is still controversial. In assessing surgical outcome, the authors reviewed their VATD experience in children with empyema or empyema with necrotizing pneumonia. The charts of 42 children who underwent VATD at our institution between July 2001 and July 2005 were retrospectively reviewed for surgical outcome. For purposes of analysis, patients were cohorted into four classes with increasing severity of pneumonia: 1 (-) intraoperative pleural fluid cultures, (-) necrotizing pneumonia, 18 (43%); 2 (+) pleural fluid cultures, (-) necrotizing pneumonia, 10 (24%); 3 (-) pleural fluid cultures, (+) necrotizing pneumonia, 6 (14%); 4 (+) pleural fluid cultures, (+) necrotizing pneumonia, 8 (19%). A P value of < 0.05 via Student's t test or Fischer's exact analysis was considered an indicator of significant difference in the comparison of group outcomes. VATD was successfully completed in all 42 patients with no mortality and without significant morbidity (82% had less than 20 cc blood loss). There was found to be no significant difference (p = NS) in time to surgical discharge (removal of chest tube) among all groups. Hospital length of stay postsurgery was found to be significantly increased between 1 and 4 (6 days vs 9 days; P = 0.038). 14/14 (100%) of children with necrotizing pneumonia were found to have evidence of lung parenchymal preservation with improved aeration on follow-up CT scan and/or chest x-rays. The authors conclude that early VATD in children with advanced pneumonia with empyema is indicated to avoid unnecessarily lengthy hospitalization and prolonged intravenous antibiotic therapy. Furthermore, early VATD can be safely performed in various stages of advanced pneumonia with empyema, promoting lung salvage, and accelerating clinical recovery.

Sequential linear stapling technique for perineal resection of intractable pediatric rectal prolapse.

Rectal prolapse (RP), although most frequently encountered in the frail elderly, may also occur in children. This condition is most troublesome in the premature infant with significant associated comorbidities. Pediatric RP most often can be managed conservatively with expectant and/or judicious use of laxative-based bowel regimens. In rare instances of intractable RP, surgical intervention ranging from simple (sclerotherapy, Thiersch wire) to complex (perineal or transabdominal bowel resection) becomes necessary. We describe a modification of the Altemeier technique using a novel sequential linear stapling technique to treat intractable RP in a 5.0-kg infant with severe coexisting life-threatening comorbidities. The child had resumption of bowel movements on postoperative Day 1 and has had no recurrences. Sequential linear stapling technique for perineal resection of intractable pediatric RP appears to be a safe and potentially attractive alternative.