[show abstract][hide abstract] ABSTRACT: Tumor-derived exosomes are emerging mediators of tumorigenesis. We explored the function of melanoma-derived exosomes in the formation of primary tumors and metastases in mice and human subjects. Exosomes from highly metastatic melanomas increased the metastatic behavior of primary tumors by permanently 'educating' bone marrow progenitors through the receptor tyrosine kinase MET. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites and reprogrammed bone marrow progenitors toward a pro-vasculogenic phenotype that was positive for c-Kit, the receptor tyrosine kinase Tie2 and Met. Reducing Met expression in exosomes diminished the pro-metastatic behavior of bone marrow cells. Notably, MET expression was elevated in circulating CD45(-)C-KIT(low/+)TIE2(+) bone marrow progenitors from individuals with metastatic melanoma. RAB1A, RAB5B, RAB7 and RAB27A, regulators of membrane trafficking and exosome formation, were highly expressed in melanoma cells. Rab27A RNA interference decreased exosome production, preventing bone marrow education and reducing, tumor growth and metastasis. In addition, we identified an exosome-specific melanoma signature with prognostic and therapeutic potential comprised of TYRP2, VLA-4, HSP70, an HSP90 isoform and the MET oncoprotein. Our data show that exosome production, transfer and education of bone marrow cells supports tumor growth and metastasis, has prognostic value and offers promise for new therapeutic directions in the metastatic process.
Nature medicine 05/2012; 18(6):883-91. · 27.14 Impact Factor
[show abstract][hide abstract] ABSTRACT: Metastasis is a multistep process that requires acquisition of malignant cell phenotypes which allow tumor cells to escape from the primary tumor site. Each of the steps during metastatic progression involves co-evolution of the tumor and its microenvironment. Although tumor cells are the driving force of metastasis, new findings suggest that the host cells within the tumor microenvironment play a key role in influencing metastatic behavior. Many of these contributing cells are derived from the bone marrow; in particular, recruited bone marrow progenitor cells generate the "pre-metastatic niche" to which the tumor cells metastasize. Analysis of the molecular mechanisms involved in pre-metastatic niche formation has revealed that secreted soluble factors are key players in bone marrow cell mobilization during metastasis. In addition, membrane vesicles derived from both tumor and host cells have recently been recognized as new candidates with important roles in the promotion of tumor growth and metastasis. This review describes old ideas and presents new insights into the role of tumor and bone marrow-derived microvesicles and exosomes in pre-metastatic niche formation and metastasis.
Seminars in Cancer Biology 01/2011; 21(2):139-46. · 7.44 Impact Factor
[show abstract][hide abstract] ABSTRACT: Despite the growing demand for board-certified intensivists in the United States, the roles for medically trained intensivists (MTIs) in leadership positions in surgical ICUs remain limited. This report explores some of the challenges facing internal medicine (IM) critical care fellows who are considering careers as surgical intensivists or MTIs who are moving to a surgical ICU. A practical framework is provided for attaining these jobs and thriving in these positions once obtained. The article explores the nuances between medical and surgical ICUs and concludes by describing how surgical critical care can be a gratifying career for the IM-trained intensivist and an asset to the surgical ICU.
[show abstract][hide abstract] ABSTRACT: The approach to small bowel obstruction, when unrelieved with medical management, is open or laparoscopic exploration, often necessitating lysis of adhesions and the resection of any compromised bowel. In patients with prior bowel resections, the surgeon must tread a fine line, so as not to precipitate the clinical derangement known as short bowel syndrome (SBS). Techniques have been described that curtail the extent of intestinal resection, but these are primarily limited to the pediatric literature and are not commonly practiced in the general surgical population.
We report a case of a complicated small bowel obstruction in a patient with pre-existing short bowel length, in which a tapering enteroplasty was performed.
Antimesenteric tapering successfully achieved a return of bowel function, avoiding the morbidity of an extended small bowel resection and the possibility of developing SBS.
In such patients who are at high risk of developing SBS, in whom a segment of dilated small bowel has become defunctionalized, leading to significant and life-threatening symptoms, this procedure has the potential to help prevent SBS and its lifelong complications and associated mortality.
European Surgical Research 07/2009; 43(2):208-10. · 0.75 Impact Factor