ABSTRACT
Interactions between tumor cells and cancer-associated fibroblasts (CAFs) in the tumor microenvironment significantly influence cancer growth and metastasis. Transforming growth factor-ß (TGF-ß) is known to be a critical mediator of the CAF phenotype, and osteopontin (OPN) expression in tumors is associated with more aggressive phenotypes and poor patient outcomes. The potential link between these two pathways has not been previously addressed. Utilizing in vitro studies using human mesenchymal stem cells (MSCs) and MDA-MB231 (OPN+) and MCF7 (OPN-) human breast cancer cell lines, we demonstrate that OPN induces integrin-dependent MSC expression of TGF-ß1 to mediate adoption of the CAF phenotype. This OPN-TGF-ß1 pathway requires the transcription factor, myeloid zinc finger 1 (MZF1). In vivo studies with xenotransplant models in NOD-scid mice showed that OPN expression increases cancer growth and metastasis by mediating MSC-to-CAF transformation in a process that is MZF1 and TGF-ß1 dependent. We conclude that tumor-derived OPN engenders MSC-to-CAF transformation in the microenvironment to promote tumor growth and metastasis via the OPN-MZF1-TGF-ß1 pathway.
Subject(s)
Breast Neoplasms/pathology , Cell Transformation, Neoplastic/metabolism , Fibroblasts/pathology , Mesenchymal Stem Cells/pathology , Neoplastic Stem Cells/pathology , Osteopontin/physiology , Animals , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Transformation, Neoplastic/genetics , Female , Fibroblasts/drug effects , Fibroblasts/metabolism , Humans , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolism , MCF-7 Cells , Mesenchymal Stem Cells/metabolism , Mice , Mice, Inbred NOD , Mice, SCID , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Osteopontin/pharmacology , Signal Transduction/drug effects , Signal Transduction/genetics , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolism , Tumor Cells, CulturedABSTRACT
The role of humoral alloreactivity in ABO-compatible liver transplantation remains unclear. To understand the significance of donor-specific HLA alloantibodies (DSA) in liver rejection, we applied the currently used strategy for detection of antibody-mediated rejection of other solid allografts. For this purpose we reviewed the data on 43 recipients of ABO identical/compatible donor livers who had indication liver biopsy stained for complement element C4d and contemporaneous circulating DSA determination. Seventeen (40%) patients had significant circulating DSA in association with diffuse portal C4d deposition (DSA+/diffuse C4d+). These DSA+/diffuse C4d+ subjects had higher frequency of acute cellular rejection (ACR) 15/17 versus 13/26 (88% vs. 50%), p = 0.02, and steroid resistant rejection 7/17 versus 5/26 (41% vs. 19%), p = 0.03. Based on detection of the combination DSA+/diffuse C4d+, 53.6% of cases of ACR had evidence of concurrent humoral alloreactivity. Six of the 10 patients with ductopenic rejection had circulating DSA and diffuse portal C4d, three of whom (2 early and 1 late posttransplantation) developed unrelenting cholestasis, necessitating specific antibody-depleting therapy to salvage the allografts. Thus, in ABO-compatible liver transplantation humoral alloreactivity mediated by antibodies against donor HLA molecules appears to be frequently intertwined with cellular mechanisms of rejection, and to play a role in ductopenia development.
Subject(s)
ABO Blood-Group System/immunology , Bile Duct Diseases/etiology , Graft Rejection/immunology , Histocompatibility Antigens Class I/immunology , Isoantibodies/blood , Liver Transplantation/immunology , Tissue Donors , Adolescent , Adult , Aged , Bile Duct Diseases/pathology , Complement C4b/immunology , Complement C4b/metabolism , Female , Flow Cytometry , Humans , Liver Transplantation/mortality , Male , Middle Aged , Peptide Fragments/immunology , Peptide Fragments/metabolism , Risk Factors , Transplantation, Homologous/immunology , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Laparoscopic ventral hernia repair in comparison to open herniorrhaphy results in reduced length of stay, less post-operative pain, earlier return to work, and reduced complications for the repair of complex ventral hernias. The laparoscopic approach has been the standard of care for complex or large ventral hernias for non-pregnant patients over the past decade. Despite evidence that demonstrates that laparoscopy is safe during pregnancy, there is currently no consensus regarding the indications, contraindications, patient selection and post-operative care of pregnant patients evaluated for laparoscopic ventral herniorrhaphy. METHODS: The medical records of our pregnant patient who underwent laparoscopic ventral herniorrhaphy were reviewed for demographics, operative indications, surgical technique, perioperative complications, recurrence, and outcome of the pregnancy. A Medline search using the terms: laparoscopy, surgery, and pregnancy was performed to review the literature from 1997 to 2007. RESULTS: This case report represents the first published description of a safe and successful laparoscopic approach to the repair of a complex ventral hernia in a woman at 21 weeks gestation. The discussion reviews the current literature regarding the safety of laparoscopy in pregnant women and highlights techniques to reduce perioperative morbidity and risk to the fetus. CONCLUSIONS: Laparoscopic ventral hernia repair can be safe during pregnancy with appropriate fetal monitoring and consideration of physiologic changes that occur during parturition. Elective procedures should be delayed until after delivery and all semi-elective surgeries until organogenesis is completed during the second trimester.
