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Abstract Background Cell transdifferentiation is characterized by loss of some phenotypes along with acquisition of new phenotypes in differentiated cells. The differentiated state of a given cell is not irreversible. It depends on the up- and downregulation exerted by specific molecules. Results We report here that HCCR-1, previously shown to play an oncogenic role in human cancers, induces epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) in human and mouse, respectively. The stem cell factor receptor CD117/c-Kit was induced in this transdifferentiated (EMT) sarcoma tissues. This MET occurring in HCCR-1 transfected cells is reminiscent of the transdifferentiation process during nephrogenesis. Indeed, expression of HCCR-1 was observed during the embryonic development of the kidney. This suggests that HCCR-1 might be involved in the transdifferentiation process of cancer stem cell. Conclusions Therefore, we propose that HCCR-1 may be a regulatory factor that stimulates morphogenesis of epithelia or mesenchyme during neoplastic transformation.

Simple Summary: Two vascular endothelial growth factor (VEGF) receptors, FLT-1 and KDR, are expressed preferentially in proliferating endothelium. There is increasing evidence that soluble VEGF receptor domains that compete for VEGF binding may inhibit tumor angiogenesis, growth and metastatic spread. We tested whether soluble FLT-1 (sFLT-1) could inhibit breast cancer tumor growth in mice by blocking angiogenesis. A viral vector carrying the sflt-1 cDNA (Adsflt) was used to overexpress the receptor in MCF-7 cells, which produce VEGF. After six weeks, tumors were treated either with Adsflt or a negative control virus. After six months, average tumor volume in the Adsflt-treated group was decreased by 91% and vascular density was reduced 50%, relative to negative controls (p < 0.05), yet mice treated with Adsflt showed no delay in healing cutaneous wounds. These results provide evidence that viral sFLT-1 overexpression may be an effective anti-angiogenic therapy for cancer without the risk of systemic anti-angiogenic effects. Two vascular endothelial growth factor (VEGF) receptors, FLT-1 and KDR, are expressed preferentially in proliferating endothelium. There is increasing evidence that recombinant, soluble VEGF receptor domains interfering with VEGF signaling may inhibit in vivo neoangiogenesis, tumor growth and metastatic spread. We hypothesized that a soluble form of FLT-1 receptor (sFLT-1) could inhibit the growth of pre-established tumors via an anti-angiogenic mechanism. A replication-deficient adenovirus (Ad) vector carrying the sflt-1 cDNA (Adsflt) was used to overexpress the sFLT-1 receptor in a breast cancer animal model. MCF-7 cells, which produce VEGF, were used to establish solid tumors in the mammary fat pads of female nude mice. After six weeks, tumors were injected either with Adsflt or a negative control virus (AdCMV.βgal). After six months, average tumor volume in the Adsflt-infected group (33 ± 22 mm3) decreased by 91% relative to that of the negative control group (388 ± 94 mm3; p < 0.05). Moreover, 10 of 15 Adsflt-infected tumors exhibited complete regression. The vascular density of Adsflt-infected tumors was reduced by 50% relative to that of negative controls (p < 0.05), which is consistent with sFLT-1-mediated tumor regression through an anti-angiogenic mechanism. Moreover, cell necrosis and fibrosis associated with long-term regression of Adsflt–infected tumors were preceded by apoptosis of tumor vascular endothelial cells. Mice treated with Adsflt intratumorally showed no delay in the healing of cutaneous wounds, providing preliminary evidence that Ad-mediated sFLT-1 overexpression may be an effective anti-angiogenic therapy for cancer without the risk of systemic anti-angiogenic effects. [ABSTRACT FROM AUTHOR]

Hepatocyte growth factor (HGF) is critical for tissue homeostasis and repair in many organs including the lung, heart, kidney, liver, nervous system, and skin. HGF is a heterodimeric protein containing 20 disulfide bonds distributed among an amino-terminal hairpin, four kringle domains, and a serine protease-like domain. Due to its complex structure, recombinant production of HGF in prokaryotes requires denaturation and refolding, processes that are impractical for large-scale manufacture. Thus, pharmaceutical quantities of HGF are not available despite its potential applications. A fragment of the Listeria monocytogenes internalin B protein from amino acids 36-321 ([InlB.sub.36-321]) was demonstrated to bind to and partially activate the HGF receptor Met. [InlB.sub.36-321] has a stable [beta]-sheet structure and is easily produced in its native conformation by Escherichia coli. We cloned [InlB.sub.36-321] (1x[InlB.sub.36-321]) and engineered a head-to-tail repeat of [InlB.sub.36-321] with a linker peptide (2x[InlB.sub.36-321]); 1x[InlB.sub.36-321] and 2x[InlB.sub.36-321] were purified from E. coli. Both 1x and 2x[InlB.sub.36-321] activated the Met tyrosine kinase. We subsequently compared signal transduction of the two proteins in primary lung endothelial cells. 2x[InlB.sub.36-321] activated ERK1/2, STAT3, and phosphatidylinositol 3-kinase/Akt pathways, whereas 1x[InlB.sub.36-321] activated only STAT3 and ERK1/2. The 2x[InlB.sub.36-321] promoted improved motility compared with 1x[InlB.sub.36-321] and additionally stimulated proliferation equivalent to full-length HGF. Both the 1x and 2x[InlB.sub.36-321] prevented apoptosis by the profibrotic peptide angiotensin II in cell culture and ex vivo lung slice cultures. The ease of large-scale production and capacity of 2x[InlB.sub.36-321] to mimic HGF make it a potential candidate as a pharmaceutical agent for tissue repair. apoptosis, angiotensin II; Akt; ERK1/2 doi: 10.1152/ajplung.00094.2010.

Bleomycin, a chemotherapeutic agent, can cause pulmonary fibrosis in humans and is commonly used to induce experimental pulmonary fibrosis in rodents. In cell culture, bleomycin causes single- and double-stranded DNA breaks and produces reactive oxidative species, both of which require iron ([Fe.sup.2+]) and [O.sub.2]. The mechanism of bleomycin-induced apoptosis is controversial due to its complexity. We investigated bleomycin apoptotic signaling events in primary pulmonary endothelial cells. Time course experiments revealed that bleomycin induced apoptosis within 4 h. Caspase-8, the initiator caspase for the extrinsic pathway, was activated within 2 h and preceded activation of the effector caspases-3 and -6 (4 h). Caspase-9, the initiator of the intrinsic pathway and release of cytochrome c from the mitochondria were not detected at these time points. Bleomycin induced the expression of Bcl-2 and Bcl-[x.sub.L], Bcl-2 family member proteins that protect cells from the mitochondria-dependent intrinsic apoptosis. Real-time quantitative RT-PCR results demonstrated that. at 4-8 h, bleomycin induced expression of TNF and TNF receptor family genes known to induce the extrinsic apoptotic pathway. Silencing of the death receptor adaptor protein Fas-associated death domain by short interfering RNA significantly reduced bleomycin-induced apoptosis. Apoptosis was also abrogated by caspase-8 inhibition, but only slightly reduced by caspase-3 inhibition. Together, these data suggest that bleomycin initiates apoptosis via the extrinsic pathway. deoxyribonucleic acid damage; deoxyribonucleic acid laddering; death receptor; Fas-associated death domain; caspase doi: 10.1152/ajplung.00322.2009.