Bystander effects are induced by CENU treatment and associated with altered protein secretory activity of treated tumor cells A relay for chemotherapy?

In a previous study, it was reported that secondary untreated melanoma tumors implanted several weeks after and at distance from primary chloroethylnitrosourea (CENU)‐treated tumors underwent differentiation and growth inhibition. To see whether the primary treated tumor released soluble factors tha...

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Bibliographic Details
Published in:International journal of cancer 2006-09, Vol.119 (5), p.992-1004
Main Authors: Demidem, Aicha, Morvan, Daniel, Madelmont, Jean Claude
Format: Article
Language:English
Subjects:
Actins - analysis
Angiogenesis Inhibitors - pharmacology
Animals
Antineoplastic agents
Antineoplastic Agents - pharmacology
Biological and medical sciences
Bystander Effect - drug effects
bystander effects
Cell Proliferation - drug effects
Chemotherapy
chloroethylnitrosoureas
distant double tumor models
Down-Regulation - drug effects
Electrophoresis, Gel, Two-Dimensional
Ethylnitrosourea - analogs & derivatives
Ethylnitrosourea - pharmacology
Flow Cytometry
Gene Expression Regulation, Neoplastic - drug effects
growth inhibition
Heat-Shock Proteins - analysis
Intracellular Signaling Peptides and Proteins
Magnetic Resonance Spectroscopy - methods
Male
Medical sciences
Melanoma - blood supply
Melanoma - drug therapy
Melanoma - metabolism
Melanoma - pathology
Mice
Mice, Inbred C57BL
Neoplasm Proteins - analysis
Neoplasm Proteins - drug effects
Neoplasm Proteins - secretion
Pharmacology. Drug treatments
Phosphatidylethanolamine Binding Protein - analysis
Protein-Serine-Threonine Kinases - analysis
proteomics
rho-Associated Kinases
Tumors
Up-Regulation - drug effects
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Summary:In a previous study, it was reported that secondary untreated melanoma tumors implanted several weeks after and at distance from primary chloroethylnitrosourea (CENU)‐treated tumors underwent differentiation and growth inhibition. To see whether the primary treated tumor released soluble factors that mediated the secondary tumor response, serum transfer experiments were performed in vivo. Administration of serum from CENU‐treated tumor‐bearing donors arrested tumor proliferation, decreased vessel formation and induced tumor metabolite alterations encompassing glutathione decrease and polyunsaturated fatty acid and phosphoethanolamine increase. These changes mimicked secondary tumor phenotype. To reproduce the model in vitro, cell culture supernatant transfer experiments were performed. CENU‐treated cell cultures showed polyploidy and reactive oxygen species (ROS) production. Cell cultures challenged by a conditioned medium of CENU‐treated cells underwent growth inhibition, cytoskeleton disorders, cytokinesis retardation, metabolite alterations, glutathione decrease and phosphoethanolamine increase, without ROS elicitation. Proteomics of CENU‐treated cell conditioned media revealed altered protein secretion activity by CENU‐treated cells. Among de novo secreted proteins, the most expressed were phosphatidylethanolamine‐binding protein (PEBP), cardiovascular heat shock protein (cHsp), Rho‐associated coiled‐coil forming kinase 2 (ROCK) and actin fragments. These proteins testified of cytoskeleton disorders, growth inhibition and metabolite alterations. This article demonstrates the release by CENU‐treated tumors of growth inhibitory differentiation‐inducing soluble factors. These factors mediate remote bystander effects and attest persistent biological activity of residual tumors after chemotherapy. © 2006 Wiley‐Liss, Inc.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.21761