title: Platelet-derived growth factor primes cancer-associated fibroblasts for apoptosis.
abstract: Desmoplastic malignancies such as cholangiocarcinoma (CCA) are characterized by a dense stroma containing an abundance of myofibroblasts termed cancer-associated fibroblasts (CAF). The CAF phenotype represents an "activated state" in which cells are primed for cell death triggered by BH3 mimetics. Accordingly, this primed state may be therapeutically exploited. To elucidate the mechanisms underlying this poorly understood apoptotic priming, we examined the role of platelet-derived growth factor (PDGF) in CAF priming for cell death given its prominent role in CAF activation. PDGF isomers PDGF-B and PDGF-D are abundantly expressed in CCA cells derived from human specimens. Either isomer sensitizes myofibroblasts to cell death triggered by BH3 mimetics. Similar apoptotic sensitization was observed with co-culture of myofibroblasts and CCA cells. Profiling of Bcl-2 proteins expressed by PDGF-primed myofibroblasts demonstrated an increase in cellular levels of Puma. PDGF-mediated increases in cellular Puma levels induced proapoptotic changes in Bak, which resulted in its binding to Bcl-2. Short hairpin RNA-mediated down-regulation of Puma conferred resistance to PDGF-mediated apoptotic priming. Conversely, the BH3 mimetic navitoclax disrupted Bcl-2/Bak heterodimers, allowing Bak to execute the cell death program. Treatment with a Bcl-2-specific BH3 mimetic, ABT-199, reduced tumor formation and tumor burden in a murine model of cholangiocarcinoma. Collectively, these findings indicate that apoptotic priming of CAF by PDGF occurs via Puma-mediated Bak activation, which can be converted to active full-blown apoptosis by navitoclax or ABT-199 for therapeutic benefit.
authors: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905.
authors: Sumera I
authors: SI
authors: Ilyas
authors: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich 8091, Switzerland, and.
authors: Joachim C
authors: JC
authors: Mertens
authors: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905.
authors: Steven F
authors: SF
authors: Bronk
authors: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905.
authors: Petra
authors: P
authors: Hirsova
authors: Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905.
authors: Haiming
authors: H
authors: Dai
authors: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905.
authors: Lewis R
authors: LR
authors: Roberts
authors: Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905.
authors: Scott H
authors: SH
authors: Kaufmann
authors: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905,. Electronic address: gores.gregory@mayo.edu.
authors: Gregory J
authors: GJ
authors: Gores
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002460:Cell Line; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D010446:Peptide Fragments / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C494772:BAK1 protein, human; C474007:Bax protein (53-86); D019086:Bridged Bicyclo Compounds, Heterocyclic; D010446:Peptide Fragments; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; C579720:venetoclax; C528561:navitoclax
keywords: Apoptosis; B-cell Lymphoma 2 (Bcl-2); BH3 Mimetics; Cancer Biology; Cholangiocarcinoma; Myofibroblast; PDGF; Tumor Microenvironment