Combined targeting of TGF-β, EGFR and HER2 suppresses lymphangiogenesis and metastasis in a pancreatic cancer model.
Pancreatic ductal adenocarcinomas (PDACs) are aggressive with frequent lymphatic spread. By analysis of data from The Cancer Genome Atlas, we determined that ~35% of PDACs have a pro-angiogenic gene signature. We now show that the same PDACs exhibit increased expression of lymphangiogenic genes and lymphatic endothelial cell (LEC) markers, and that LEC abundance in human PDACs correlates with endothelial cell microvessel density. Lymphangiogenic genes and LECs are also elevated in murine PDACs arising in the KRC (mutated Kras; deleted RB) and KIC (mutated Kras; deleted INK4a) genetic models. Moreover, pancreatic cancer cells (PCCs) derived from KRC tumors express and secrete high levels of lymphangiogenic factors, including the EGF receptor ligand, amphiregulin. Importantly, TGF-β1 increases lymphangiogenic genes and amphiregulin expression in KRC PCCs but not in murine PCCs that lack SMAD4, and combinatorial targeting of the TGF-β type I receptor (TβRI) with LY2157299 and EGFR/HER2 with lapatinib suppresses tumor growth and metastasis in a syngeneic orthotopic model, and attenuates tumor lymphangiogenesis and angiogenesis while reducing lymphangiogenic genes and amphiregulin and enhancing apoptosis. Therefore, this combination could be beneficial in PDACs with lymphangiogenic or angiogenic gene signatures.
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; The Pancreatic Cancer Signature Center at Indiana University Simon Cancer Center, Indianapolis, IN 46202, USA. Electronic address: ajgore@iu.edu.
Jesse
J
Gore
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Imade E
IE
Imasuen-Williams
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Abass M
AM
Conteh
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Kelly E
KE
Craven
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Monica
M
Cheng
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; The Pancreatic Cancer Signature Center at Indiana University Simon Cancer Center, Indianapolis, IN 46202, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Murray
M
Korc
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000556:secondary; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D016161:Genes, Retinoblastoma; D020022:Genetic Predisposition to Disease; D006801:Humans; D000077341:Lapatinib; D042583:Lymphangiogenesis / Q000187:drug effects* / Q000235:genetics; D008297:Male; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009154:Mutation; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D019941:Cyclin-Dependent Kinase Inhibitor p16; D066246:ErbB Receptors; D000077341:Lapatinib; D017346:Protein Serine-Threonine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D011720:Pyrazoles; D011799:Quinazolines; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C557799:LY-2157299; C541485:EGFR protein, mouse; C524056:Erbb2 protein, mouse; C495971:Hras protein, mouse
Lymphangiogenesis; Mouse model; Pancreatic cancer; TCGA; TGF-β