Targeting the Notch pathway: A potential therapeutic approach for desmoid tumors.
BACKGROUND
Desmoid tumors (DTs) are rare mesenchymal lesions that can recur repeatedly. When it is feasible, DTs are surgically resected; however, this often results in high recurrence rates. Recently, treatment with PF-03084014, a potent γ-secretase inhibitor, has been shown to have antitumor activity in several tumor types by affecting the WNT/β-catenin pathway. Consequently, Notch pathway inhibition by PF-03084014 might be a promising approach for DT treatment.


METHODS
The expression of Notch pathway components was analyzed in DT tissues and cell strains with immunohistochemistry and Western blotting, respectively. A panel of DT cell strains was exposed to PF-03084014 and evaluated for cell proliferation. Antitumor effects were assessed via cell cycle, apoptosis, and migration and invasion analysis. Cells treated with PF-03084014 were characterized with a gene array analysis combined with Ingenuity Pathway Analysis.


RESULTS
The results showed that Notch pathway components were expressed at different levels in DTs. Hes1 (Hes Family BHLH Transcription Factor 1) was overexpressed in DT tumors versus dermal scar tissue, and PF-03084014 caused significant decreases in Notch intracellular domain and Hes1 expression in DT cell strains. PF-03084014 decreased DT cell migration and invasion and also caused cell growth inhibition in DT cell strains, most likely through cell cycle arrest. Gene array analysis combined with Ingenuity Pathway Analysis showed that Wnt1-inducible signaling pathway protein 2 possibly regulated Notch and WNT pathways after treatment with PF-03084014 through integrin.


CONCLUSIONS
Our findings suggest that the Notch pathway is an important DT therapeutic target. Furthermore, PF-03084014 has significant antitumor activity against DTs, and it may be an alternative strategy for DT treatment.
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Orthopedics, Taihe Hospital, Hubei University of Medicine, Shiyan, China.
Hui
H
Shang
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Surgical Oncology, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio.|Department of Investigative Pathology, International Center for Research, A. C. Camargo Cancer Center, São Paulo, Brazil.
Danielle
D
Braggio
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Ya-Jung
YJ
Lee
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Ghadah A
GA
Al Sannaa
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
Chad J
CJ
Creighton
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Svetlana
S
Bolshakov
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Sarcoma Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Alexander J F
AJ
Lazar
Surgery B, Sheba Medical Center, Tel Aviv, Israel.
Dina
D
Lev
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Surgical Oncology, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio.|Sarcoma Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Raphael E
RE
Pollock
D055511:CCN Intercellular Signaling Proteins / Q000502:physiology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018222:Desmoid Tumors / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D006801:Humans; D009361:Neoplasm Invasiveness; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000502:physiology; D012097:Repressor Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
D055511:CCN Intercellular Signaling Proteins; C413323:CCN5 protein, human; D051880:Receptors, Notch; D012097:Repressor Proteins; D013764:Tetrahydronaphthalenes; D014633:Valine; C550722:nirogacestat
Notch; desmoid tumors; signaling pathways; wingless; γ-secretase inhibitor