Intrinsic and evasive antiangiogenic drug (AAD) resistance is frequently developed in cancer patients, and molecular mechanisms underlying AAD resistance remain largely unknown. Here we describe AAD-triggered, lipid-dependent metabolic reprogramming as an alternative mechanism of AAD resistance. Unexpectedly, tumor angiogenesis in adipose and non-adipose environments is equally sensitive to AAD treatment. AAD-treated tumors in adipose environment show accelerated growth rates in the presence of a minimal number of microvessels. Mechanistically, AAD-induced tumor hypoxia initiates the fatty acid oxidation metabolic reprogramming and increases uptake of free fatty acid (FFA) that stimulates cancer cell proliferation. Inhibition of carnitine palmitoyl transferase 1A (CPT1) significantly compromises the FFA-induced cell proliferation. Genetic and pharmacological loss of CPT1 function sensitizes AAD therapeutic efficacy and enhances its anti-tumor effects. Together, we propose an effective cancer therapy concept by combining drugs that target angiogenesis and lipid metabolism.
Pubmed ID: 29861385 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This monoclonal targets I-A/I-E
View all literature mentionsThis monoclonal targets Ly-6C
View all literature mentionsThis monoclonal targets Ly-6G
View all literature mentionsThis monoclonal targets CD11c
View all literature mentionsThis monoclonal targets NK-1.1
View all literature mentionsThis monoclonal targets CD45R
View all literature mentionsThis monoclonal targets CD45
View all literature mentionsThis monoclonal targets CD11b
View all literature mentionsThis monoclonal targets CD8a
View all literature mentionsThis monoclonal targets CD4
View all literature mentionsThis monoclonal targets CD3epsilon
View all literature mentionsThis monoclonal targets CD16/CD32
View all literature mentionsThis unknown targets Goat IgG (H+L)
View all literature mentionsThis unknown targets Goat IgG (H+L)
View all literature mentionsThis polyclonal targets NG2 Chondroitin Sulfate Proteoglycan
View all literature mentionsThis polyclonal targets CD31/PECAM-1
View all literature mentionsThis unknown targets Rabbit IgG (H+L)
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis unknown targets Rat IgG (H+L)
View all literature mentionsThis polyclonal targets Laminin
View all literature mentionsThis polyclonal targets Collagen IV antibody
View all literature mentionsThis polyclonal targets Fibronectin
View all literature mentionsThis monoclonal targets Mouse F4/80 ANTIGEN
View all literature mentionsThis polyclonal targets Iba1
View all literature mentionsThis unknown targets Carbonic Anhydrase IX
View all literature mentionsThis polyclonal targets Cleaved Caspase-3 (Asp175)
View all literature mentionsThis monoclonal targets Ki-67
View all literature mentionsThis unknown targets IgG
View all literature mentionsThis unknown targets IgG
View all literature mentionsThis monoclonal targets beta-actin
View all literature mentionsThis polyclonal targets HIF1 alpha antibody
View all literature mentionsThis monoclonal targets AMPK
View all literature mentionsThis monoclonal targets AMPK-alpha, phospho (Thr172)
View all literature mentionsThis isotype control targets Not Applicable
View all literature mentionsThis monoclonal targets CSF1R (CD115)
View all literature mentionsThis isotype control targets Not Applicable
View all literature mentionsMus musculus with name CB17/Icr-Prkdcscid/IcrIcoCrl from IMSR.
View all literature mentionsMus musculus with name C57BL/6NJ from IMSR.
View all literature mentions