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Modeling Chemotherapy Resistant Leukemia In Vitro
Published on: February 9, 2016
Lysophospholipids secreted by splenic macrophages induce chemotherapy resistance via interference with the DNA damage
Julia M Houthuijzen1, Laura G M Daenen2, Jeanine M L Roodhart2
1Department of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Abstract:
Host responses to systemic anti-cancer treatment play important roles in the development of anti-cancer drug resistance. Here we show that F4/80(+)/CD11b(low) splenocytes mediate the resistance to DNA-damaging chemotherapeutics induced by two platinum-induced fatty acids (PIFAs), 12-S-keto-5,8,10-heptadecatrienoic acid and 4,7,10,13-hexadecatetraenoic acid (16:4(n-3)) in xenograft mouse models. Splenectomy or depletion of splenic macrophages by liposomal clodronate protects against PIFA-induced chemoresistance. In addition, we find that 12-S-HHT, but not 16:4(n-3), functions via leukotriene B4 receptor 2 (BLT2). Genetic loss or chemical inhibition of BLT2 prevents 12-S-HHT-mediated resistance. Mass spectrometry analysis of conditioned medium derived from PIFA-stimulated splenic macrophages identifies several lysophosphatidylcholines as the resistance-inducing molecules. When comparing cisplatin and PIFA-treated tumours with cisplatin alone treated tumours we found overall less γH2AX, a measure for DNA damage. Taken together, we have identified an intricate network of lysophospholipid signalling by splenic macrophages that induces systemic chemoresistance in vivo via an altered DNA damage response.
Insights
Splenic macrophages induce chemoresistance to platinum-based drugs through lysophospholipid signaling. Inhibiting this pathway, particularly leukotriene B4 receptor 2 (BLT2), can overcome drug resistance in cancer treatment.
Area of Science:
- Immunology
- Cancer Biology
- Pharmacology
Background:
- Host responses significantly influence anti-cancer drug efficacy.
- Drug resistance is a major challenge in cancer therapy, often mediated by complex biological mechanisms.
Purpose of the Study:
- To investigate the role of splenic macrophages in platinum-induced fatty acid (PIFA)-mediated chemoresistance.
- To identify the molecular mechanisms underlying PIFA-induced chemoresistance.
Main Methods:
- Utilized xenograft mouse models to study chemoresistance.
- Employed splenectomy and liposomal clodronate for macrophage depletion.
- Investigated the function of 12-S-keto-5,8,10-heptadecatrienoic acid (12-S-HHT) via leukotriene B4 receptor 2 (BLT2).
- Performed mass spectrometry to identify signaling molecules.
Main Results:
- F4/80(+)/CD11b(low) splenocytes were identified as mediators of chemoresistance.
- Splenectomy or macrophage depletion abrogated PIFA-induced chemoresistance.
- 12-S-HHT mediated resistance through BLT2, which was blocked by genetic or chemical inhibition.
- Lysophosphatidylcholines were identified as resistance-inducing molecules from PIFA-stimulated splenic macrophages.
- Reduced DNA damage marker (γH2AX) was observed in tumors treated with cisplatin and PIFA compared to cisplatin alone.
Conclusions:
- Splenic macrophages orchestrate systemic chemoresistance via lysophospholipid signaling.
- The 12-S-HHT/BLT2 axis is a key component of this resistance mechanism.
- Targeting this macrophage-mediated signaling pathway offers a potential strategy to enhance chemotherapy effectiveness.
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