Back to Search
Start Over
Co-targeting of Tiam1/Rac1 and Notch ameliorates chemoresistance against doxorubicin in a biomimetic 3D lymphoma model
- Source :
- Oncotarget
- Publication Year :
- 2017
- Publisher :
- Impact Journals, LLC, 2017.
-
Abstract
- Lymphoma is a heterogeneous disease with a highly variable clinical course and prognosis. Improving the prognosis for patients with relapsed and treatment-resistant lymphoma remains challenging. Current in vitro drug testing models based on 2D cell culture lack natural tissue-like structural organization and result in disappointing clinical outcomes. The development of efficient drug testing models using 3D cell culture that more accurately reflects in vivo behaviors is vital. Our aim was to establish an in vitro 3D lymphoma model that can imitate the in vivo 3D lymphoma microenvironment. Using this model, we explored strategies to enhance chemosensitivity to doxorubicin, an important chemotherapeutic drug widely used for the treatment of hematological malignancies. Lymphoma cells grown in this model exhibited excellent biomimetic properties compared to conventional 2D culture including (1) enhanced chemotherapy resistance, (2) suppressed rate of apoptosis, (3) upregulated expression of drug resistance genes (MDR1, MRP1, BCRP and HIF-1α), (4) elevated levels of tumor aggressiveness factors including Notch (Notch-1, -2, -3, and -4) and its downstream molecules (Hes-1 and Hey-1), VEGF and MMPs (MMP-2 and MMP-9), and (5) enrichment of a lymphoma stem cell population. Tiam1, a potential biomarker of tumor progression, metastasis, and chemoresistance, was activated in our 3D lymphoma model. Remarkably, we identified two synergistic therapeutic oncotargets, Tiam1 and Notch, as a strategy to combat resistance against doxorubicin in EL4 T and A20 B lymphoma. Therefore, our data suggest that our 3D lymphoma model is a promising in vitro research platform for studying lymphoma biology and therapeutic approaches.
- Subjects :
- 0301 basic medicine
tiam1
Population
Drug resistance
doxorubicin
Metastasis
03 medical and health sciences
0302 clinical medicine
In vivo
hemic and lymphatic diseases
medicine
Doxorubicin
education
education.field_of_study
business.industry
chemoresistance
3D lymphoma model
medicine.disease
Lymphoma
030104 developmental biology
Oncology
Cell culture
Tumor progression
030220 oncology & carcinogenesis
Cancer research
business
Research Paper
notch
medicine.drug
Subjects
Details
- ISSN :
- 19492553
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....7ac7d057c08d30b18e71df48b1a23737