Co-targeting of Tiam1/Rac1 and Notch ameliorates chemoresistance against doxorubicin in a biomimetic 3D lymphoma model
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Muhammad Ikram1, Yeseon Lim1, Sun-Yong Baek1, Songwan Jin2, Young Hun Jeong3, Jong-Young Kwak4 and Sik Yoon1
1Department of Anatomy, Pusan National University School of Medicine, Yangsan 50612, Korea
2Department of Mechanical Engineering, Korea Polytechnic University, Siheung 15073, Korea
3Department of Mechanical Engineering, Kyungpook National University, Daegu 41566, Korea
4Department of Pharmacology, Ajou University School of Medicine, Suwon 16499, Korea
Sik Yoon, email: [email protected]
Keywords: tiam1; notch; chemoresistance; doxorubicin; 3D lymphoma model
Received: August 31, 2017 Accepted: November 16, 2017 Published: December 08, 2017
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.
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