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.
Highlights
Lymphoma is the most common blood cancer
As tumor cells grown in 3D models that accurately reflect the 3D nature of the in vivo microenvironment are considered to exhibit a higher level of drug resistance over those in traditional 2D monolayer, we hypothesized that the 3D multicellular lymphoma spheroids grown within alginate/marine collagen/agarose (AmCA) hydrogels may exhibit enhanced chemotherapeutic resistance to antitumor agents for lymphoma compared to cells cultured in 2D
On day 10, when multicellular spheroids were formed in 3D conditions, the expression of the following four important chemoresistance genes was compared in the cells grown in 2D or 3D cultures: (1) multidrug resistance protein 1 (MDR1) which is known as permeability glycoprotein (P-glycoprotein, P-gp) or ATP-binding cassette subfamily B member 1 (ABCB1), (2) multidrug resistance-associated protein 1 (MRP1, ABCC1), (3) breast cancer resistance www.impactjournals.com/oncotarget protein (BCRP, ABCG2), and (4) hypoxia-inducible factor-1α (HIF-1α)
Summary
The incidence of malignant lymphoma around the world has been increasing at a rate of 3–4% over the last four decades. This is most likely due to improved diagnostic techniques, growth and aging of the world population, the recent trends in the acquired immune deficiency syndrome (AIDS) epidemic, and the rising number of cancer-causing behaviors the reasons behind this lymphoma epidemic are still poorly understood [1]. A major hurdle on the road to the discovery and development of new drugs is the lack of adequate testing models. One www.impactjournals.com/oncotarget of the most important steps in developing a potential therapeutic drug is target identification
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