Abstract
Acute lymphoblastic leukemia (ALL) initiates and progresses in the bone marrow, and as such, the marrow microenvironment is a critical regulatory component in development of this cancer. However, ALL studies were conducted mainly on flat plastic substrates, which do not recapitulate the characteristics of marrow microenvironments. To study ALL in a model of in vivo relevance, we have engineered a 3-D microfluidic cell culture platform. Biologically relevant populations of primary human bone marrow stromal cells, osteoblasts and human leukemic cells representative of an aggressive phenotype were encapsulated in 3-D collagen matrix as the minimal constituents and cultured in a microfluidic platform. The matrix stiffness and fluidic shear stress were controlled in a physiological range. The 3-D microfluidic as well as 3-D static models demonstrated coordinated cell-cell interactions between these cell types compared to the compaction of the 2-D static model. Tumor cell viability in response to an antimetabolite chemotherapeutic agent, cytarabine in tumor cells alone and tri-culture models for 2-D static, 3-D static and 3-D microfluidic models were compared. The present study showed decreased chemotherapeutic drug sensitivity of leukemic cells in 3-D tri-culture models from the 2-D models. The results indicate that the bone marrow microenvironment plays a protective role in tumor cell survival during drug treatment. The engineered 3-D microfluidic tri-culture model enables systematic investigation of effects of cell-cell and cell-matrix interactions on cancer progression and therapeutic intervention in a controllable manner, thus improving our limited comprehension of the role of microenvironmental signals in cancer biology.
Highlights
Acute lymphoblastic leukemia (ALL), a cancer that starts from overproduction of cancerous, immature white blood cells in bone marrow and spreads to other organs rapidly, affects both children and adults
Tumor cells, bone marrow stromal cells (BMSC) and Human osteoblasts (HOB) embedded in collagen I were injected through the “Cells In” inlet into four microchannels, which were 500 μm in width, 75 μm in height and 2 cm in length (Fig 2A and 2B)
The determination of the microchannel dimensions considered the nutrient diffusion limits and provided the space for tumor cells to interact with other cells and matrix [44]
Summary
Acute lymphoblastic leukemia (ALL), a cancer that starts from overproduction of cancerous, immature white blood cells (lymphoblasts) in bone marrow and spreads to other organs rapidly, affects both children and adults. Bone marrow provides the most common site of leukemia relapse, indicating that this unique anatomical niche is conducive to ALL cell survival in vivo [4,5]. It is a site of metastasis for many solid tumors including breast, lung, and prostate cancer [6,7,8]. Held in common to all tumor cells that either originate from or migrate to this site is the propensity to be refractory to treatment, positioning them to contribute to relapse of disease. It is important to model this site appropriately to investigate tumor cell survival in this context and to develop drug screens that incorporate its complexity
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