Embedded Three-Dimensional Tumour Spheroid Models

Embedded spheroid models recreate the complex interactions between cells and extracellular matrix and cell types within the contents of secondary cell types and tumour heterogeneity. The combination of natural matrices with spheroids lends itself to study cancer invasion, progression and response to treatment and drug responses (1).

Tumours do not exist as a homogenous population of malignant cells but rather as a heterogeneous population of malignant cells and their assorted support of various tumour-associated cells that includes macrophages, fibroblasts, and immune cells (1).

2D Versus 3D cultures

A review of genetic differences in cells cultured in 2D versus 3D found upregulation of cell cycling, metabolism and turnover of macromolecules, and hence enabling enhanced proliferation. Culturing cells in a 2D monolayer produces several downstream effects that differentiate it from cells present in a 3D tumour microenvironment (2).

Thus, for applications in drug discovery and drug delivery, the change from 2D to 3D cell cultures dramatically increases the robustness of cell to toxicity in both normal and cancerous ones, highlighting the need for 3D cell cultures (3,4).

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Yet, another factor that differentiates cells in a monolayer form from a 3D tumour is the tumour macrostructure and macro environment that it supports. Microstructure represents a microenvironment that differs from normal tissue in term of oxygenation, pH, perfusion, and metabolic states. After tumour cell reaches 2mm3 in size, diffusion supplies insufficient oxygen for tumour thus affecting its hypoxic state, linked to hypoxia the extracellular pH of a tumour is often lower in range of 6-7 than a normal tissue 7.4 due to use of glycolysis as an energy source for hypoxic cells. Hence, the improper development of a mature vascularized system, translates to hypoxic regions even in vascularised tumours. The result is a heterogenous range of metabolic states (5,6,7).


1. Kristie M. Tevis,1 Yolonda L. Colson,2, * and Mark W. Grinstaff1, *embedded Spheroids as Models of the Cancer Microenvironment, PubMed Central,

2. Almany L, Seliktar D. Biomaterials. 2005; 26:2467

3. Birgersdotter A, Sandberg R, Ernberg I. Semin. Cancer Biol. 2005; 15:405.

4. Loessner D, Stok KS, Lutolf MP, Hutmacher DW, Clements JA, Rizzi SC. Biomaterials. 2010; 31:8494.

5. Sun T, Jackson S, Haycock JW, MacNeil S. J. Biotechnol. 2006; 122:372.

6. Danhier F, Feron O, Préat V. J. Control. Release. 2010; 148:135.

7. Bergers G, Benjamin LE. Nat. Rev. Cancer. 2003; 3:401