Multicellular tumor spheroids

Therapeutic Efficacy Of Multicellular Tumor Spheroids

Despite the much advancement seen in tumor related research and drug discovery, cancer research still experiences a significant amount of challenges due the complex behaviour of tumor cells. Multicellular tumor spheroids (MCTs) bear remarkable similarities to in vivo solid tumors and are thus presented as a viable candidate to examine and predict response to chemotherapy and radiotherapy. However the efficiency of MCTs as a reproducible model relies on the availability of appropriate evaluation methods.

Changes in shape and volume of MCTs

Drug and therapeutic efficacy of MCTs is firstly evaluated by changes in the shape and volume of the spheroids as a direct response to therapeutic intervention. With continuous drug treatment, these morphological changes are followed by alterations in cell-cell and cell – extracellular matrix (ECM) connections, leading to disruptions in cellular aggregations. As the cytotoxicity increases, the outer layer cells begins to fall away, ultimately resulting in the collapse of spherical shape. As treatment progresses, the volume of the spheroid also decreases in a dose dependent fashion (1-2).

Role of compactness and size in evaluating drug efficacy

Therapeutic efficacy of MCTs is also determined by the compactness of the spheroids. Compact spheroids exhibit higher drug resistance compared the loosely aggregated spheroids. This is primarily due to high content of ECM present in compact spheroids, hindering drug delivery to the core of the spheroid. Thus in order to obtain a reliable drug efficacy result the MCTs must be of a uniformly shaped and compact aggregate (3).

The size of the spheroid also plays a role in its drug response. Smaller spheroids are found more sensitive to therapeutic treatment, whereas larger spheroids indicate increased drug resistance (4-7). For example, doxorubicin (DOX), a chemotherapeutic drug is able to easily penetrate smaller MCF-7 spheroids, but is only able to affect the outer layer of the larger spheroids (8). Therefore, much attention is now being devoted to developing MCTS that are uniform, compact and homogenous in size, in order to be standardized as an appropriate solid tumor model that can be used on a high throughout platform.

Riferimenti

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7. Gaze MN, Mairs RJ, Boyack SM, Wheldon TE, Barrett A. 1’I-meta-iodobenzylguanidine therapy in neuroblastoma spheroids of diferent size. Br J Cancer. 1992;66(6):1048–52.

8. Deisboeck TS, Berens ME, Kansal AR, Torquato S, Stemmer-Rachamimov AO, Chiocca EA. Pattern of self-organization in tumour systems: complex growth dynamics in a novel brain tumour spheroid model. Cell Prolif. 2001;34(2):115–34