Rise of the machines: Towards the industrial-scale generation of cellular platforms for the screening of anti-cancer stem cells agents

Vuelta de Obligado, Argentina - January 20, 2016

Contributed by

Luciano Vellón, PhD

Investigador Adjunto CONICET

Laboratorio de Células Madre/Stem Cells Lab.

Instituto de Biología y Medicina Experimental (Ibyme)-CONICET

Vuelta de Obligado 2490, C.A.B.A, Argentina

Teléfono/Phone: +54 11 47832869 Int/Ext 261


One of the main barriers for the development of cancer stem cells-targeted therapies is their scarcity in vivo, limiting their availability as experimental systems for pharmaceutical development, which raises the need for the production at a scale large enough to fulfil academia and industry requirements. Thus, developing forefront, high-throughput screening platforms to identify cytotoxic inhibitors or differentiation-promoting agents targeting cancer stem cells would require the optimization of a series of bioprocesses to enable the massive culture of undifferentiated cancer cells. The endpoint of such bioprocesses would be high-content, multiwell plate formats that could then be available for the automatic application of multiple (known or experimental) anti-cancer compounds and the cellular response in terms of viability and/or stemness markers. However, when it comes to these applications, it should be taken into consideration that cells must be cultured in a reproducible manner without loss of function, and in sufficient numbers to create cost-effective therapeutic products. Routinely used cell culture techniques are material-, labour-consuming tasks that generate a great amount of inter-culture variability and contamination risks. Traditional cell culture at a large scale is also cost-ineffective in terms of the high investment in cell culture media and growth factors.

Unlike the seemingly never-ending saga of Terminator movies, in which the future humans wage a long war against an enemy known as “The Machines”, bioreactors have risen and saved the day, playing a pivotal role in the history of animal cell production at a large scale by offering great advantages in the monitoring and reproducibility of the cell cultures. Indeed, physiological and hydrodynamic factors affecting growth and differentiation of normal and cancer stem cells, such as dissolved oxygen, pH, nutrients availability and agitation speed can now be controlled more efficiently. Although some drawbacks such as differentiation and clumping of the cellular aggregates must be avoided by fine-tuning cell culture conditions, bioreactors also provide a great platform to regulate the stem cell microenvironment or “niche” to impact stem cell fate decision. Niche factors that can be controlled in bioreactors include oxygen, extracellular matrix (synthetic and de-cellularized), paracrine/autocrine signalling and physical forces (i.e. mechanical force, electrical force and flow shear) all of which play a critical role in deriving functional, terminally differentiated cell populations from stem cells.

Recently, microfluidic devices and micro-bioreactors have been used for high throughput regulation of environmental factors to better understand stem cell niches for drug screening. Considering that cancer occurs through the aberrant differentiation of the corresponding normal tissue, it is reasonable to think of re-engineering the parameters that regulate cell differentiation in bioreactors to resemble, at least in part, the pathological environmental conditions that mediate stem-like cellular state transitions in tumors. Collectively, these devices would offer a unique opportunity for the highly accurate recapitulation of putative environmental factors (i.e. growth factors, glycolytic metabolism-promoting factors) key to the generation of stem-like cellular states. Mimicking these environments in high volume reactors will create enough material to guarantee industrial scale production and standardization, allowing for the commercialisation of ready-to-use solutions designed to accelerate drug discovery targeting cancer stem cells. Besides, these platforms will allow valuable insights into the complex mechanisms that govern stem cell function acquisition within a tumor, providing a tool for the ex-vivo examination of tumor evolution and therapeutic evaluation of novel compounds.

As anti-cancer stem cell drug design becomes mainstream, so will systems for production of industry-grade testing materials, benefiting the industry as a whole.

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