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Essential operating principles for tumor spheroid growth.

Engelberg JA, Ropella GE, Hunt CA - BMC Syst Biol (2008)

Bottom Line: Each agent used an identical set of axiomatic operating principles.In sequence, we used the list of targeted attributes to falsify and revise these axioms, until the analogue exhibited behaviors and attributes that were within prespecified ranges of those targeted, thereby achieving a level of validation.The finalized analogue required nine axioms.

View Article: PubMed Central - HTML - PubMed

Affiliation: UCSF/UC Berkeley Joint Graduate Group in Bioengineering, University of California, San Francisco, CA, USA. jesse.engelberg@gmail.com

ABSTRACT

Background: Our objective was to discover in silico axioms that are plausible representations of the operating principles realized during characteristic growth of EMT6/Ro mouse mammary tumor spheroids in culture. To reach that objective we engineered and iteratively falsified an agent-based analogue of EMT6 spheroid growth. EMT6 spheroids display consistent and predictable growth characteristics, implying that individual cell behaviors are tightly controlled and regulated. An approach to understanding how individual cell behaviors contribute to system behaviors is to discover a set of principles that enable abstract agents to exhibit closely analogous behaviors using only information available in an agent's immediate environment. We listed key attributes of EMT6 spheroid growth, which became our behavioral targets. Included were the development of a necrotic core surrounded by quiescent and proliferating cells, and growth data at two distinct levels of nutrient.

Results: We then created an analogue made up of quasi-autonomous software agents and an abstract environment in which they could operate. The system was designed so that upon execution it could mimic EMT6 cells forming spheroids in culture. Each agent used an identical set of axiomatic operating principles. In sequence, we used the list of targeted attributes to falsify and revise these axioms, until the analogue exhibited behaviors and attributes that were within prespecified ranges of those targeted, thereby achieving a level of validation.

Conclusion: The finalized analogue required nine axioms. We posit that the validated analogue's operating principles are reasonable representations of those utilized by EMT6/Ro cells during tumor spheroid development.

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Related in: MedlinePlus

An SMS cross-section at 67 DAYS at high NUTRIENT level. SMS shape is no longer circular. Scale bar 100 μm. Parameter values were those listed in Table 2.
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Figure 5: An SMS cross-section at 67 DAYS at high NUTRIENT level. SMS shape is no longer circular. Scale bar 100 μm. Parameter values were those listed in Table 2.

Mentions: The AXIOMS used to manage CELL STRESS were effective at maintaining stable small and medium sized SMS. However, when growth was extended beyond 50 DAYS under high NUTRIENT, SMS began to lose their circular shapes. The 67-DAY old SMS in Fig. 5 is an example. Because of the stochastic nature of the events involving each CELL, the growth trajectories, shapes, and sizes of separate SMS executions can be different under identical conditions. For the same reason, small regional differences in large, mature SMS can gradually become amplified, resulting in large subregions having measurably different characteristics. This leads to an unstable system. Measures of SMS long-term growth at high and low NUTRIENT are provided in Additional file 1, Fig. S1. EMT6 spheroids do exhibit varied shapes during growth. However, we are not aware of in vitro observations that can be used to validate this SMS behavior, possibly because it is challenging (and expensive) to maintain large EMT6 spheroids in culture for 50 days or more (although Chignola et al. have maintained Rat 9L spheroids to 70 days [16]). If maintenance of generally circular shapes beyond 50 days under high NUTRIENT were to be added to the targeted attributes list, the current SMS would be falsified. Inclusion of additional mechanisms would be needed to reestablish validation.


Essential operating principles for tumor spheroid growth.

Engelberg JA, Ropella GE, Hunt CA - BMC Syst Biol (2008)

An SMS cross-section at 67 DAYS at high NUTRIENT level. SMS shape is no longer circular. Scale bar 100 μm. Parameter values were those listed in Table 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2667182&req=5

Figure 5: An SMS cross-section at 67 DAYS at high NUTRIENT level. SMS shape is no longer circular. Scale bar 100 μm. Parameter values were those listed in Table 2.
Mentions: The AXIOMS used to manage CELL STRESS were effective at maintaining stable small and medium sized SMS. However, when growth was extended beyond 50 DAYS under high NUTRIENT, SMS began to lose their circular shapes. The 67-DAY old SMS in Fig. 5 is an example. Because of the stochastic nature of the events involving each CELL, the growth trajectories, shapes, and sizes of separate SMS executions can be different under identical conditions. For the same reason, small regional differences in large, mature SMS can gradually become amplified, resulting in large subregions having measurably different characteristics. This leads to an unstable system. Measures of SMS long-term growth at high and low NUTRIENT are provided in Additional file 1, Fig. S1. EMT6 spheroids do exhibit varied shapes during growth. However, we are not aware of in vitro observations that can be used to validate this SMS behavior, possibly because it is challenging (and expensive) to maintain large EMT6 spheroids in culture for 50 days or more (although Chignola et al. have maintained Rat 9L spheroids to 70 days [16]). If maintenance of generally circular shapes beyond 50 days under high NUTRIENT were to be added to the targeted attributes list, the current SMS would be falsified. Inclusion of additional mechanisms would be needed to reestablish validation.

Bottom Line: Each agent used an identical set of axiomatic operating principles.In sequence, we used the list of targeted attributes to falsify and revise these axioms, until the analogue exhibited behaviors and attributes that were within prespecified ranges of those targeted, thereby achieving a level of validation.The finalized analogue required nine axioms.

View Article: PubMed Central - HTML - PubMed

Affiliation: UCSF/UC Berkeley Joint Graduate Group in Bioengineering, University of California, San Francisco, CA, USA. jesse.engelberg@gmail.com

ABSTRACT

Background: Our objective was to discover in silico axioms that are plausible representations of the operating principles realized during characteristic growth of EMT6/Ro mouse mammary tumor spheroids in culture. To reach that objective we engineered and iteratively falsified an agent-based analogue of EMT6 spheroid growth. EMT6 spheroids display consistent and predictable growth characteristics, implying that individual cell behaviors are tightly controlled and regulated. An approach to understanding how individual cell behaviors contribute to system behaviors is to discover a set of principles that enable abstract agents to exhibit closely analogous behaviors using only information available in an agent's immediate environment. We listed key attributes of EMT6 spheroid growth, which became our behavioral targets. Included were the development of a necrotic core surrounded by quiescent and proliferating cells, and growth data at two distinct levels of nutrient.

Results: We then created an analogue made up of quasi-autonomous software agents and an abstract environment in which they could operate. The system was designed so that upon execution it could mimic EMT6 cells forming spheroids in culture. Each agent used an identical set of axiomatic operating principles. In sequence, we used the list of targeted attributes to falsify and revise these axioms, until the analogue exhibited behaviors and attributes that were within prespecified ranges of those targeted, thereby achieving a level of validation.

Conclusion: The finalized analogue required nine axioms. We posit that the validated analogue's operating principles are reasonable representations of those utilized by EMT6/Ro cells during tumor spheroid development.

Show MeSH
Related in: MedlinePlus