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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

SMS cross-sections at varied quiConsumeRate and low NUTRIENT. All images were recorded at 13 DAYS. Scale bar: 100 μm. Except for quiConsumeRate, parameter values were those listed in Table 2. (A)-(H) quiConsumeRate values are shown. *: quiConsumeRate value in Table 2.
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Figure 8: SMS cross-sections at varied quiConsumeRate and low NUTRIENT. All images were recorded at 13 DAYS. Scale bar: 100 μm. Except for quiConsumeRate, parameter values were those listed in Table 2. (A)-(H) quiConsumeRate values are shown. *: quiConsumeRate value in Table 2.

Mentions: The value of quiConsumeRate determined the amount of NUTRIENT per SECOND consumed by each quiescent CELL. The value was tuned between zero and proConsumeRate. Varying quiConsumeRate produced consistent and dramatic results. Increasing the amount of NUTRIENT consumed by QUIESCENT CELLS reduced the number of QUIESCENT CELLS capable of existing within the SMS. The consequences are clearly visible in Fig. 8: as quiConsumeRate increased, the width of the viable rim decreased, as did the number of QUIESCENT CELLS in the system and overall SMS size. Figure 9 shows that the growth rate and saturation size steadily decreased. ProConsumeRate specified the amount of NUTRIENT per SECOND consumed by proliferating CELLS. For simplicity, PROLIFERATING CELLS consumed the same amount of NUTRIENT regardless of whether they were actively creating a new CELL, waiting for an opportunity to do so, or were unable to do so because they were surrounded by other CELLS. ProConsumeRate's value in Table 2 was purposefully selected to be within the range of glucose consumption rates reported in [17].


Essential operating principles for tumor spheroid growth.

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

SMS cross-sections at varied quiConsumeRate and low NUTRIENT. All images were recorded at 13 DAYS. Scale bar: 100 μm. Except for quiConsumeRate, parameter values were those listed in Table 2. (A)-(H) quiConsumeRate values are shown. *: quiConsumeRate value in Table 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: SMS cross-sections at varied quiConsumeRate and low NUTRIENT. All images were recorded at 13 DAYS. Scale bar: 100 μm. Except for quiConsumeRate, parameter values were those listed in Table 2. (A)-(H) quiConsumeRate values are shown. *: quiConsumeRate value in Table 2.
Mentions: The value of quiConsumeRate determined the amount of NUTRIENT per SECOND consumed by each quiescent CELL. The value was tuned between zero and proConsumeRate. Varying quiConsumeRate produced consistent and dramatic results. Increasing the amount of NUTRIENT consumed by QUIESCENT CELLS reduced the number of QUIESCENT CELLS capable of existing within the SMS. The consequences are clearly visible in Fig. 8: as quiConsumeRate increased, the width of the viable rim decreased, as did the number of QUIESCENT CELLS in the system and overall SMS size. Figure 9 shows that the growth rate and saturation size steadily decreased. ProConsumeRate specified the amount of NUTRIENT per SECOND consumed by proliferating CELLS. For simplicity, PROLIFERATING CELLS consumed the same amount of NUTRIENT regardless of whether they were actively creating a new CELL, waiting for an opportunity to do so, or were unable to do so because they were surrounded by other CELLS. ProConsumeRate's value in Table 2 was purposefully selected to be within the range of glucose consumption rates reported in [17].

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