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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 moveEmptyBias values and low NUTRIENT. All images were recorded at 21 DAYS. Scale bar: 100 μm. Other parameter values were as listed in Table 2. (A)-(F) moveEmptyBias values are shown. *: moveEmptyBias value in Table 2. Cross-sections at moveEmptyBias = 0 are not shown because they grew too quickly and filled the available space before 21 DAYS elapsed. As moveEmptyBias increased, more empty spaces were visible within the SMS.
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Figure 6: SMS cross-sections at varied moveEmptyBias values and low NUTRIENT. All images were recorded at 21 DAYS. Scale bar: 100 μm. Other parameter values were as listed in Table 2. (A)-(F) moveEmptyBias values are shown. *: moveEmptyBias value in Table 2. Cross-sections at moveEmptyBias = 0 are not shown because they grew too quickly and filled the available space before 21 DAYS elapsed. As moveEmptyBias increased, more empty spaces were visible within the SMS.

Mentions: We conducted experiments in which we varied parameter values and observed the effect on measures of SMS growth and morphology. The results, summarized in Table 5, indicate whether increasing a parameter increased, decreased, or did not affect a specific measure (such as maximum size reached). In addition, we examined the consequences of changing parameter values in more detail. Changing moveEmptyBias had a limited but significant effect on SMS morphology (Fig. 6) and growth (Fig. 7). The parameter moveEmptyBias influenced movement of CELLS exposed to the outside surface of the SMS or adjacent to a fissure. The larger the value of moveEmptyBias, the less likely a CELL at the edge experiencing low STRESS (defined under Methods) would move into an adjacent empty space when given the opportunity. A larger moveEmptyBias value hindered fissure elongation. MoveEmptyBias was tuned empirically to control SMS shape but still allow CELL-free spaces to exit the SMS rather than be trapped inside for an extended duration. CELLS with larger moveEmptyBias values experiencing low STRESS rarely moved into adjacent empty spaces, whereas CELLS under high STRESS are likely to do so.


Essential operating principles for tumor spheroid growth.

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

SMS cross-sections at varied moveEmptyBias values and low NUTRIENT. All images were recorded at 21 DAYS. Scale bar: 100 μm. Other parameter values were as listed in Table 2. (A)-(F) moveEmptyBias values are shown. *: moveEmptyBias value in Table 2. Cross-sections at moveEmptyBias = 0 are not shown because they grew too quickly and filled the available space before 21 DAYS elapsed. As moveEmptyBias increased, more empty spaces were visible within the SMS.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: SMS cross-sections at varied moveEmptyBias values and low NUTRIENT. All images were recorded at 21 DAYS. Scale bar: 100 μm. Other parameter values were as listed in Table 2. (A)-(F) moveEmptyBias values are shown. *: moveEmptyBias value in Table 2. Cross-sections at moveEmptyBias = 0 are not shown because they grew too quickly and filled the available space before 21 DAYS elapsed. As moveEmptyBias increased, more empty spaces were visible within the SMS.
Mentions: We conducted experiments in which we varied parameter values and observed the effect on measures of SMS growth and morphology. The results, summarized in Table 5, indicate whether increasing a parameter increased, decreased, or did not affect a specific measure (such as maximum size reached). In addition, we examined the consequences of changing parameter values in more detail. Changing moveEmptyBias had a limited but significant effect on SMS morphology (Fig. 6) and growth (Fig. 7). The parameter moveEmptyBias influenced movement of CELLS exposed to the outside surface of the SMS or adjacent to a fissure. The larger the value of moveEmptyBias, the less likely a CELL at the edge experiencing low STRESS (defined under Methods) would move into an adjacent empty space when given the opportunity. A larger moveEmptyBias value hindered fissure elongation. MoveEmptyBias was tuned empirically to control SMS shape but still allow CELL-free spaces to exit the SMS rather than be trapped inside for an extended duration. CELLS with larger moveEmptyBias values experiencing low STRESS rarely moved into adjacent empty spaces, whereas CELLS under high STRESS are likely to do so.

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