1. Modelling aspects of solid tumour growth Philip K. Maini Centre for Mathematical Biology Mathematical Institute; Oxford Centre for Integrative Systems Biology, Biochemistry; Oxford

2. More precisely Using mathematical models to explore the interaction of a VERY SMALL subset of processes in cancer with a view to increasing our intuition in a very small way and eventually …

3. Outline Acid-mediated invasion/Somatic evolution/therapeutic strategies ________________________________________ Vascular Tumour Growth Colorectal Cancer

4. Cancer Cell proliferation and cell death (apoptosis) are tightly controlled by genes to maintain homeostasis (steady state). Mutations in these genes upset the balance and the system moves out of steady state. How can we control a growing population of cells?

5. The Warburg Effect Tumour cells undergo glycolytic (anaerobic) metabolism presumably because there is a lack of oxygen. But sometimes in the presence of sufficient oxygen they still do this – seems very strange because it is 20 times less efficient than aerobic metabolism

6. Acid Mediated Invasion Hypothesis A bi-product of the glycolytic pathway is lactic acid – this lowers the extracellular pH so that it favours tumour cell proliferation AND it is toxic to normal cells. Gatenby and Gawslinski (1996)

7. Gatenby-Gawlinski Model

8. Bifurcation parameter

12. Experimental results (Martin and Jain)

13. Fasano et al, Slow and fast invasion waves (Math Biosciences, 220, 45-56, 2009)

17. Tumour encapsulation Predicts ECM density is relatively unchanged – inconsistent with other models but consistent with experimental observations.

19. Metabolic changes during carcinogenesis K. Smallbone, D.J. Gavaghan (Oxford) R.A. Gatenby, R.J. Gillies (Moffitt Cancer Research Inst) J.Theor Biol, 244, 703-713, 2007

20. Cell-environment Interactions Nature Rev Cancer 4: 891-899 (2004) DCIS Model

21. Model Development Hybrid cellular automaton: –Cells as discrete individuals Proliferation, death, adaptation –Oxygen, glucose, H+ as continuous fields –Calculate steady-state metabolite fields after each generation Heritable phenotypes: –Hyperplastic: growth away from basement membrane –Glycolytic: increased glucose uptake and utilisation –Acid-resistant: Lower extracellular pH to induce toxicity

22. Cellular Metabolism Aerobic: Anaerobic: Assume: –All glucose and oxygen used in these two processes –Normal cells under normal conditions rely on aerobic respiration alone Two parameters: n = 1/18 1 < k ≤ 500

23. Automaton Rules At each generation, an individual cell’s development is governed by its rate of ATP production φ a and extracellular acidity h –Cell death Lack of ATP: High acidity: –Proliferation –Adaptation

24. Variation in Metabolite Concentrations glucose oxygen H+H+

27. For further details, see Gatenby, Smallbone, PKM, Rose, Averill, Nagle, Worrall and Gillies, Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer, British J. of Cancer, 97, 646-653 (2007)

28. Therapeutics Add bicarbonate to neutralise the acid (Natasha Martin, Eamonn Gaffney, Robert Gatenby, Robert Gillies)

30. Metastatic Lesions

33. Model Equations: Tumour Compartment

34. Model Equations: Blood Compartment

35. Equivalent dose less effective in humans

36. Analysis There are 3 timescales and lots of small and large parameters so can do asymptotics and obtain an approximate uniformly valid solution on which to do sensitivity analysis.

37. Sensitivity Analysis

38. Proton inhibitor + bicarbonate

39. Clinical Ideas

40. Effects of Exercise Periodic pulsing of acid may affect somatic evolution by delaying the onset of the invasive phenotype (hyperplastic, glycolytic and acid-resistant) (Smallbone, PKM, Gatenby, Biology Direct, 2010)

42. Cancer Growth Tissue Level Signalling: (Tumour Angiogenesis Factors) Oxygen etc Cells: Intracellular: Cell cycle, Molecular elements Partial Differential Equations Automaton Elements Ordinary differential equations

43. Tomas Alarcon Markus Owen Helen Byrne James Murphy Russel Bettridge

46. Vascular Adaptation Series of papers by Secomb and Pries modelling vessels in the rat mesentry – they conclude: R(t) = radius at time t: R(t+dt) = R(t) + R dt S

47. S = M + Me – s + C M = mechanical stimulus (wall shear stress) Me = metabolic demand s = shrinkage C= conducted stimuli: short-range (chemical release under hypoxic stress?) long-range (mediated through membrane potential?)

49. By varying the strengths of the different adaptation mechanisms we can hypothesise how defects in vasculature lead to different types of tumours: Conclude that losing the long range stimuli looks a reasonable assumption Tim Secomb has shown this more convincingly recently (PLoS Comp Biol 2009)

50. Potential uses of the model Chemotherapy Impact of cell crowding and active movement Vessel normalisation

52. Angiogenesis Recently, we have added in angiogenesis (Owen, Alarcon, PKM and Byrne, J.Math. Biol, 09) and gone to 3D (Holger Perfahl)

54. Movie – both2_mov

56. An integrative computational model for intestinal tissue renewal Van Leeuwen, Mirams, Walter, Fletcher, Murray, Osbourne, Varma, Young, Cooper, Pitt-Francis, Momtahan, Pathmanathan, Whiteley, Chapman, Gavaghan, Jensen, King, PKM, Waters, Byrne (Cell Proliferation, 2009)

57. CHASTE – Cancer, Heart And Soft Tissue Environment Modular

62. The effects of different individual cell-based approaches (to appear in Phil Trans R Soc A)

63. Conclusions and Criticisms Simple multiscale model – gain some insight into why combination therapies might work Heterogeneities in environment play a key role No matrix included! – Anderson has shown adhesivity could be important Cellular automaton model – what about using Potts model, cell centred, cell vertex models? – DOES IT MAKE A DIFFERENCE (Murray et al, 2009; Byrne et al, 2010) There are many other models and I have not referred to any of them! (Jiang, Bauer, Chaplain, Anderson, Lowengrub, Drasdo, Meyer-Hermann, Rieger, Cristini, Enderling, Meinke, Loeffler, TO NAME BUT A FEW)

64. Acknowledgements Colorectal: David Gavaghan, Helen Byrne, James Osborne, Alex Fletcher, Gary Mirams, Philip Murray, Alex Walter, Joe Pitt-Francis et al (EPSRC) Vascular: Tomas Alarcon, Helen Byrne, Markus Owen, Holger Perfahl (EU -5 th and 6 th frameworks)

65. Acknowledgements Natasha Martin, Kieran Smallbone, Eamonn Gaffney, David Gavaghan, Bobs Gatenby and Gillies Funded DTC (EPSRC), NCI (NIH)