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Caterina Guiot*,†, Piero Giorgio Degiorgis †,‡ , Pier Paolo Delsanto †,§, Pietro Gabriele ¶ and Thomas S. Deisboeck #,** Dip. Neuroscience, Università di Torino, Italy and † INFM, sezioni di Torino Università e Politecnico, Italy ; ‡ S.I.A. SpA, Torino; § Dip. Fisica, Politecnico di Torino, Italy; ¶ IRCC Candiolo, Torino; # Complex Biosystems Modeling Laboratory, Harvard-MIT (HST) Athinoula A. Martinos Center for Biomedical Imaging, HST-Biomedical Engineering Center, Massachusetts Institute of Technology, Cambridge, MA 02139 and ** Molecular Neuro-Oncology Laboratory, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA 02129, USA. corresponding author: Caterina Guiot Dip. Neuroscienze 30, C. Raffaello 10125 Torino tel: +39.11.670.7710 fax: +39.11.670.7708 e-mail: firstname.lastname@example.org
which is required to ensure maintenance. 1997). the clinical history of the tumor passes through a microscopic. m. Instead of the actual mass. that in most solid malignant human tumors two or three decades elapse between the first carcinogenic stimulus and the clinical emergence of the neoplasm (Tubiana. 1986). regardless of the different masses and development times. A variety of in vitro and in vivo data are analyzed and compared with the prediction of a 'universal' law. A recent paper from West et al (2001) shows that. including its relevance for tumor metastasis and recurrence. angiogenesis and invasion. r relates to the relative proportion of total energy expenditure. relating properly rescaled tumor masses and tumor growth times. Assuming typical volume doubling times of about 100 days. it is intriguing to investigate whether tumor growth follows the same universal curve. representing a population of about 1 billion cells. Since rapid volumetric growth and neovascularization are also hallmarks of solid malignant tumors. mammals. these authors use the rescaled dimensionless time 2 . For this purpose we rescale tumor sizes and growth times according to West's recipe (West et al.Continuous tumor progression leads then eventually to local tissue invasion and metastasis. the same universal exponential curve fits their ontogenetic growth data. 2001). Here we investigate the extension of this model to the growth of solid malignant tumors. instead of the actual time. followed by angiogenesis. The authors explain this phenomenon with basic cellular mechanisms (West et al. cell turnover rates. some 30 cell doublings from the progenitory cancer cell must occur in order to reach this ‘diagnostic’ stage. necessary to sustain a macroscopic size (Folkman. Likewise. 2002).25 . where M is the asymptotic mass for the taxon. they use the ratio r = (m/M)0. A better understanding of the growth kinetics of malignant tumors is of paramount importance for the development of more successful treatment strategies. t. Since a tumor is clinically detectable with conventional diagnostic tools at approximately 1 cm3 in volume. In the next 10 volume doublings up to about 103 cm3 in size (which is reportedly lethal in primary breast cancer by Retsky. this scenario corresponds to a preclinical time of roughly 8 years .A general model for the ontogenetic growth of living organisms has been recently proposed. birds. Given the lack of clinical data at non-symptomatic stages. fish and molluscs all share a common growth pattern. Provided that masses and growth times for the different organisms are properly rescaled. The results support the notion that tumor growth follows such a universal law. depending on the particular cancer type. avascular growth phase. 1971). Several important implications of this finding are discussed. which we briefly recall here. it has been conjectured. assuming a common fractal pattern in the vascularization of the investigated taxa.
Table 1 presents an estimate of the relevant parameters and. m0 is the mass at birth. its ability to metastasize or invade. from animal models (Steel.25 where r0 = (m 0 /M)0. respectively. Cividalli et al.α r0 t + y0  where y = ln (1 – r) . we will briefly discuss possible implications of our conjecture that tumor growth also follows a universal law. spanning in vitro experiments (multicellular tumor spheroids (Chignola et al. For our analysis. m0 and M are the initial and final masses of the tumor. or its affinity for nutrients uptake). 2002) and patients(Norton. respectively. and a is a parameter expected to be related to the tumor’s characteristics (e. 2 and 3. 2000. thus yielding a preliminary estimate for y0 and α.25 a m0 and a is a parameter. The data fit the universal growth curve very well. From equations  and  we obtain: y = . Nirmala et al.25t − ln (1 − ( 0 ) 0. Using the variables τ and r . we have used available data from the literature.τ = 1 m aM − 0. the lowest and largest values of m are first assumed for m0 and M. this 'universal' growth law follows: r = 1 – exp (-τ)  In our case. which is roughly constant within a taxon and proportional to the organism’s metabolic rate across taxa. 3 . a multistep fitting procedure is adopted for their determination.. 25 ) = α r0t − ln (1 − r0 ) 4 M  –0. 1993). shows very high R2 correlation coefficients between actual and fitted data. The values of a. α = 0. Then m0 and M are allowed to respectively decrease and increase. Yorke et al. Since the definition of the parameters is non-trivial. and y0 and α reestimated until a best-fit (consistent with the available biological infomation) is obtained. y0 = ln (1 – r0 ).25 . The results are presented in Figures 1. 1988. In the following. For our fitting procedure. 1977. m0 and M are reported for many different species in West et al (2001).g. 2001) as well as in vivo data (both. further supporting our claim. Available data normally provide m as a function of t during the tumor’s growth phase. and plotted against equation .
1% in FSall and 8.6) days in recurrent Fsall tumors. which includes both cell death and cell invasion). which lead to recurrence.6 (± 0.0% in SCCVII. When local recurrence of the same tumor lines are considered.9 at 1 week to 0.a) tumor metastasis and recurrence. while it increases to 14. Some forty years ago Romsdahl et al. at a tumor diameter of 6 mm. R = 1 – r can be related to the proportion ∆N/N of the cells contributing to the growth at any 'rescaled time'.. if primary tumors are treated upon reaching a diameter of 6 mm. As another consequence of the model. is only 12.4) days in primary to ∆ t r=13.6% and 70. Furthermore. versus 46.35 after 4 weeks.8 (± 3. respectively. the diameter doubling time (± standard deviation) necessary to grow from 6 to 12 mm increases from ∆ t p =6.8) days in SCCVII. For example.3% and 41. the recurrent cancer grows much slower than the primary tumor.7 (± 0. 1988) show that. data from glioblastoma spheroids (Nirmala et al.e. The hypothesis that metastatic behaviour could be associated with a universal growing phase of the tumor is corroborated by experimental evidence. Tubiana (1986) evaluated this threshold for breast cancer. the percentage of metastasis. Eq. respectively. data from C3Hf/Sed mice inoculated with fibrosarcoma (FSall) and squamous cell carcinoma (SCCVII) (Ramsay et al.3% at a diameter of 12 mm.0% in SCCVII. (1961) had proposed that. and decreases exponentially afterwards.3%.6 (± 4. upon reaching a certain “critical” volume of the primary tumor. Following the notion of a universal law. An approximate computation from our model yields ∆ t r / ∆ t p ~ 1. Moreover. N is the total number of tumor cells and ∆N is the difference between the rates of newly generated tumor cells (growth fraction (GF)) and tumor cells being lost (i. which is in agreement with experimental results from Ramsay et al (1988). and from ∆ t p =7. respectively. cell loss factor (CLF).5) days to ∆ t r=12. metastatic dissemination would start. In fact. 2001) suggest values for ∆N/N ranging from 0. τ : ∆N N R = exp( −τ ) ≈  Here. a possible explanation for this behavior is that the residual clonogenic cells of the primary tumor. generate cells belonging to an ‘older’ developmental phase. Hence.7.5% in FSall and 43.  predicts that ∆N is larger at the onset of tumor growth. and showed that it critically depends on the axillary lymph-node involvement. b) cell turnover rates. the maximal percentage of metastasis is only 3. the relative amount of energy devoted to tumor growth. knowing the rate of cell turnover at any developmental stage can help to improve 4 . if the treatment starts at a diameter of 12 mm.
however. Correspondingly. while for local failure (LF) cases it was 68%. as the tumor mass continues to grow.25 < 0 4  likewise.e. on the successful 5 . we may define the 'lethal' dose of a given therapeutic agent as the dose D for which the rate of tumor growth post treatment. respectively. It is noteworthy that West 's model applies to organisms growing in unrestricted dietary conditions. A longitudinal study of the metastasis-free survival in prostate carcinoma (Fuks et al. c) angiogenesis.therapeutic strategies.g. respectively. non-replenished nutrient concentration. at doses larger than the lethal one) early on and that only in a small percentage of patients was the metastasis threshold already surpassed at the time of treatment. 39% and 24%. from the expression of M as a function of the metabolic rate in West et al (2001) of a single cell Bc we deduce that also dM / dB c < 0  Thus. while later it can only be locally effective. then GF(D) should become equal to the GF of the untreated tumor multiplied by SF(D). 1991) in 679 patients has shown that after 5.. Conversely.e. 82% and 77%. when a dose D has been administered. 10 and 15 years the percent survival of local control (LC) cases was 90%. the r curve is bound to shift downwards. Our formalism may yield a simple mathematical explanation for such growth behavior. From the definition of r follows: dr / dM = − 1 ⋅ (m / M 5 ) 0. differences in growth rates and saturation sizes (of up to a factor of 500) were found comparing tumor spheroids cultured in media with different oxygen and glucose concentrations. only fully replenished tumors should follow the universal growth curve. if the average value of Bc decreases. before which the dose D is curative. LF doses were inadequate and therefore. metastases were inevitable. as “ontogenetic” tumor growth should depend on the availability of nutrient replenishment or. a threshold time (corresponding to the “critical” tumor volume at inception of metastasis).. Therefore. As such. One could therefore argue that the LC tumors were correctly treated (i. And in fact. There is. such as due to the depletion of a e. as Freyer and Sutherland (1986) pointed out. GF(D) equals the rate of CLF. in vivo. If we further assume a given survival fraction SF(D) (different for each tumor). τ) and on its therapeutical response. As such. GF(D) depends then on both the developmental stage of the tumor (i. deviations from the universal curve are conceivable depending on the particular environmental conditions.
tissue invasion should facilitate further growth by reducing the constraint of confinement not only for the volumetrically expanding tumor itself but also for the aforementioned chemo-attracted endothelial cells. our findings also relate to cell motility. In summary. 2001) where. which migrate towards the angiogenic factor releasing tumor cells. another hallmark of malignant tumors. as has already previously been argued on the basis of experimental findings from human glioma spheroids (Deisboeck et al. . which include the perivascular space in the case of malignant astrocytomas (Bernstein et al. Extracellular matrix-degrading invasive cells are likely to decrease the mechanical confinement around the tumor.g.competitition for available nutrients. cell turnover. not only metastasis and angiogenesis but also tumor cell invasion may be linked to a “critical” tumor volume. These cells also appear to follow specific routes of dissemination. one can further hypothesize that in vivo the degree of deviation from the universal curve may in fact relate to the amount of paracrine endothelial cell growth factors (e. 1994). Therefore. Shweiki et al. 1992. 1989. VEGF (Plate et al. which in turn facilitates angiogenesis and ensures continuing tumor growth. 6 .. (2000) and Scalerandi et al (1999. 1992) released by the nutrient-deprived tumor cells in order to induce the extent of neovascularization necessary to provide the required level of nutrient replenishment. but could also induce an increase in the extent and dynamics of tissue invasion. The results from fitting a variety of in vitro data from multicellular tumor spheroids and of in vivo data from both experimental models as well as patients support the notion that neoplasms also follow a universal growth law. 2001). following the Local Interaction Simulation Approach (LISA) (Schechter et al. any marked deviation between the universal and the real growth curve may indicate the amount of additional nutrients necessary to satisfy the metabolic demand of the growing tumor. we have investigated the applicability of West’s general model for the ontogenetic growth of living organisms to the case of solid malignant tumors.) VEGF secretion. amenable to direct numerical simulations of cancer growth both in the avascular and vascular case. As such. 1999). Thus. a progressive decrease in Bc may not only trigger an increase in (e.g. Vajkoczy et al. It is noteworthy that the importance of nutrient availability has been pointed out also by a model proposed by Delsanto et al. Accordingly. d) Invasion. at least in this case. angiogenesis and invasion. Finally. Our paradigm-shifting finding has far-reaching implications concerning the mechanism of tumor metastasis and recurrence. a consistent set of rules governing the microscopic interactions (at the cellular level) has been formulated.
(1989) Human malignant astrocytoma xenografts migrate in rat brain: a model for central nervous system cancer research. Fuks. S. Torquato. Yuri Mansury (Complex Biosystems Modeling Laboratory. 7 . et al. Berens. W. E. The authors would like to thank Dr.A. M. P. Freyer. & Pescarmona. N. (2000) Forecasting the growth of multicell tumour spheroids: implication for the dynamic growth of solid tumours.E. Neuroscience Res. 34. & Laws Jr. Radiat. 3504-3512.. 62. A. A. E. 33. Cancer Res. Massachusetts Institute of Technology) for helpful suggestions. J. Cividalli. Scalerandi. E. Folkman J. Chignola. & Chiocca. Phys. 125 I implantation. (2000) Analysis of a phase transition from tumor growth to latency. Oncol. Oncol.J. Int. J. J. Harvard-MIT (HST) Athinoula A. (1986) Regulation of growth saturation and development of necrosis in EMT6 multicellular spheroids by the glucose and oxygen supply. 52. R. Romano. Kansal.. Cell Prolif. & Sutherland. 22. (2001) Pattern of self-organization in tumour systems: complex growth dynamics in a novel brain tumour spheroid model. (1991) The effect of local control on metastatic dissemination in carcinoma of the prostate: long-term results in patients treated with Phys. J. et al.ACKNOWLEDGEMENTS: The work has been partially supported by the 'Compagnia di S. Cell Prolif. Biol. et al. Torino.. 285. Italy. J. Paolo'. M. REFERENCES Bernstein. T. Martinos Center for Biomedical Imaging.S. Engl.P. 46. 1092-1098 and private communication. Radiat.G.R. R. Phys. 115-134 . 537-547.P. Stemmer-Rachamimov.O. Delsanto.J. Int..R. P. Med.. 219-229. Go ldberg. A.. J.. (1971) Tumor angiogenesis: therapeutic implications. 21. 134-143. (2002) Radiosensitazion by oxaliplatin in a mouse adenocarcinoma: influence of treatment schedule. Biol. 2547-54. 1182-1186.M. Deisboeck.. Rev. Z. A.
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05 cm3 and final volumes of 1 to 5 cm3 . West.. 2000).H. after an elapsed time between 9 . B. G.H. r = (m/M) 0. & Enquist. respectively (Steel.. & Brown.C. L. 167-184. P..B. Radiother.C. all data fit well eq. 2987-2993. Vince. G. R. Vajkoczy. L.. J. W. Oncol.. Yorke. FIGURE CAPTIONS: Fig. Brown. Neuroscience 17. Schmiedek. 6. Tonn. Tumor growth curves (replenished multicellular tumor spheroids). West. The fitting lines were obtained by the same authors using a Gompertzian model. respectively). In spite of the different dimensions (after 30 days. 557-563.1 (Walker) to 1 cm3 (Fibro). (1986) The growth and progression of human tumors: implications for management strategy. 53. Int. C.. with the cell culture medium replenished once every other day) and reaching a maximum volume of about 0. 1977).. Cancer Res. M. Nature 413. (2002) Allometric scaling of metabolic rate from molecules and mitochondria to cells and mammals. G. W. The other murine tumors: a mammary adenocarcinoma (KHJJ).H.001 and 0. Dev. Whitmore.Tubiana. M. M. Fuks. (2001) A general model for ontogenetic growth. E. the 9L and U118 spheroids measured 0. (1999) Glioma cell migration is associated with glioma-induced angiogenesis in vivo..15 mm3 are also included.. Z. 2001). J.. Norton.J. 2473-2478.25 vs the 'rescaled' time τ for various multicellular spheroids. Woodruff. 628-631. suppl 1.D. (1993) Modeling the development of metastases from primary and locally recurrent tumors: comparison with a clinical data base for prostatic cancer. J. and final volumes approached 100 cm3 after 180 days and 25 days. Data from another human glioblastoma line (SNB19) (Nirmala et al. Goldbrunner.5 mm3 and 0. PNAS 99. Fibroadenoma (Fibro) and Walker carcinoma (Walker) were transplanted into rats: their initial tumor volumes ranged from 0. Schilling.D. P. J. & Menger.9 mm3 . Fig. a sarcoma (EMT6) and two osteosarcomas (NCTC2472 and osteo) had initial volumes ranging between 0. Farhadi. 1. Rat gliosarcoma (9L) and human glioblastoma (U118) were cultured over 60 days on agarose with the medium superlayer routinely replaced every seven days (Chignola et al. a mammary carcinoma (C3H). 2. Tumor growth curves (rodent models).. cultured over a shorter time (30 days. which is also plotted for reference.B. & Ling..
3. Eq  is again plotted for reference.15 and 100 days. Yorke et al. 1977). As in the previous figures. Eq  is plotted here for reference. Additional data on another murine mammary carcinoma (Ch3 ISS) (Cividalli et al. Fig. 2002) are also included. Tumor growth curves (breast and prostate tumors from patients). 1988. since often only few observations of the same untreated tumor are available and the tumor’s asymptomatic hystory is unknown. Data are extrapolated using the Gompertzian curve parameters (Norton. For patient data the analysis is more difficult. 10 . 1993). depending on the tumor (Steel.
99 0. An asterix * in the second column denotes in vivo data. Tumor 9L (exp) 9L (fitted) U118 (exp) U118 (fitted) SNB19 fibro walker KHJJ C3H EMT6 NCTC 2472 osteo C3H ISS human breast human prostate Reference Chignola.54 0. 1988 * Yorke.0058 0.000037 0. 2002* Norton.0000189 0.1977 * Steel. 1993 * mo (g) 0.348 0.37 0.85 11 .2 1 1 M(g) 0.81 0.000037 0.000515 0.084 0.2001 Steel.1977 * Steel.1977 * Steel.95 0.TABLE 1: Estimates of the relevant parameters from Figures 1-3.64 0. 2000 Nirmala. 2000 Chignola.000823 3 200 150 2 5 3 7 7 8 646 641 a (g 0.0012 0.97 0. R2 represents the correlation coefficient between actual and fitted data.075 0.5 0.114 0.025 1 0.99 0.98 0.99 0.49 0.23 0.000515 0.000812 0. M and a are estimated by means of the fitting procedure described after eq.95 0.124 0.0348 0. The values of the parameters m0 .21 0.92 0.1977 * Cividalli.96 0.1977 * Steel.0000605 0.97 0.69 0.00135 0. 2000 Chignola. 2000 Chignola.102 0.25 /day) 0.98 0.99 0.052 0. .1977 * Steel.084 0.1977 * Steel.14 1.42 R2 0.
fitted) r 0.'in vitro' data (spheroids) 1 9L (ref6. exp) 9L (ref6. exp) U118 (ref6.5 U118 (ref6. fitted) 0 0 2 4 6 8 10 SNB19 (ref7. exp) τ Eq(2) 12 .
'in vivo' data (rodents) 1 Fibro (ref8) Walker (ref8) KHJJ (ref8) C3H (ref8) EMT6 (ref8) r 0.5 NCTC2472 (ref8) Osteo (ref8) 0 0 1 2 3 C33 ISS (ref9) Eq(2) τ 13 .
5 0 0 2 4 τ 6 8 10 14 .'in vivo' data (patients) 1 r breast (ref10) prostate (ref11) Eq(2) 0.
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