individual-based model approach to tumour growth in vitro
Max-Planck-Institute for Mathematics in the Sciences, Leipzig,
what extent is tumour growth controlled by nutrients, biomechanical forces,
and other factors? The main mechanisms that determine the growth kinetics
of tumours at different stages and in different environments are still largely
unknown. This question is usually addressed by examining in vitro
model systems, which are experimentally well accessible and hence allow
for systematic studies of parameter and growth condition dependencies. However
even in vitro experiments are rarely free of unknown or uncontrolled
influences. We present a mathematical model to study the spatio-temporal
growth dynamics of two-dimensional tumour monolayers and three-dimensional
tumour spheroids as a complementary tool to in-vitro experiments. Within
our model each cell is represented individually and parameterized by experimentally
completely measurable cell-biophysical and cell-kinetic parameters. Hence
our modeling strategy allows us to study which mechanisms on the microscopic
level of individual cells, determine the macroscopic properties of tumour
growth. We quantitatively compare our in silico results to published
experimental observations on avascular tumour spheroids and on monolayer
cultures. Our findings stress the potential significance of a biomechanically-mediated
inhibition during the experimentally observed transition from exponential
to sub-exponential growth at sufficiently large tumour sizes. The good correspondence
between our in silico results and the experimental data suggests
that our model strategy may provide a starting point from which a quantitative
modeling of in vivo tumour growth under normal and therapy conditions
may also become feasible.
role of post-operative azotemia in enhanced
survival of patients with metastatic renal cancer following
Temple University, USA
recent clinical trials have found longer survival in patients with metastatic
renal cancer if cytoreductive nephrectomy is performed prior to systemic therapy.
Typically these studies show a modest but statistically significant increase
in length of survival in patients undergoing cytoreductive nephrectomy compared
to controls (non-nephrectomy) regardless of the subsequent systemic therapy
employed. Spontaneous regressions of metastases following resection of the
primary renal cancer, although rare, have also been reported in up to 6% of
subjects. These effects are generally ascribed to systemic changes related
to resection of the primary tumor including reduction of the total tumor burden,
removal of a source for later metastases, and enhanced immune response.
We propose, as an alternative hypothesis, the observed clinical benefit from
cytoreductive nephrectomy results from resection of the kidney rather than
the cancer. This hypothesis is based on mathematical models of the tumour-host
interface that demonstrate tumour-induced acidification of the microenvironment
of peritumoral normal tissues is a necessary component of the invasive phenotype.
These models indicate that the graded metabolic acidosis associated with mild
chronic renal failure following resection of one kidney may be sufficient
in some cancers to alter the dynamical interactions at the tumour-host interface
reducing and even reversing the rate of invasion.
To test the modeling results we conducted a retrospective review of patients
who underwent cytoreductive nephrectomy prior to systemic therapy with interferon
alfa-2b in SWOG 8949. We find a significant correlation between postoperative
decrease in renal function as measured by increased serum BUN and creatinine
and improved patient survival and progression free survival.
We conclude that further investigation of this phenomenon is warranted to
confirm our findings and determine if systemic acidification mediates the
observed survival benefit of mild azotemia following cytoreductive nephrectomy
in patients with metastatic renal cancer.
Contribution of Net Proliferation and Invasion in the
Development of Successful Treatment for Gliomas
University of Washington, USA
Coauthor(s): E. C. Alvord,
are complex, heterogeneous brain tumors associated with a humbling prognosis.
Despite several decades of continued bench and clinical work on these tumors,
the effective treatment of gliomas remains elusive. We propose that part of
this failure lies in the lack of understanding of the interaction of both
net proliferation and migration of glioma cells in defining the actual extent
of growth and invasion of the lesion beyond what medical imaging can show.
Our studies of the relationship between these two basic components of glioma
progression through mathematical modelling have already successfully predicted
the behaviour of groups of patients, both low-grade and high-grade. We demonstrate
how the extension of our mathematical modelling approach to individual patients
permits much more rapid identification of successful new therapies.