Pattern of self‐organization in tumour systems: complex growth dynamics in a novel brain tumour spheroid model

Abstract

We propose that a highly malignant brain tumour is an opportunistic, self-organizing and adaptive complex dynamic biosystem rather than an unorganized cell mass. To test the hypothesis of related key behaviour such as cell proliferation and invasion, we have developed a new in vitro assay capable of displaying several of the dynamic features of this multiparameter system in the same experimental setting. This assay investigates the development of multicellular U87MGmEGFR spheroids in a specific extracellular matrix gel over time. The results show that key features such as volumetric growth and cell invasion can be analysed in the same setting over 144 h without continuously supplementing additional nutrition. Moreover, tumour proliferation and invasion are closely correlated and both key features establish a distinct ratio over time to achieve maximum cell velocity and to maintain the system's temporo-spatial expansion dynamics. Single cell invasion follows a chain-like pattern leading to the new concept of a intrabranch homotype attraction. Since preliminary studies demonstrate that heterotype attraction can specifically direct and accelerate the emerging invasive network, we further introduce the concept of least resistance, most permission and highest attraction as an essential principle for tumour invasion. Together, these results support the hypothesis of a self-organizing adaptive biosystem.

Three-Dimensional (3D) Tumor Spheroid Invasion Assay

“…Invasion can be measured in terms of number of invading cells and/or distance travelled from the gel surface 9 . Tumor cells can also be completely embedded into a matrix either as a single cell suspension or as spheroids -usually placed between two layers of ECM gel-allowing cells to invade out of the tumor mass into the surrounding matrix 2,6,10,11 .…”

Identifying the necrotic zone boundary in tumour spheroids with pair-correlation functions

“…These estimates provide a simple metric to classify and categorize tumour spheroids, which has potential application to high-throughput comparative assays [8][9][10]. For example, the PCF method could be used to investigate population-level variability in the size of the necrotic zone by using a larger sample of mature tumour spheroids from the same cell line, grown from the same number of seeded cells.…”

“…The schematic diagram of figure 1 illustrates the necrotic, quiescent and proliferative zones within a tumour spheroid. Identifying and quantifying these three regions is important in the analysis of comparative assays on tumour spheroids [8][9][10] and mathematical models of the tumour growth process [11][12][13][14].…”

Computational modeling of brain tumors: discrete, continuum or hybrid?

“…To investigate highly malignant brain tumors as complex, dynamic, and self-organizing biosystems [20], Deisboeck and co-workers have been focusing on the development of ABMs simulating tumor properties across multiple scales in time and space. First, the spatio-temporal expansion of virtual glioma cells in a 2D microscopic setup and the relationship between rapid growth and extensive tissue infiltration were investigated [44,45].…”