Pattern of self-organization in tumour systems: complex growth dynamics ina novel brain tumour spheroid model

We propose that a highly malignant brain tumour is an opportunistic, self-o rganizing and adaptive complex dynamic biosystem rather than an unorganized cell mass. To test the hypothesis of related key behaviour such as cell pr oliferation and invasion, we have developed a new in vitro assay capable of displaying several of the dynamic features of this multiparameter system i n the same experimental setting. This assay investigates the development of multicellular U87MGmESFR 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 conti nuously supplementing additional nutrition. Moreover, tumour proliferation and invasion are closely correlated and both key features establish a disti nct ratio over time to achieve maximum cell velocity and to maintain the sy stem's temporo-spatial expansion dynamics. Single cell invasion follows a c hain-like pattern leading to the new concept of a intrabranch homotype attr action. Since preliminary studies demonstrate that heterotype attraction ca n specifically direct and accelerate the emerging invasive network: we furt her introduce the concept of least resistance, most permission and highest attraction as an essential principle for tumour invasion. Together, these r esults support the hypothesis of a self-organizing adaptive biosystem.