In Vitro/In Silico Study on the Role of Doubling Time Heterogeneity among Primary Glioblastoma Cell Lines

Abstract

The application of accurate cancer predictive algorithms validated with experimental data is a field concerning both basic researchers and clinicians, especially regarding a highly aggressive form of cancer, such as Glioblastoma. In an aim to enhance prediction accuracy in realistic patient-specific environments, accounting for both inter- and intratumoral heterogeneity, we use patient-derived Glioblastoma cells from different patients. We focus on cell proliferation using in vitro experiments to estimate cell doubling times and sizes for established primary Glioblastoma cell lines. A preclinically driven mathematical model parametrization is accomplished by taking into account the experimental measurements. As a control cell line we use the well-studied U87MG cells. Both in vitro and in silico results presented support that the variance between tumor staging can be attributed to the differential proliferative capacity of the different Glioblastoma cells. More specifically, the intratumoral heterogeneity together with the overall proliferation reflected in both the proliferation rate and the mechanical cell contact inhibition can predict the in vitro evolution of different Glioblastoma cell lines growing under the same conditions. Undoubtedly, additional imaging techniques capable of providing spatial information of tumor cell physiology and microenvironment will enhance our understanding regarding Glioblastoma nature and verify and further improve our predictability.

Integrating in vitro experiments with in silico approaches for Glioblastoma invasion: the role of cell-to-cell adhesion heterogeneity

“…Aliquots of zero stage, as well as various passages of in vitro cell tissue were cryopreserved, nucleic acids were extracted for further analysis and immunohistopathology was performed. The average doubling time intervals were estimated following a simple protocol in adherent cultures for both the established primary GB culture and the U87MG cell line which was used as a control (as described in 64 ). All possible steps and procedures have been approved by the Institutional Ethical Committees.…”

“…If a quiescent cell finds an empty space, it immediately proliferates. The neighbourhood chosen for the proliferation was the Moore neighbourhood of size r equal to 2 (for more details also see 64 ).…”

Combined radiotherapy and concurrent tumor treating fields (TTFields) for glioblastoma: Dosimetric consequences on non-coplanar IMRT as initial results from a phase I trial

“…In our study all treatments were performed following the specifications made by the vendor, henceforth all dose analyses were based upon these terms [13]. Table 1 Characteristics of the 7 glioblastoma patients: Tumor localization in the patient; study arm A or B; treatment technique; skin high dose area (surface dose > 70% of the prescribed dose within or up to 6 mm below the skin on a scalp area are of > 50 cm 2 Note: doses are given as relative doses normalized to the prescribed dose; five adjacent scalp + calvaria layers were defined as tissue slices of 2 mm thickness below the surface of the scalp in a depth of 0-2 mm, 2-4 mm, 4-6 mm, 6-8 mm and 8-10 mm; D95: minimum dose in 95% most exposed voxel of the structure; D2: minimum dose in the 2% most exposed voxels of the structure Previous film dosimetry measurements showed that transducer arrays may increase the dose build-up to 82, 88 and 98% of the maximal dose build-up per beam at a depth of 0.4 mm and incident beam angles on the surface of 90°, 45°and 10° [29]. In the present study, the maximal voxel-wise dose difference with and without onlying transducer arrays ranged from 24 to 29% of the prescribed dose observed in the superficial 2 mm of the scalp outside the 1 cm 2 with the largest dose differences.…”

“…Glioblastoma (World Health Organization grade IV glioma [1]) is a rapidly proliferating tumor [2,3]. Despite a trimodal approach, overall survival and progression free survival rates remain low [4][5][6][7][8].…”

Mathematical Modeling of Metastatic Cancer Migration through a Remodeling Extracellular Matrix

“…Considering the early stages of metastatic cancer cell invasion, the length scale L is taken to be 1 cm but could be in the range of 0.1 to 1 cm. The residence time τ is taken to be 32 h, which is a representative average in vitro doubling time for the well-established human cancer cell lines of A549 lung carcinoma cells, U87MG glioma cells, and MCF-7 and MDA-MB 231 breast cancer cells [55][56][57][58]. The diffusion coefficient of the cancer cell D c has been previously determined in an experiment of cell movement by [59].…”