An in silico model to demonstrate the effects of Maspin on cancer cell dynamics

Abstract

Most cancer treatments efficacy depends on tumor metastasis suppression, where tumor suppressor genes play an important role. Maspin (Mammary Serine Protease Inhibitor), an non-inhibitory serpin has been reported as a potential tumor suppressor to influence cell migration, adhesion, proliferation and apoptosis in in vitro and in vivo experiments in last two decades. Lack of computational investigations hinders its ability to go through clinical trials. Previously, we reported first computational model for maspin effects on tumor growth using artificial neural network and cellular automata paradigm with in vitro data support.This paper extends the previous in silico model by encompassing how maspin influences cell migration and the cell-extracellular matrix interaction in subcellular level. A feedforward neural network was used to define each cell behavior (proliferation, quiescence, apoptosis) which followed a cell-cycle algorithm to show the microenvironment impacts over tumor growth. Furthermore, the model concentrates how the in silico experiments results can further confirm the fact that maspin reduces cell migration using specific in vitro data verification method. The data collected from in vitro and in silico experiments formulates an unsupervised learning problem which can be solved by using different clustering algorithms. A density based clustering technique was developed to measure the similarity between two datasets based on the number of links between instances. Our proposed clustering algorithm first finds the nearest neighbors of each instance, and then redefines the similarity between pairs of instances in terms of how many nearest neighbors share the two instances. The number of links between two instances is defined as the number of common neighbors they have. The results showed significant resemblances with in vitro experimental data. The results also offer a new insight into the dynamics of maspin and establish as a metastasis suppressor gene for further molecular research.

A quantitative image analysis for the cellular cytoskeleton during in vitro tumor growth

“…Also, cells transfected with wild type maspin showed a slight increase in the content of both G-actin and F-actin which corresponds with its phenotype of a thick actin periphery and large flattened phenotype. It supports the finding that MCF7 cells stably expressing wild type maspin significantly increased cell adhesion by 113±5% on a laminin matrix and by 4576% on either collagen I or fibronectin matrices, in comparison to cells expressing vector only (Al-Mamun et al, 2016a). Also, GLCM values from our current analysis, we saw that ruffling regions of control cells (without maspin) are polarized and elongated as their entropy value is lower.…”

“…It has been reported previously that maspin triggers several cellular processes which get reflected on cell behavior and cytoskeletal architecture (Odero-Marah et al, 2003;Qin & Zhang, 2010;Lara et al, 2012;Al-Mamun et al, 2016a). In a recent attempt, Al-Mamun et al, (2016b) showed that an image processing tool can be used to quantify three cellular parts: nuclei, cytoplasm and ruffling regions to observe the changes in shape and behavior.…”

“…But, exogenous activities of maspin are still debatable (Teoh et al, 2010;. To date, few computational attempts have been taken to investigate the fact that maspin resides exogenously and acts as cytoskeleton regulator by reducing cell migration and increasing cell-ECM adhesion (Al-Mamun et al, 2013;2016a). Recently, Al-Mamun et al, (2016b) presented a multidisciplinary quantitative image model where reduction of cell migration phenomena was investigated through both in vitro and computational study.…”

The Iron Chelator, Dp44mT, Effectively Inhibits Human Oral Squamous Cell Carcinoma Cell Growth in Vitro and in Vivo

“…We further demonstrated that incubation of SAS and OECM-1 cells with iron chelators enhanced the expressions of NDRG3 dose-dependently ( Figure 2 and Figure 3 ). Maspin is a non-inhibitory serpin and has been reported as a potential tumor suppressor gene in several cancers including OSCC [ 24 , 25 , 26 , 27 , 37 , 38 ]. Our results indicate that Dp44mT treatment enhanced Maspin expressions in SAS and OECM-1 cells; however, DFO increased Maspin expressions only in SAS cells, and deferasirox treatment did not affect Maspin expressions in both OSCC cell lines.…”

Combinations of SERPINB5 gene polymorphisms and environmental factors are associated with oral cancer risks

“…SERPINB5 was reported to be a tumor suppressor by inducing apoptosis and inhibiting proliferation, invasion, and migration of tumor cells [19, 20]. No studies had examined associations of SERPINB5 rs17071138 T/C , rs3744941 C/T , and rs8089104 T/C genetic polymorphisms with susceptibility to oral cancer.…”