Transforming growth factor (TGF) $\beta$ is known to have properties of both a tumor suppressor and a tumor promoter. While it inhibits cell proliferation, it also increases cell motility and decreases cell--cell adhesion. Coupling mathematical modeling and experiments, we investigate the growth and motility of oncogene--expressing human mammary epithelial cells under exposure to TGF--$\beta$. We use a version of the well--known Fisher--Kolmogorov equation, and prescribe a procedure for its parametrization. We quantify the simultaneous effects of TGF--$\beta$ to increase the tendency of individual cells and cell clusters to move randomly and to decrease overall population growth. We demonstrate that in experiments with TGF--$\beta$ treated cells \textit{in vitro}, TGF--$\beta$ increases cell motility by a factor of 2 and decreases cell proliferation by a factor of 1/2 in comparison with untreated cells.
Deep Dive into A mathematical model quantifies proliferation and motility effects of TGF--$beta$ on cancer cells.
Transforming growth factor (TGF) $\beta$ is known to have properties of both a tumor suppressor and a tumor promoter. While it inhibits cell proliferation, it also increases cell motility and decreases cell–cell adhesion. Coupling mathematical modeling and experiments, we investigate the growth and motility of oncogene–expressing human mammary epithelial cells under exposure to TGF–$\beta$. We use a version of the well–known Fisher–Kolmogorov equation, and prescribe a procedure for its parametrization. We quantify the simultaneous effects of TGF–$\beta$ to increase the tendency of individual cells and cell clusters to move randomly and to decrease overall population growth. We demonstrate that in experiments with TGF–$\beta$ treated cells \textit{in vitro}, TGF–$\beta$ increases cell motility by a factor of 2 and decreases cell proliferation by a factor of 1/2 in comparison with untreated cells.
In normal organisms, the growth of cells is under tight regulation by growth factors and is highly dependent on the developmental stage during the lifespan of the organism. Disruption of this regulation is the most frequent cause of cancer diseases. Unlike normal differentiated cells, cancer cells are usually hyperproliferative as a result of the abnormal activation of multiple growth-stimulating intracellular signalling pathways and loss of tumour suppressors. In cancer cells, these pathways do not respond to normal regulatory signals but are manipulated by one or more oncogenic signals, often encoded by oncogenes. Expression of oncogenes alters signalling pathways that under normal conditions maintain cell growth homeostasis. Thus, altering these pathways may favour increased cell and cancer growth. A good example is the transforming growth factor (TGF) β family, which is known to be able to act as both a tumour suppressor and tumour promoting factor.
The TGF-β family consists of multitasking cytokines that play important roles in cell proliferation, cell motility, apoptosis, lineage determination, extracellular matrix production, and modulation of immune function [22]. These ligands November 23, 2021 21:13
Computational and Mathematical Methods in Medicine TGF-beta˙May˙1 2 S. E. Wang et al. bind to a heteromeric complex of transmembrane serine/threonine kinases, the type I and type II receptors (TβRI and TβRII). The receptors are activated upon ligand binding, leading to the subsequent phosphorylation and activation of a family of transcription factors called Smads, which regulate transcription of a subset of genes [23]. In addition to Smads, other signalling pathways have been implicated in TGF-β actions in recent studies. These include the extracellular signal-regulated kinase (ERK, MAPK), c-Jun NH2-terminal kinase (JNK), p38MAPK, phosphatidylinositol-3 kinase (PI3K), and Rho GTPases (reviewed in [7,11,39,43]). The critical role of these non-Smad pathways on mediating the cellular effects of TGF-β remains to be fully characterised.
TGF-β was originally reported to induce transformation of mouse fibroblasts [24]. Subsequent studies indicated that TGF-β is a potent inhibitor of cell proliferation and a tumour suppressor [32,36]. Consistent with its tumour suppressor role, many cancers lose or attenuate TGF-β-mediated anti-mitogenic action by mutational inactivation of TGF-β receptors or their signal transducer Smads [13,15,16,20,40,41]. There is increasing evidence to show that excess production and/or activation of TGF-β in tumours can accelerate cancer progression through enhancement of tumour cell motility and survival, increase in tumour angiogenesis, extracellular matrix production and peritumoural proteases, and the inhibition of immune surveillance mechanisms in the cancer host (reviewed in [7,9,11]). Cancer progression and metastasis consist of a series of sequential events. After initial cell transformation, often mediated by the function of oncogenes, tumour cells growing at the primary site will invade the surrounding stroma and migrate towards blood vessels. Through various mechanisms such as epithelial-mesenchymal transition (EMT), tumour cells will enter the blood vessels and travel to other parts of the body through the circulatory system. Some of the cells will then arrest at distant sites where they may proliferate and invade into the adjacent organs. Cell motility is therefore a critical element during the spread of tumour cells from their initial sites of residence. In this study, we focus on the tumour-promoting effect of TGF-β through inducing cell motility.
The receptor tyrosine kinase HER2 (ErbB2, Neu) belongs to the family of epidermal growth factor receptor (EGFR). Gene amplification or overexpression of HER2 is observed in about 25% of breast cancers. TGF-β has been shown to synergize with the oncogene ErbB2 in cancer progression. Overexpression of active TGF-β 1 or active mutants TβRI (Alk5) in the mammary gland of bigenic mice also expressing mouse mammary tumour virus (MMTV)/Neu (ErbB2) accelerates metastases from Neu-induced mammary cancers [25,26,27,35]. Exogenous as well as transduced TGF-β confer motility and invasiveness to MCF10A nontransformed human mammary epithelial cells (HMEC) stably expressing transfected HER2 [34,38]. Expression of the oncogene HER2 in these cells does not affect the function of TGF-β on inhibiting cell proliferation [38]. It is likely that in many cancers, TGF-β may still attenuate proliferation while inducing cellular events associated with metastatic dissemination, such as cell motility. In this paper we report experiments with MCF10A/HER2 cells to study and to separate the effects of TGF-β on cell proliferation and motility. Due to the complexity of TGF-β signalling that simultaneously affects several biological parameters, it is important to computationally simulate the behaviour of cells under TGF-β exposure. Our model, which can also b
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