Chemotaxis Model for Breast Cancer Cells Based on Signal/Noise Ratio

Abstract

Chemotaxis, a biased migration of cells under a chemical gradient, plays a significant role in diverse biological phenomena including cancer metastasis. Stromal cells release signaling proteins to induce chemotaxis, which leads to organ-specific metastasis. Epidermal growth factor (EGF) is an example of the chemical attractants, and its gradient stimulates metastasis of breast cancer cells. Hence, the interactions between EGF and breast cancer cells have long been a subject of interest for oncologists and clinicians. However, most current approaches do not systematically separate the effects of gradient and absolute concentration of EGF on chemotaxis of breast cancer cells. In this work, we develop a theoretical model based on signal/noise ratio to represent stochastic properties and report our microfluidic experiments to verify the analytical predictions from the model. The results demonstrate that even under the same EGF concentration gradients (0-50 or 0-150 ng/mL), breast cancer cells reveal a more evident chemotaxis pattern when the absolute EGF concentrations are low. Moreover, we found that reducing the number of EGF receptors (EGFRs) with addition of EGFR antibody (1 ng/mL) can promote chemotaxis at an EGF gradient of 0-1 ng/mL as shown by chemotaxis index (0.121 5 0.037, reduced EGFRs vs. 0.003 5 0.041, control). This counterintuitive finding suggests that EGFR-targeted therapy may stimulate metastasis of breast cancer because the partial suppression of the receptors makes the number of receptors close to the optimal one for chemotaxis. This analysis should be considered in anticancer drug design.

Cytotoxic T cells swarm by homotypic chemokine signalling

“…Cells close to the tumouroid start moving towards it at early timepoints but lose some of their directionality over time ( Figure 3E). It has previously been shown that chemotactic responses can be lost under excess local concentrations of ligand (Lim, Nam, and Jeon 2018), which could account for the behaviour observed here. For cells furthest from the tumouroid, directional migration commences at later timepoints ( Figure 3E).…”

“…As additional antigen-specific CTLs are recruited and engage cognate targets, they contribute to the chemoattractive signal, thus further amplifying CTL recruitment in a positive feedback loop, which leads to swarming behaviour. Interestingly, it appears as though CTLs closest to the source of the chemotactic signal become desensitised over time and lose directional bias, which could be due to exposure to excess ligand concentrations ( Lim et al, 2018 ) or rapid internalisation of the CCR5 receptor ( Escola et al, 2010 ).…”

Protective Role of IRBIT on Sodium Bicarbonate Cotransporter-n1 for Migratory Cancer Cells

“…Epidermal growth factor (EGF)/EGF receptor (EGFR) signaling is a key factor in tumor growth and the development of metastasis, and is considered a target for chemotaxis in cancer therapy [ 44 , 45 , 46 , 47 ]. In order to explore the role of EGF signaling on cell migration, migration of invasive A549 cells into agarose spots was compared between EGF (recombinant human EGF)-treated and control conditions, and between IRBIT-overexpressed and IRBIT-knockdown conditions ( Figure 6 A).…”

Invasion of homogeneous and polyploid populations in nutrient-limiting environments

“…Models of infiltration are typically formulated under two critical assumptions. First, that energy production and consumption are non-uniform, leading to the formation of an energy gradient [51][52][53]; or second, that energy consumption is very slow compared to production, leading to an essentially infinite energetic resource [54].…”