Chemotactic Field Research Articles

Abstract A110: Detailed resolution analysis reveals spatial heterogeneity of T cell distribution in the invasive margin of colorectal cancer liver metastases

Abstract On a broader scale T cell density and localization in colorectal cancer liver metastases (CRC-LM) have prognostic and predictive implications, while T cell distribution at higher resolutions has not been fully investigated. As the invasive front of CRC-LM represents a clear border between malignant tissue and adjacent normal liver tissue, a detailed resolution analysis of T cell distribution in this region could be performed. Tissue areas of 1 square millimeter size from different patients were analyzed by high-throughput whole slide imaging technology, showing distinct density patterns of T cell localization in relation to the malignant tissue across the invasive margins. Unsupervised clustering revealed specific groups of patients with T cell aggregates limited to a given distance from the tumor. Furthermore, regions with T cells in close contact to the tumor usually had elevated T cell numbers further away from the tumor, whereas the intermediate area showed limited enrichment. There seems to be a distance of around 10 to 30 micrometer from the tumor where a decrease in T cells is common. Interestingly, 68 percent of distant T cells were identified to be in close contact with tumor-associated macrophages. Therefore, the spatial heterogeneity of T cell distribution in the invasive margin could be accounted for interactions with immunosuppressive cells, cell-matrix interactions or chemotactic fields potentially generated by tumor or endothelial cells, which is currently investigated. Whether the presence of the observed patterns has clinical importance and might change under therapy remains to be seen. In summary, this high resolution analysis of T cell distribution within the invasive front of CRC-LM reveals insights into the detailed localization of T cells and possible spatial immunosuppressive hurdles that need to be overcome by immunotherapies. The analysis of reversal of these spatial profiles could serve as a biomarker for successful therapies. Citation Format: Anna Berthel, Inka Zoernig, Meggy Suarez-Carmona, Christoph Kahlert, Fee Klupp, Alexis Ulrich, Juergen Weitz, Dirk Jaeger, Halama Niels. Detailed resolution analysis reveals spatial heterogeneity of T cell distribution in the invasive margin of colorectal cancer liver metastases [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A110.

A computational method for the coupled solution of reaction-diffusion equations on evolving domains and manifolds: Application to a model of cell migration and chemotaxis.

In this paper, we devise a moving mesh finite element method for the approximate solution of coupled bulk–surface reaction–diffusion equations on an evolving two dimensional domain. Fundamental to the success of the method is the robust generation of bulk and surface meshes. For this purpose, we use a novel moving mesh partial differential equation (MMPDE) approach. The developed method is applied to model problems with known analytical solutions; these experiments indicate second-order spatial and temporal accuracy. Coupled bulk–surface problems occur frequently in many areas; in particular, in the modelling of eukaryotic cell migration and chemotaxis. We apply the method to a model of the two-way interaction of a migrating cell in a chemotactic field, where the bulk region corresponds to the extracellular region and the surface to the cell membrane.

First-passage time of run-and-tumble particles

We solve the problem of first-passage time for run-and-tumble particles in one dimension. Exact expression is derived for the mean first-passage time in the general case, considering external force fields and chemotactic fields, giving rise to space-dependent swim speed and tumble rate. Agreement between theoretical formulae and numerical simulations is obtained in the analyzed case studies --constant and sinusoidal force fields, constant gradient chemotactic field. Reported findings can be useful to get insights into very different phenomena involving active particles, such as bacterial motion in external fields, intracellular transport, cell migration, animal foraging.

Abstract 795: Patterns of T-cell distribution at the invasive margin of colorectal cancer liver metastases: Downstream recruitment of T cells and spatial heterogeneity

Abstract The local immunological cancer microenvironment influences the clinical course of colorectal cancer. The interface between colorectal cancer liver metastases and adjacent normal liver represents a clear border. Typically, T cells in the vicinity of the tumor are located on the stromal compartment of the tumor and only few cells are in direct contact with the tumor epithelium. Patterns of T cell distribution at the invasive margin are heterogeneous and have not been analyzed systematically. Using high-throughput whole slide imaging technology, tissue areas of 1 mm2 size were analyzed for precise T cell density and localization, showing distinct density patterns of localization in relation to the malignant tissue across the invasive margins of samples from different patients. Unsupervised clustering revealed distinct patterns: regions with T cells in close contact to the tumor usually had significantly elevated T cell numbers further away from the tumor, whereas the other groups showed limited enrichment. Additionally, in the distance of around 20 to 40 µm from the tumor a decrease in T cells was found. The distribution of the cells in the tissues could be accounted for by cell-matrix interactions, immune cell – immune cell interactions or chemotactic fields potentially generated by tumor or other cells. Direct T cell – tumor interaction however leads to subsequent far-reaching attraction and activation of T cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 795. doi:10.1158/1538-7445.AM2011-795

Gradient sensing in defined chemotactic fields.

Cells respond to a variety of secreted molecules by modifying their physiology, growth patterns, and behavior. Motile bacteria and eukaryotic cells can sense extracellular chemoattractants and chemorepellents and alter their movement. In this way fibroblasts and leukocytes can find their way to sites of injury and cancer cells can home in on sites that are releasing growth factors. Social amoebae such as Dictyostelium are chemotactic to cAMP which they secrete several hours after they have initiated development. These eukaryotic cells are known to be able to sense extremely shallow gradients but the processes underlying their exquisite sensitivity are still largely unknown. In this study we determine the responses of developed cells of Dictyostelium discoideum to stable linear gradients of cAMP of varying steepness generated in 2 μm deep gradient chambers of microfluidic devices. The gradients are generated by molecular diffusion between two 80 μm deep flow-through channels, one of which is perfused with a solution of cAMP and the other with buffer, serving as continuously replenished source and sink. These low ceiling gradient chambers constrained the cells in the vertical dimension, facilitating confocal imaging, such that subcellular localization of fluorescently tagged proteins could be followed for up to 30 min without noticeable phototoxicity. Chemotactic cells enter these low ceiling chambers by flattening and elongating and then move almost as rapidly as unconstrained cells. By following the localization of activated Ras (RasGTP) using a Ras Binding Domain fused to Green Fluorescent Protein (RBD-GFP), we observed the rapid appearance of membrane associated patches at the tips of pseudopods. These patches remained associated with pseudopods while they continued to extend but were rapidly disassembled when pseudopods stalled and the cell moved past them. Likewise, fluorescence associated with localized RasGTP rapidly disappeared when the gradient was turned off. Correlation of the size and persistence of RasGTP patches with extension of pseudopods may set the rules for understanding how the signal transduction mechanisms convert a weak external signal to a strong directional bias.

Existence of global solutions of a macroscopic model of cellular motion in a chemotactic field

Existence of global classical solutions of a class of reaction–diffusion systems with chemotactic terms is demonstrated. This class contains a system of equations derived recently as a continuous limit of the stochastic discrete cellular Potts model. This provides mathematical justification for using numerical solutions of this system for modeling cellular motion in a chemotactic field.

Tumoral mast cells exhibit a common spatial distribution

Mast cells (MCs) accumulate in the stroma surrounding tumors and take part in the inflammatory reaction occurring at the margin of the neoplasia. Moreover, MC secretes angiogenic cytokines and matrix metalloproteinases. The aim of this study was to investigate the pattern of distribution of MCs in biopsy samples obtained from four different human tumors, utilizing an image analysis system and a mathematical model to make a quantitative approach to characterizing their spatial distribution. Results showed a similar spatial arrangement of MCs in all the neoplastic tissues examined, despite histological and/or pathologic differences. In all these tissues MCs demonstrated a virtually random spatial distribution, albeit with varying densities. These results suggest that MC–MC interactions could play a minor role in the formation of the MC pattern in neoplastic tissues. The random distribution of the cells in the tissues could be accounted for by a random walk-migration under the influence of cell-matrix interactions or chemotactic fields potentially generated by tumor or endothelial cells.

Modeling cell movement in anisotropic and heterogeneous network tissues

Cell motion and interaction with the extracellular matrix is studied deriving a kinetic model and considering its diffusive limit. The model takes into account the chemotactic and haptotactic effects, and obtains friction as a result of the interactions between cells and between cells and the fibrous environment. The evolution depends on the fibre distribution, as cells preferentially move along the fibre direction and tend to cleave and remodel the extracellular matrix when their direction of motion is not aligned with the fibre direction. Simulations are performed to describe the behavior of an ensemble of cells under the action of a chemotactic field and in the presence of heterogeneous and anisotropic fibre networks.

Chemotropism indices for polymorphonuclear leukocytes

Trajectories of polymorphonuclear leukocytes which are responding to a chemical gradient are analyzed in order to deduce probability distributions of the angles between successive path segments. The turn angle probability distributions thus obtained are seen to be strongly dependent on the direction of locomotion prior to a turn, in that cells usually turn to maintain alignment along an axis directed towards the chemoattractant source. A mathematical model based on these observations is developed in order to understand the relationship between net chemotactic response and parameters characterizing stochastic movements of individual cells. In particular, the manner in which the chemotropism index depends on details of the turn-angle distributions is examined. When bias in the direction of turn is induced by a chemotactic field, transition from random motion to directed response occurs most abruptly if the turn-angle distribution is narrow. "Accommodation," viz., a dependence of the mean angle of turn upon prior orientation, is found to have relatively little effect on the magnitude of the response.

A technique for studying chemotaxis of leucocytes in well-defined chemotactic fields

A new technique for observing the chemotaxis of leucocytes in well-defined chemotactic fields has been developed. This technique is also applicable to other studies in cell physiology in which an efficient method of generating known chemical concentration gradients on microscope slides is needed. This study reports the range of concentrations and gradients of cyclic adenosine 3′, 5′-monophosphate which will result in chemotactic ameboid motion of human polymorphonuclear granulocytes. We have identified a threshold gradient and a range of concentration near the solubility limit in which chemotaxis is impaired.

Experimental studies in insect parasitism. IX. The reactions of a stick insect to an alien parasite.

Eggs and larvae of an ichneumon fly, Nenteritis canescens , injected into adults of a stick insect, Carausius morosus , elicited two defence reactions. Dark material, probably melanin, was deposited on their surface; and they were invested with haemocytes which, within 24 h, formed unorganized clumps of irregular shape about them. The haemocytic reaction was less vigorous in confined spaces than in the main blood stream, and several observations support the view that the haemocytes did not flock to the parasite from a distance but accumulated by chance encounter of, at most, a small chemotactic field. The size of the clumps reached a maximum about 24 h after injection of the parasite. The melanin reaction, on the other hand, was as strong in confined spaces as in the main blood stream, and was progressive, eventually encasing the parasite in a brittle black sheath. In nymphs of 1/2, and in young nymphs of 1/20, adult weight, the two reactions were essentially the same as in adults; the melanin reaction was indistinguishable from that in the adult; the haemocytic reaction in the large nymphs was a little, and in the small nymphs was much, less massive. The deposition of melanin about the parasite was inhibited by simultaneous injection of phenylthiourea. The haemocytic reaction could not be inhibited by injections of Chinese ink, because blood cells blackened by the carbon particles they had engulfed nevertheless invested the parasite. The two reactions were elicited both by living and by dead parasites; the haemocytic reaction appeared to be elicited by clean glass rods, but the melanin reaction was not. Most Nenteritis eggs failed to hatch in Carausius although the fully developed larva could be seen moving within them, and no Nenteritis larva was observed to live longer than 48 h in this host. But larvae that had hatched in Carausius and after 24 h were transferred to the normal host, Ephestia , lived and developed. Moreover, eggs hatched normally in the blood of Carausius in hanging-drop cultures, and the larvae lived as long as 75 h. The death of this parasite in Carausius does not appear to be due either to toxic properties of the blood as a fluid, or to its unsuitability as food, but to active processes, the haemocytic and melanin reactions, that take place in the living host.