scholarly journals A mathematical framework for modelling the metastatic spread of cancer

2018 ◽  
Author(s):  
Linnéa C Franßen ◽  
Tommaso Lorenzi ◽  
Andrew EF Burgess ◽  
Mark AJ Chaplain
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Complex Disease ◽  
Single Cells ◽  
The Body ◽  
Metastatic Spread ◽  
Surrounding Tissue ◽  
Mathematical Framework ◽  
Cell Clusters ◽  
Modelling Framework

AbstractCancer is a complex disease that starts with mutations of key genes in one cell or a small group of cells at a primary site in the body. If these cancer cells continue to grow successfully and, at some later stage, invade the surrounding tissue and acquire a vascular network (tumour-induced angiogenesis), they can spread to distant secondary sites in the body. This process, known as metastatic spread, is responsible for around 90% of deaths from cancer and is one of the so-called hallmarks of cancer.To shed light on the metastatic process, we present a mathematical modelling framework that captures for the first time the interconnected processes of invasion and metastatic spread of individual cancer cells in a spatially explicit manner — a multi-grid, hybrid, individual-based approach. This framework accounts for the spatio-temporal evolution of mesenchymal- and epithelial-like cancer cells, as well as MT1-MMP and MMP-2 dynamics, and interactions with the extracellular matrix.Using computational simulations, we demonstrate that our model captures all the key steps of the invasion-metastasis cascade, i.e. invasion by both heterogeneous cancer cell clusters and by single mesenchymal-like cancer cells; intravasation of these clusters and single cells both via active mechanisms mediated by matrix degrading enzymes (MDEs) and via passive shedding; circulation of cancer cell clusters and single cancer cells in the vasculature with the associated risk of cell death and disaggregation of clusters; extravasation of clusters and single cells; and metastatic growth at distant secondary sites in the body. By faithfully reproducing experimental results, our simulations support the evidence-based hypothesis that the membrane-bound MT1-MMP is the main driver of invasive spread rather than diffusible MDEs like MMP-2.

scholarly journals Rigid tumors contain soft cancer cells

2021 ◽  
Author(s):  
Thomas Fuhs ◽  
Franziska Wetzel ◽  
Anatol Fritsch ◽  
Xinzhi Li ◽  
Roland Stange ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Primary Tumor ◽  
Single Cells ◽  
Tissue Level ◽  
Surrounding Tissue ◽  
Primary Tumors ◽  
Tumor Mass ◽  
Cell Clusters ◽  
Cell Shapes

Abstract Palpation, as already mentioned in the ancient Egyptian medical text Ebers Papyrus, utilizes that solid tumors are stiffer than the surrounding tissue. However, cancer cell lines tend to soften, which may intuitively foster invasion by enhancing the ability of cancer cells to squeeze through dense tissue. This paradox raises questions besides the oxymoron itself: Does softness emerge from adaptation to the external microenvironment? Or are soft cells already present inside a rigid primary tumor mass to support cancer cell unjamming? We investigate primary tumor explants from patients with breast and cervix carcinomas on multiple length scales from the tissue level down to single cells. We find that primary tumors are highly heterogeneous in their mechanical properties. From the tissue level this heterogeneity persists down to the scale of individual cells in cancer cell clusters, resulting in a broad distribution of cell rigidities with a higher fraction of softer, more squeezable cells. Plus, squeezed cell shapes correlate with cancer cell motility. Mechanical modelling based on patient data reveals that a tumor mass as a whole is able to maintain a rigid, solid behavior even when it contains a significant fraction of very soft cells. Cell softening induced cancer cell unjamming generates heterogeneous cancer cell clusters with a solid backbone of rigid cells surrounded by soft motile cells.

scholarly journals Hydrodynamic stress stimulates growth of cell clusters via the ANXA1/PI3K/AKT axis in colorectal cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Takeshi Hagihara ◽  
Jumpei Kondo ◽  
Hiroko Endo ◽  
Masayuki Ohue ◽  
Yoshiharu Sakai ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Single Cells ◽  
Membrane Damage ◽  
Metastatic Potential ◽  
Blood Stream ◽  
Cancer Tissue ◽  
Hydrodynamic Stress ◽  
Cell Clusters

AbstractCancer cells are exposed to various stresses in vivo, including hydrodynamic stress (HDS). HDS on cancer cells in the blood stream can influence the metastatic potential. Recent studies revealed that circulating tumor cell clusters are more responsible for metastasis than circulating single cells. Nevertheless, most studies on HDS are based on single cells prepared from established cancer cell lines. Here, we used cancer tissue-originated spheroids (CTOS) as a patient-derived, 3D organoid model to investigate the effect of HDS on cancer cell clusters. We found that HDS induced the growth of cancer cell clusters in a population of colorectal CTOSs. Microarray analyses revealed that the multifunctional protein, Annexin 1 (ANXA1), was upregulated upon HDS exposure. Chemically-induced membrane damage also triggered the expression of ANXA1. A knockdown of ANXA1 revealed that ANXA1 regulated HDS-stimulated growth in colorectal CTOSs. Mechanistically, activating the PI3K/AKT pathway downstream of ANXA1 contributed to the phenotype. These findings demonstrate that HDS induces the growth of cancer cell clusters via ANXA1/PI3K/AKT axis, which helps to elucidate the pro-metastatic feature of circulating cancer cell clusters.

scholarly journals A mathematical multi-organ model for bidirectional epithelial–mesenchymal transitions in the metastatic spread of cancer

2020 ◽  
Vol 85 (5) ◽  
pp. 724-761 ◽  
Author(s):  
Linnea C Franssen ◽  
Mark A J Chaplain
Keyword(s):  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Tumour Microenvironment ◽  
The Body ◽  
Metastatic Spread ◽  
Mathematical Framework ◽  
Mesenchymal Transition ◽  
Epithelial Phenotype ◽  
Organ Model ◽  
Cell Dormancy

Abstract Cancer invasion and metastatic spread to secondary sites in the body are facilitated by a complex interplay between cancer cells of different phenotypes and their microenvironment. A trade-off between the cancer cells’ ability to invade the tissue and to metastasize, and their ability to proliferate has been observed. This gives rise to the classification of cancer cells into those of mesenchymal and epithelial phenotype, respectively. Additionally, mixed phenotypic states between these two extremes exist. Cancer cells can transit between these states via epithelial–mesenchymal transition (EMT) and the reverse process, mesenchymal–epithelial transition (MET). These processes are crucial for both the local tissue invasion and the metastatic spread of cancer cells. To shed light on the role of these phenotypic states and the transitions between them in the invasive and metastatic process, we extend our recently published multi-grid, hybrid, individual-based mathematical metastasis framework (Franssen et al. 2019, A mathematical framework for modelling the metastatic spread of cancer. Bull. Math. Biol., 81, 1965). In addition to cancer cells of epithelial and of mesenchymal phenotype, we now also include those of an intermediate partial-EMT phenotype. Furthermore, we allow for the switching between these phenotypic states via EMT and MET at the biologically appropriate steps of the invasion-metastasis cascade. We also account for the likelihood of spread of cancer cells to the various secondary sites and differentiate between the tissues of the organs involved in our simulations. Finally, we consider the maladaptation of metastasized cancer cells to the new tumour microenvironment at secondary sites as well as the immune response at these sites by accounting for cancer cell dormancy and death. This way, we create a first mathematical multi-organ model that explicitly accounts for EMT-processes occurring at the level of individual cancer cells in the context of the invasion-metastasis cascade.

scholarly journals Curcumin Inhibits Cell Proliferation, Stimulates Apoptosis and Down-Regulates Aldehyde Dehydrogenase Expresion in Gastric cancer Cell line MKN45

2020 ◽  
Vol 36 (3) ◽  
Author(s):  
Nguyen Phu Hung ◽  
Le Thi Thanh Huong ◽  
Nguyen Trung Thanh
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Stomach Cancer ◽  
Cancer Cell ◽  
Aldehyde Dehydrogenase ◽  
Gastric Cancer Cell ◽  
Gastric Cancer Cell Line ◽  
The Body ◽  
World Health ◽  
The World

According to estimates by the World Health Organization (WHO), in 2018 there were over one million new stomach cancer patients. Vietnam ranks the tenth among the countries with the highest rates of stomach cancer in the world, with the rate of 15.9 cases per 100,000 populations. Research on compounds or drugs that can inhibit cancer cell growth but are less toxic to the body is necessary. In this study, using MTT assays, we have shown that curcumin has ability to inhibit proliferation of stomach cancer cells MKN45. Flow cytometry analysis showed that curcumin increased the percentage of apoptosis cells by 27 - 56% at concentrations of 10 µM - 20 µM and resulted in a typical nuclear morphology of apoptosis. Further, this study showed that curcumin significantly reduced the expression of aldehyde dehydrogenase protein in MKN45 gastric cancer cells. This finding shows that curcumin is a potential therapeutic candidate for gastric cancer cell treatment.

MATHEMATICAL MODELLING OF CANCER CELL INVASION OF TISSUE: THE ROLE OF THE UROKINASE PLASMINOGEN ACTIVATION SYSTEM

2005 ◽  
Vol 15 (11) ◽  
pp. 1685-1734 ◽  
Author(s):  
M. A. J. CHAPLAIN ◽  
G. LOLAS
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Cell Invasion ◽  
The Body ◽  
Plasminogen Activation ◽  
Cancer Cell Invasion ◽  
Plasminogen Activation System ◽  
Activation System ◽  
Spatio Temporal

The growth of solid tumours proceeds through two distinct phases: the avascular and the vascular phase. It is during the latter stage that the insidious process of cancer invasion of peritumoral tissue can and does take place. Vascular tumours grow rapidly allowing the cancer cells to establish a new colony in distant organs, a process that is known as metastasis. The progression from a single, primary tumour to multiple tumours in distant sites throughout the body is known as the metastatic cascade. This is a multistep process that first involves the over-expression by the cancer cells of proteolytic enzyme activity, such as the urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs). uPA itself initiates the activation of an enzymatic cascade that primarily involves the activation of plasminogen and subsequently its matrix degrading protein plasmin. Degradation of the matrix then enables the cancer cells to migrate through the tissue and subsequently to spread to secondary sites in the body. In this paper we consider a mathematical model of cancer cell invasion of tissue (extracellular matrix) which focuses on the role of the plasminogen activation system. The model consists of a system of reaction-diffusion-taxis partial differential equations describing the interactions between cancer cells, urokinase plasminogen activator (uPA), uPA inhibitors, plasmin and the host tissue. The focus of the modelling is on the spatio-temporal dynamics of the uPA system and how this influences the migratory properties of the cancer cells through random motility, chemotaxis and haptotaxis. The results obtained from numerical computations carried out on the model equations produce rich, dynamic heterogeneous spatio-temporal solutions and demonstrate the ability of rather simple models to produce complicated dynamics, all of which are associated with tumour heterogeneity and cancer cell progression and invasion.

scholarly journals Inhibition of Ovarian Cancer Cell Spheroid Formation by Synthetic Peptides Derived from Nectin-4

2020 ◽  
Vol 21 (13) ◽  
pp. 4637
Author(s):  
Kristin L.M. Boylan ◽  
Rory D. Manion ◽  
Heena Shah ◽  
Keith M. Skubitz ◽  
Amy P. N. Skubitz
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Synthetic Peptides ◽  
Ovarian Cancer Cell ◽  
Single Cells ◽  
Ovarian Cancer Cells ◽  
Dependent Manner ◽  
Spheroid Formation ◽  
Multicellular Spheroids

The formation of 3D multicellular spheroids in the ascites fluid of ovarian cancer patients is an understudied component of the disease progression. Spheroids are less sensitive to chemotherapy, in part due to the protection afforded by their structure, but also due to their slower proliferation rate. Previous studies suggest that the cell adhesion molecule Nectin-4 plays a key role in the formation of ovarian cancer spheroids. In this study, we further examined the role of Nectin-4 at early time points in spheroid formation using real-time digital photography. Human NIH:OVCAR5 ovarian cancer cells formed aggregates within 8 h, which further contracted into compact spheroids over 24 h. In contrast, Nectin-4 knockdown cells did not form tightly compacted spheroids. Synthetic peptides derived from Nectin-4 were tested for their ability to alter spheroid formation in two ovarian cancer cell lines. Nectin-4 peptide 10 (N4-P10) had an immediate effect on disrupting ovarian cancer spheroid formation, which continued for over 24 h, while a scrambled version of the peptide had no effect. N4-P10 inhibited spheroid formation in a concentration-dependent manner and was not cytotoxic; suggesting that N4-P10 treatment could maintain the cancer cells as single cells which may be more sensitive to chemotherapy.

scholarly journals Mesenchymal stem cells carry and transport clusters of cancer cells

2021 ◽  
Author(s):  
Jana Zarubova ◽  
Mohammad Mahdi Hasani-Sadrabadi ◽  
Sam CP Norris ◽  
Andrea M Kasko ◽  
Song Li
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cell Migration ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cancer Cell ◽  
Cell Types ◽  
Cell Clusters ◽  
Different Cell Types

AbstractCell clusters that collectively migrate from primary tumors appear to be far more potent in forming distant metastases than single cancer cells. A better understanding of collective cell migration phenomenon and the involvement of different cell types during this process is needed. Here, we utilize a micropatterned surface composed of a thousand of low-adhesive microwells to screen motility of spheroids containing different cell types by analyzing their ability to move from the bottom to the top of the microwells. Mesenchymal stem cells (MSCs) spheroid migration was efficient in contrast to cancer cell only spheroids. In spheroids with both cell types mixed together, MSCs were able to carry the low-motile cancer cells during migration. As the percentage of MSCs increased in the spheroids, more migrating spheroids were detected. Extracellular vesicles secreted by MSCs also contributed to the pro-migratory effect exerted by MSCs. However, the transport of cancer cells was more efficient when MSCs were physically present in the cluster. Similar results were obtained when cell clusters were encapsulated within a micropatterned hydrogel, where collective migration was guided by micropatterned matrix stiffness. These results suggest that stromal cells facilitate the migration of cancer cell clusters, which is contrary to the general belief that malignant cells metastasize independently.SignificanceDuring metastasis, tumor cells may migrate as a cluster, which exhibit higher metastatic capacity compared to single cells. However, whether and how non-cancer cells contained in tumor cluster regulate it’s migration is not clear. Here, we utilize two unique approaches to study collective tumor cell migration in vitro: first, in low-adhesive microwells and second, in micropatterned hydrogels to analyze migration in 3D microenvironment. Our results indicate that MSCs in tumor cell clusters could play an important role in the dissemination of cancer cells by actively transporting low-motile cancer cells. In addition, MSC-released paracrine factors also increase the motility of tumor cells. These findings reveal a new mechanism of cancer cell migration and may lead to new approaches to suppress metastases.

A Novel 3D Co-Culture System for Isolation and Amplification of Primary Liquid Cancer Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 426-426
Author(s):  
Carlos Caicedo-Carvajal ◽  
Qing Liu ◽  
Andre Goy ◽  
Andrew L Pecora ◽  
Anthony R Mato ◽  
...  
Keyword(s):  
Cell Culture ◽  
Cancer Cells ◽  
Culture System ◽  
Single Cells ◽  
Primary Cancer ◽  
3D Scaffold ◽  
Lymphoma Cells ◽  
3D Scaffolds ◽  
Cell Clusters

Abstract Abstract 426 One of the important challenges in screening anti-cancer drugs is the lack of available “primary cultures systems” that is easy to use to screen new compounds or their combinations. The low yield of primary cancer cell cultures is mainly due to suboptimum environment in vitro and inefficient 2-dimensional cell culture conditions. To create an optimum in vitro environment, lymphoma cell lines were grown in 3-dimension model by using a scaffold and the stromal cells derived from neonatal foreskin was used as the feeder component. This 3-dimensional (3D) stromal co-culture generates an in-vitro model that may mimic the conditions/microenvironment of blood cancer cells interacting with stromal compartments. A specific 3D tissue culture scaffold 3D Insert-PS™ (300 μ m in fiber diameter and 400μ m in pore size) significantly enhances the cell proliferation and maintenance of liquid cancer cells in comparison to 2D stromal co-culture control. The combination of the neonatal stroma cells, a novel 3D scaffold, the constant gyration and a frequent nutrient stimulation allows the lymphoma cells to proliferate 10-fold faster than the cells grown in 2D under the same condition. Starting from the 2nd day of 3D cell culture, these lymphoma cells grew to form layers of aggregated clusters and caused disappearance of single cells morphology and phenotype that is typical of cells growing in suspension. The cell aggregates are continuously produced from the 3D scaffold, subsequently dislodge from the scaffold and then remain viable at the bottom of the dish below the scaffold. When the cell clusters are harvested and cultured in 3D condition, the contamination of fibroblasts is over 1,000 fold less than the cell clusters that are generated from 2D environment. In addition, the clusters of cancer cells generated from 3D co-culture using 3D scaffolds contained the fibroblasts contamination that is less than 0.00001% of the total cell count, suggesting that this novel 3D environment can be implicated for the isolation of primary lymphoma/cancer cells from patient's blood or tissue specimen. To investigate this feasibility, <1% lymphoma cells were premixed with 100 fold excess of neonatal stroma cells, and the mixture was grown using our 3D scaffolds. In 7 days, the 3D culture system was able to amplify lymphoma cells over 100 fold or over 10,000 % of the starting cell number. This preliminary data indicate that this 3D scaffold and co-culturing environment can be customized to amplify primary cancer cells from blood or tumor tissues and subsequently used for personalized drug screening procedures. Disclosures: Goy: Allos Therapeutics, Inc.: Consultancy, Honoraria.

scholarly journals Cancer Metastases to Bone: Concepts, Mechanisms, and Interactions with Bone Osteoblasts

Cancers ◽  
2018 ◽  
Vol 10 (6) ◽  
pp. 182 ◽  
Author(s):  
Alison Shupp ◽  
Alexus Kolb ◽  
Dimpi Mukhopadhyay ◽  
Karen Bussard
Keyword(s):  
Breast Cancer ◽  
Bone Resorption ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Metastatic Cancer ◽  
The Body ◽  
Bone Homeostasis ◽  
Inflammatory Stress ◽  
Bone Gain

The skeleton is a unique structure capable of providing support for the body. Bone resorption and deposition are controlled in a tightly regulated balance between osteoblasts and osteoclasts with no net bone gain or loss. However, under conditions of disease, the balance between bone resorption and deposition is upset. Osteoblasts play an important role in bone homeostasis by depositing new bone osteoid into resorption pits. It is becoming increasingly evident that osteoblasts additionally play key roles in cancer cell dissemination to bone and subsequent metastasis. Our laboratory has evidence that when osteoblasts come into contact with disseminated breast cancer cells, the osteoblasts produce factors that initially reduce breast cancer cell proliferation, yet promote cancer cell survival in bone. Other laboratories have demonstrated that osteoblasts both directly and indirectly contribute to dormant cancer cell reactivation in bone. Moreover, we have demonstrated that osteoblasts undergo an inflammatory stress response in late stages of breast cancer, and produce inflammatory cytokines that are maintenance and survival factors for breast cancer cells and osteoclasts. Advances in understanding interactions between osteoblasts, osteoclasts, and bone metastatic cancer cells will aid in controlling and ultimately preventing cancer cell metastasis to bone.

scholarly journals Tumour-suppressor microRNAs regulate ovarian cancer cell physical properties and invasive behaviour

Open Biology ◽  
2016 ◽  
Vol 6 (11) ◽  
pp. 160275 ◽  
Author(s):  
Clara K. Chan ◽  
Yinghong Pan ◽  
Kendra Nyberg ◽  
Marco A. Marra ◽  
Emilia L. Lim ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Physical Properties ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Single Cells ◽  
Tumour Suppressor ◽  
Ovarian Cancer Cells ◽  
Human Ovarian Cancer ◽  
The Impact

The activities of pathways that regulate malignant transformation can be influenced by microRNAs (miRs). Recently, we showed that increased expression of five tumour-suppressor miRs, miR-508-3p, miR-508-5p, miR-509-3p, miR-509-5p and miR-130b-3p, correlate with improved clinical outcomes in human ovarian cancer patients, and that miR-509-3p attenuates invasion of ovarian cancer cell lines. Here, we investigate the mechanism underlying this reduced invasive potential by assessing the impact of these five miRs on the physical properties of cells. Human ovarian cancer cells (HEYA8, OVCAR8) that are transfected with miR mimics representing these five miRs exhibit decreased invasion through collagen matrices, increased cell size and reduced deformability as measured by microfiltration and microfluidic assays. To understand the molecular basis of altered invasion and deformability induced by these miRs, we use predicted and validated mRNA targets that encode structural and signalling proteins that regulate cell mechanical properties. Combined with analysis of gene transcripts by real-time PCR and image analysis of F-actin in single cells, our results suggest that these tumour-suppressor miRs may alter cell physical properties by regulating the actin cytoskeleton. Our findings provide biophysical insights into how tumour-suppressor miRs can regulate the invasive behaviour of ovarian cancer cells, and identify potential therapeutic targets that may be implicated in ovarian cancer progression.

Sign in / Sign up

Export Citation Format

Share Document