Cell-extracellular Matrix Interactions Research Articles

Triple-negative mouse breast cancer initiating cells show high expression of beta1 integrin and increased malignant features.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that exhibits aggressive tumor phenotypes, including rapid metastasis and tumor recurrence. Integrins belong to the family of transmembrane glycoproteins involved in regulating cell adhesion, proliferation, and differentiation through cell-cell and cell-extracellular matrix interactions. Aberrant β1 integrin signaling has been implicated in cancer invasion and metastasis processes. The present work aimed to investigate the role of β1 integrin in TNBC cancer progression using a mouse 4T1 cell line as a model system. We have sorted a subset of tumor-initiating cells (TICs) from the 4T1 cell line based on CD133 positivity by flow cytometry. RT-PCR and protein analysis studies showed the transcriptional upregulation of β1 integrin and its downstream target focal adhesion kinase in 4T1-TICs compared to parental 4T1 cells. In addition, the expression of β1 receptors in TICs is significantly higher than in parental population cells. Furthermore, in vitro cellular assays revealed that CD133+ TICs have higher clonogenic ability, invasion, and sphere formation potential. These findings suggest that β1 integrin has a potential role in TNBC invasion and metastasis. Hence, β1 integrin could be a possible factor for future targeted cancer therapies.

Role of GPR56 in Platelet Activation and Arterial Thrombosis.

The adhesion G protein-coupled receptor GPR56 mediates cell-cell and cell-extracellular matrix interactions. To examine the function of GPR56 in platelet activation and arterial thrombosis, we generated GPR56-knockout mice and evaluated GPR56 expression in human and mouse platelets. The results revealed that the levels of the GPR56 N-terminal fragment were significantly higher on the first day after myocardial infarction than on the seventh day in the plasma of patients with ST-segment-elevation myocardial infarction. Next, we investigated the effects of GPR56 on platelet function in vitro and in vivo. We observed that collagen-induced aggregation and adenosine triphosphate release were reduced in Gpr56 -/- platelets. Furthermore, P-selectin expression on the Gpr56 -/- platelet surface was also reduced, and the spreading area on immobilized collagen was decreased in Gpr56 -/- platelets. Furthermore, collagen-induced platelet activation in human platelets was inhibited by an anti-GPR56 antibody. Gpr56 -/- mice showed an extended time to the first occlusion in models with cremaster arteriole laser injury and FeCl3-induced carotid artery injury. GPR56 activated the G protein 13 signaling pathway following collagen stimulation, which promoted platelet adhesion and thrombus formation at the site of vascular injury. Thus, our study confirmed that GPR56 regulated the formation of arterial thrombosis. Inhibition of the initial response of GPR56 to collagen could significantly inhibit platelet activation and thrombus formation. Our results provide new insights for research into antiplatelet drugs.

Abstract P6-14-09: Non-canonical Wnt/Ror2 signaling regulates tumor cell invasion and dissemination in breast cancer through cell-matrix crosstalk

Abstract BACKGROUND: Metastasis is the main cause of mortality for breast cancer patients. The early steps of cancer metastasis require that tumor cells actively invade and disseminate from the primary tumor to distant organs. Cell-extracellular matrix (ECM) interactions represent fundamental interactions during tumor invasion and metastasis, yet how particular signal-transduction factors prompt the conversion of tumor cells into migratory populations capable of systemic dissemination remains elusive. OBJECTIVES: Wnt signaling is a known regulator of cell fate, migration, and polarity during various key biological processes. We previously discovered an inverse correlation between the canonical Wnt signature and a non-canonical Wnt receptor, Ror2, across breast cancers in TCGA. The objective of this study is to investigate how canonical and non-canonical Wnt signaling orchestrate tumor cell behavior during cancer invasion and metastasis. METHODS: We used clinically relevant syngeneic TP53-null Genetically Engineered Mouse Model (GEMM) tumors that molecularly reflect the different breast cancer intrinsic subtypes. In vivo transplantation of GEMM models and in vitro 3D tumor organoids were employed to elucidate the molecular mechanism underlying the migration, invasion, and metastasis of tumor cells upon genetic perturbation of Wnt/Ror2 signaling. RESULTS/DISCUSSION: From 3-dimensional (3D) tumor organoid models, we identified novel transcriptional alterations encompassing cell-cell adhesion, cytoskeletal remodeling, and ECM organization upon Ror2 loss. At protein levels, we discovered a significant increase in collagen fibril organization and integrin-α5 and integrin-β3 expression following Ror2 depletion. In addition, the matrisomal protein fibronectin (FN) was concomitantly upregulated and assembled in Ror2-deficient tumor cells at sites of invasion. Consequently, we observed FAK activation and actin cytoskeleton alterations in Ror2-deficient tumor cells, leading to a promigratory tumor cell behavior. The altered cytoskeleton and cell-ECM interaction enhanced the rigidity of the Ror2-depleted cells. Furthermore, Inhibition of either integrin or FAK activation abrogated the increased invasion driven by Ror2-loss. Unexpectedly, these changes were distinct from processes regulated by Wnt/ß-catenin activation. From both spontaneous metastasis and experimental metastasis models, we discovered a shift from canonical to non-canonical Wnt signaling throughout the progression of lung metastasis, indicating that the balance of Wnt signaling may serve as a switch to dictate cell functions at different stages of metastatic development. Consistently, we found enhanced initial colonization in the lungs when Ror2 is depleted in these breast cancer cells. Together, these studies provide new insight into how canonical and alternative Wnt pathways coordinate cell-cell and cell-ECM exchanges during breast cancer progression and metastasis. Supported by grant NIH-CA016303 Citation Format: Hongjiang Si, Na Zhao, Andrea Pedroza, Chad Creighton, Jeffrey Rosen, Kevin Roarty. Non-canonical Wnt/Ror2 signaling regulates tumor cell invasion and dissemination in breast cancer through cell-matrix crosstalk [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-09.

Establishment and Culture of Patient-Derived Breast Organoids.

Breast cancer is a complex disease that has been classified into several different histological and molecular subtypes. Patient-derived breast tumor organoids developed in our laboratory consist of a mix of multiple tumor-derived cell populations, and thus represent a better approximation of tumor cell diversity and milieu than the established 2D cancer cell lines. Organoids serve as an ideal in vitro model, allowing for cell-extracellular matrix interactions, known to play an important role in cell-cell interactions and cancer progression. Patient-derived organoids also have advantages over mouse models as they are of human origin. Furthermore, they have been shown to recapitulate the genomic, transcriptomic as well as metabolic heterogeneity of patient tumors; thus, they are capable of representing tumor complexity as well as patient diversity. As a result, they are poised to provide more accurate insights into target discovery and validation and drug sensitivity assays. In this protocol, we provide a detailed demonstration of how patient-derived breast organoids are established from resected breast tumors (cancer organoids) or reductive mammoplasty-derived breast tissue (normal organoids). This is followed by a comprehensive account of 3D organoid culture, expansion, passaging, freezing, as well as thawing of patient-derived breast organoid cultures.

Periosteal topology creates an osteo-friendly microenvironment for progenitor cells.

The periosteum on the skeletal surface creates a unique micro-environment for cortical bone homeostasis, but how this micro-environment is formed remains a mystery. In our study, we observed the cells in the periosteum presented elongated spindle-like morphology within the aligned collagen fibers, which is in accordance with the differentiated osteoblasts lining on the cortical surface. We planted the bone marrow stromal cells(BMSCs), the regular shaped progenitor cells, on collagen-coated aligned fibers, presenting similar cell morphology as observed in the natural periosteum. The aligned collagen topology induced the elongation of BMSCs, whichfacilitated the osteogenic process. Transcriptome analysis suggested the aligned collagen induced the regular shaped cells to present part of the periosteum derived stromal cells(PDSCs) characteristics by showing close correlation of the two cell populations. In addition, the elevated expression of PDSCs markers in the cells grown on the aligned collagen-coated fibers further indicated the function of periosteal topology in manipulating cells' behavior. Enrichment analysis revealed cell-extracellular matrix interaction was the major pathway initiating this process, which created an osteo-friendly micro-environment as well. At last, we found the aligned topology of collagen induced mechano-growth factor expression as the result of Igf1 alternative splicing, guiding the progenitor cells behavior and osteogenic process in the periosteum. This study uncovers the key role of the aligned topology of collagen in the periosteum and explains the mechanism in creating the periosteal micro-environment, which gives the inspiration for artificial periosteum design.

The Use of Biomaterials in Three-Dimensional Culturing of Cancer Cells.

Cell culture is an important tool in biological research. Most studies use 2D cell culture, but cells grown in 2D cell culture have drawbacks, including limited cell and cell-extracellular matrix interactions, which make it inaccurate to model conditions in vivo. Anticancer drug screening is an important research and development process for developing new drugs. As an experiment to mimic the cancer environment in vivo, several studies have been carried out on 3-dimensional (3D) cell cultures with added biomaterials. The use of hydrogel in 3D culture cells is currently developing. The type of hydrogel used might influence cell morphology, viability, and drug screening outcome. Therefore, this review discusses 3D cell culture research regarding the addition of biomaterials.

An indispensable role of TAZ in anoikis resistance promoted by OTUB1 deubiquitinating enzyme in basal-like triple-negative breast cancer cells

Aggressive cancers, such as triple-negative breast cancer (TNBC), are mostly fatal because of their potential to metastasize to distant organs. Cancer cells acquire various abilities to metastasize, including resistance to anoikis, an apoptotic cell death induced by loss of anchorage to the extracellular matrix. Transcriptional coactivator with PDZ binding motif (TAZ) and Yes-associated protein (YAP), the downstream effectors of the Hippo pathway, regulate cell- and tissue-level architectures by responding to mechanical microenvironments of cells, including the cell–extracellular matrix interaction. The Hippo pathway is frequently disrupted in cancer cells, and TAZ and YAP are irrelevantly activated, potentially resulting in anchorage-independent survival/proliferation of cancer cells and metastatic progression. The study aims to investigate the roles of TAZ and YAP in anoikis resistance in basal-like (BL) TNBC cells, which comprise a major subtype (>70%) of TNBC. We found that TAZ and YAP had nonredundant roles in anchorage-independent cancer cell survival or anoikis resistance. Particularly, TAZ was indispensable for anoikis resistance in BL-TNBC cells but not for survival of non-transformed mammary epithelial cells (MECs). In contrast, YAP, a paralog of TAZ, was indispensable for survival of both non-transformed MECs and cancer cells. Therefore, TAZ might be a preferable therapeutic target against dissemination of aggressive cancer cells without killing normal cells. Interestingly, TAZ was abnormally stabilized in BL-TNBC cells under non-adherent conditions, which promoted anoikis resistance. Furthermore, OTUB1, a deubiquitinating enzyme, was responsible for the stabilization of TAZ in detached BL-TNBC cells. Importantly, simultaneous high expression of TAZ and OTUB1 was associated with poor prognosis in BC. Thus, OTUB1 has emerged as a potentially druggable target. Successful inhibition of OTUB1 enzymatic activity is expected to downregulate TAZ and eventually prevents metastasis of aggressive cancers, such as BL-TNBC.

Spheroid Engineering in Microfluidic Devices.

Two-dimensional (2D) cell culture techniques are commonly employed to investigate biophysical and biochemical cellular responses. However, these culture methods, having monolayer cells, lack cell-cell and cell-extracellular matrix interactions, mimicking the cell microenvironment and multicellular organization. Three-dimensional (3D) cell culture methods enable equal transportation of nutrients, gas, and growth factors among cells and their microenvironment. Therefore, 3D cultures show similar cell proliferation, apoptosis, and differentiation properties to in vivo. A spheroid is defined as self-assembled 3D cell aggregates, and it closely mimics a cell microenvironment in vitro thanks to cell-cell/matrix interactions, which enables its use in several important applications in medical and clinical research. To fabricate a spheroid, conventional methods such as liquid overlay, hanging drop, and so forth are available. However, these labor-intensive methods result in low-throughput fabrication and uncontrollable spheroid sizes. On the other hand, microfluidic methods enable inexpensive and rapid fabrication of spheroids with high precision. Furthermore, fabricated spheroids can also be cultured in microfluidic devices for controllable cell perfusion, simulation of fluid shear effects, and mimicking of the microenvironment-like in vivo conditions. This review focuses on recent microfluidic spheroid fabrication techniques and also organ-on-a-chip applications of spheroids, which are used in different disease modeling and drug development studies.

Reduced Cell-ECM Interactions in the EpiSC Colony Center Cause Heterogeneous Differentiation.

Mechanoregulation of cell-extracellular matrix (ECM) interactions are crucial for dictating pluripotent stem cell differentiation. However, not all pluripotent cells respond homogeneously which results in heterogeneous cell populations. When cells, such as mouse epiblast stem cells (EpiSCs), are cultured in clusters, the heterogeneity effect during differentiation is even more pronounced. While past studies implicated variations in signaling pathways to be the root cause of heterogeneity, the biophysical aspects of differentiation have not been thoroughly considered. Here, we demonstrate that the heterogeneity of EpiSC differentiation arises from differences in the colony size and varying degrees of interactions between cells within the colonies and the ECM. Confocal imaging demonstrates that cells in the colony periphery established good contact with the surface while the cells in the colony center were separated by an average of 1-2 µm from the surface. Traction force measurements of the cells within the EpiSC colonies show that peripheral cells generate large tractions while the colony center cells do not. A finite element modeling of EpiSC colonies shows that tractions generated by the cells at the colony periphery lift off the colony center preventing the colony center from undergoing differentiation. Together, our results demonstrate a biophysical regulation of heterogeneous EpiSC colony differentiation.

The Tumor Microenvironment in Tumorigenesis and Therapy Resistance Revisited.

Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis, and highlight various ways through which tumor cells reprogram normal cells into phenotypes that are pro-tumorigenic, including cancer associated- fibroblasts, -macrophages and -endothelial cells. Tumor cells secrete numerous factors leading to the transformation of a previously anti-tumorigenic environment into a pro-tumorigenic environment. Once formed, solid tumors continue to interact with various stromal cells, including local and infiltrating fibroblasts, macrophages, mesenchymal stem cells, endothelial cells, pericytes, and secreted factors and the ECM within the tumor microenvironment (TME). The TME is key to tumorigenesis, drug response and treatment outcome. Importantly, stromal cells and secreted factors can initially be anti-tumorigenic, but over time promote tumorigenesis and induce therapy resistance. To counter hypoxia, increased angiogenesis leads to the formation of new vascular networks in order to actively promote and sustain tumor growth via the supply of oxygen and nutrients, whilst removing metabolic waste. Angiogenic vascular network formation aid in tumor cell metastatic dissemination. Successful tumor treatment and novel drug development require the identification and therapeutic targeting of pro-tumorigenic components of the TME including cancer-associated- fibroblasts (CAFs) and -macrophages (CAMs), hypoxia, blocking ECM-receptor interactions, in addition to the targeting of tumor cells. The reprogramming of stromal cells and the immune response to be anti-tumorigenic is key to therapeutic success. Lastly, this review highlights potential TME- and hypoxia-centered therapies under investigation.

Three-Dimensional Cell Culture Methods in Infectious Diseases and Vaccine Research

Cells, the basic structures of all living organisms, reside in an extracellular matrix consisting of a complex three-dimensional architecture and interact with neighboring cells both mechanically and biochemically. Cell–cell and cell–extracellular matrix interactions form a three-dimensional network that maintains tissue specificity and homeostasis. Important biological processes in a cell cycle are regulated by principles organized by the microenvironment surrounding the cell. The conventional cell culture methods failed to mimic in vivo-like structural organization and are insufficient to examine features such as connectivity of cells, cellular morphology, viability, proliferation, differentiation, gene and protein expression, response to stimuli, and drug/vaccine metabolism. Three-dimensional cell culture studies are very important in terms of reducing the need for in vivo studies and creating an intermediate step. Three-dimensional cell culture methods have attracted attention in the literature in recent years, especially in examining the cellular distribution of organs in the presence of infectious diseases, elucidating the pathogenic mechanism of action of viruses, and examining virus–host interactions. This review highlights the use and importance of three-dimensional cell culture methods in the design and characterization of novel vaccine formulations and the pathogenesis of infectious diseases.

Understanding cell-extracellular matrix interactions for topology-guided tissue regeneration

Tissues are made up of cells and the extracellular matrix (ECM) which surrounds them. These cells and tissues are actively adaptable to enduring significant stress that occurs in daily life. This astonishing mechanical stress develops due to the interaction between the live cells and the non-living ECM. Cells in the matrix microenvironment can sense the signals and forces produced and initiate a signaling cascade that plays a crucial role in the body’s normal functioning and influences various properties of the native cells, including growth, proliferation, and differentiation. However, the matrix’s characteristic features also impact the repair and regeneration of the damaged tissues. The current study reviewed how the cell-ECM interaction regulates cellular behavior and physicochemical properties. Herein, we have described the response of cells to mechanical stresses, the importance of substrate stiffness and geometry in tissue regeneration, and the development of scaffolds to mimic the nature of native ECM in 3D for tissue engineering applications has also been discussed. Finally, the study summarizes the conclusions and promising prospects based on the cell-ECM interplay.

Di-(2-ethylhexyl) phthalate exposure impairs cortical development in hESC-derived cerebral organoids

Di-(2-ethylhexyl) phthalate (DEHP), a ubiquitous environmental endocrine disruptor, is widely used in consumer products. Increasing evidence implies that DEHP influences the early development of the human brain. However, it lacks a suitable model to evaluate the neurotoxicity of DEHP. Using an established human cerebral organoid model, which reproduces the morphogenesis of the human cerebral cortex at the early stage, we demonstrated that DEHP exposure markedly suppressed cell proliferation and increased apoptosis, thus impairing the morphogenesis of the human cerebral cortex. It showed that DEHP exposure disrupted neurogenesis and neural progenitor migration, confirmed by scratch assay and cell migration assay in vitro. These effects might result from DEHP-induced dysplasia of the radial glia cells (RGs), the fibers of which provide the scaffolds for cell migration. RNA sequencing (RNA-seq) analysis of human cerebral organoids showed that DEHP-induced disorder in cell-extracellular matrix (ECM) interactions might play a pivotal role in the neurogenesis of human cerebral organoids. The present study provides direct evidence of the neurodevelopmental toxicity of DEHP after prenatal exposure.

Gold nanostructure-integrated conductive microwell arrays for uniform cancer spheroid formation and electrochemical drug screening

Cancer spheroids, which mimic distinct cell-to-cell and cell-extracellular matrix interactions of solid tumors in vitro, have emerged as a promising tumor model for drug screening. However, owing to the unique characteristics of spheroids composed of three-dimensionally densely-packed cells, the precise characterizations of cell viability and function with conventional colorimetric assays are challenging. Herein, we report gold nanostructure-integrated conductive microwell arrays (GONIMA) that enable both highly efficient uniform cancer spheroid formation and precise electrochemical detection of cell viability. A nanostructured gold on indium tin oxide (ITO) substrate facilitated the initial cell aggregation and further 3D cell growth, while the non-cytophilic polymer microwell arrays restricted the size and shape of the spheroids. As a result, approximately 150 human glioblastoma spheroids were formed on a chip area of 1.13 cm2 with an average diameter of 224 μm and a size variation of only 5% (±11.36 μm). The high uniformity of cancer spheroids contributed to the stability of electrical signals measuring cell viability. Using the fabricated GONIMA, the effects of a representative chemotherapeutic agent, hydroxyurea, on the glioblastoma spheroids were precisely monitored under conditions of varying drug concentrations (0–0.3 mg/mL) and incubation times (24–48 h). Therefore, we conclude that the newly developed platform is highly useful for rapid and precise in vitro drug screening, as well as for the pharmacokinetic analyses of specific drugs using 3D cellular cancer models.

Integrinβ1/FAK/ERK signalling pathway is essential for Chinese mitten crab Eriocheir sinensis hemocyte survival

Integrins are cellular adhesion molecules that mediate cell-cell, cell-extracellular matrix, and cell-pathogen interactions. Integrins can stimulate various signaling pathways by binding to different ligands, thereby exerting immunological functions. While integrins have been found to primarily play a role in bacterial agglutination, phagocytosis, and inhibition of apoptosis in invertebrates, the specific signaling pathway and mechanism of action remain unclear. In vertebrates, β1 integrin and extracellular matrix interactions can associate with focal adhesion kinase (FAK) to initiate MAPK/ERK signaling and regulate cell survival; however, in invertebrates (e.g., Chinese mitten crab), the mechanisms of integrins are poorly understood. The purpose of this study was to investigate whether integrinβ1/FAK activation of the MAPK/ERK pathway regulates hemocyte survival and the associated mechanism. Treatment with an integrinβ1 inhibitor RGD (a conserved tripeptide Arg-Gly-Asp), decreased the levels of FAK and ERK expression and phosphorylation, followed by an intensification of apoptosis. Similar results were obtained following siRNA knockdown of integrinβ1 expression. We further found that the attenuation of ERK phosphorylation enhanced the level of Caspase-3 expression. Together, these findings suggest that integrinβ1 activates the FAK/ERK signaling cascade and is involved in the survival of Chinese mitten crab hemocytes.

Cell Sheet Technology as an Engineering-Based Approach to Bone Regeneration.

Bone defects that are congenital or the result of infection, malignancy, or trauma represent a challenge to the global healthcare system. To address this issue, multiple research groups have been developing novel cell sheet technology (CST)-based approaches to promote bone regeneration. These methods hold promise for use in regenerative medicine because they preserve cell-cell contacts, cell-extracellular matrix interactions, and the protein makeup of cell membranes. This review introduces the concept and preparation system of the cell sheet (CS), explores the application of CST in bone regeneration, highlights the current states of the bone regeneration via CST, and offers perspectives on the challenges and future research direction of translating current knowledge from the lab to the clinic.

Cells, growth factors and biomaterials used in tissue engineering for hair follicles regeneration.

Alopecia is a common and distressing medical condition that has affected a majority of people worldwide, which leads to great effects on the quality of life and self-esteem. Numerous treatments had been used to cure alopecia, including hair growth stimulants, herbal products, and hair transplantation. However, these treatments have their side effects, such as hypertrichosis, edema, and even cardiovascular adverse effects, which lead to the urgent requirement to explore a new hair-follicle (HF) regeneration approach. Tissue engineering could be the potential way for HF regeneration by simulating the epithelial-mesenchymal interaction and cell-extracellular matrix interactions. This review summarized the potential cells that are used in tissue engineering, commonly used tissue engineering techniques, and most importantly, the biomaterials that have been applied for invitro three-dimensional cell culture or invivo co-transplantation in HF regeneration. The literature shows that advances in this field toward functional HF development have progressively increased. Although the clinical application of biomaterial co-transplantation for HF regeneration still faces various challenges, numerous studies have proved that this is a promising direction that could be achieved in the future.

Notch-dependent Abl signaling regulates cell motility during ommatidial rotation in Drosophila.

A collective cell motility event that occurs during Drosophila eye development, ommatidial rotation (OR), serves as a paradigm for signaling-pathway-regulated directed movement of cell clusters. OR is instructed by the EGFR and Notch pathways and Frizzled/planar cell polarity (Fz/PCP) signaling, all of which are associated with photoreceptor R3 and R4 specification. Here, we show that Abl kinase negatively regulates OR through its activity in the R3/R4 pair. Abl is localized to apical junctional regions in R4, but not in R3, during OR, and this apical localization requires Notch signaling. We demonstrate that Abl and Notch interact genetically during OR, and Abl co-immunoprecipitates in complexes with Notch in eye discs. Perturbations of Abl interfere with adherens junctional organization of ommatidial preclusters, which mediate the OR process. Together, our data suggest that Abl kinase acts directly downstream of Notch in R4 to fine-tune OR via its effect on adherens junctions.

Glucose-Dependent Insulin Secretion from β Cell Spheroids Is Enhanced by Embedding into Softer Alginate Hydrogels Functionalised with RGD Peptide.

Type 1 diabetes results from the loss of pancreatic β cells, reduced insulin secretion and dysregulated blood glucose levels. Replacement of these lost β cells with stem cell-derived β cells, and protecting these cells within macro-device implants is a promising approach to restore glucose homeostasis. However, to achieve this goal of restoration of glucose balance requires work to optimise β cell function within implants. We know that native β cell function is enhanced by cell-cell and cell-extracellular matrix interactions within the islets of Langerhans. Reproducing these interactions in 2D, such as culture on matrix proteins, does enhance insulin secretion. However, the impact of matrix proteins on the 3D organoids that would be in implants has not been widely studied. Here, we use native β cells that are dispersed from islets and reaggregated into small spheroids. We show these β cell spheroids have enhanced glucose-dependent insulin secretion when embedded into softer alginate hydrogels conjugated with RGD peptide (a common motif in extracellular matrix proteins). Embedding into alginate-RGD causes activation of integrin responses and repositioning of liprin, a protein that controls insulin secretion. We conclude that insulin secretion from β cell spheroids can be enhanced through manipulation of the surrounding environment.

Roles of intercellular cell adhesion molecule-1 (ICAM-1) in colorectal cancer: expression, functions, prognosis, tumorigenesis, polymorphisms and therapeutic implications.

Colorectal cancer (CRC) is a major global health problem and one of the major causes of cancer-related death worldwide. It is very important to understand the pathogenesis of CRC for early diagnosis, prevention strategies and identification of new therapeutic targets. Intercellular adhesion molecule-1 (ICAM-1, CD54) displays an important role in the the pathogenesis of CRC. It is a cell surface glycoprotein of the immunoglobulin (Ig) superfamily and plays an essential role in cell-cell, cell-extracellular matrix interaction, cell signaling and immune process. It is also expressed by tumor cells and modulates their functions, including apoptosis, cell motility, invasion and angiogenesis. The interaction between ICAM-1 and its ligand may facilitate adhesion of tumor cells to the vascular endothelium and subsequently in the promotion of metastasis. ICAM-1 expression determines malignant potential of cancer. In this review, we will discuss the expression, function, prognosis, tumorigenesis, polymorphisms and therapeutic implications of ICAM-1 in CRC.