Bone morphogenetic protein receptor inhibitors suppress the growth of glioblastoma cells.

Glioblastomas (GBMs) are aggressive brain tumors that are resistant to chemotherapy and radiation. Bone morphogenetic protein (BMP) ligand BMP4 is being examined as a potential therapeutic for GBMs because it induces differentiation of cancer stem cells (CSCs) to an astrocyte phenotype. ID1 is reported to promote self-renewal and inhibit CSC differentiation.

Single-cell mechanical analysis and tension quantification via electrodeformation relaxation.

The mechanical behavior and cortical tension of single cells are analyzed using electrodeformation relaxation. Four types of cells, namely, MCF-10A, MCF-7, MDA-MB-231, and GBM, are studied, with pulse durations ranging from 0.01 to 10 s.

Plexin-B2 facilitates glioblastoma infiltration by modulating cell biomechanics.

Infiltrative growth is a major cause of high lethality of malignant brain tumors such as glioblastoma (GBM). We show here that GBM cells upregulate guidance receptor Plexin-B2 to gain invasiveness. Deletion of Plexin-B2 in GBM stem cells limited tumor spread and shifted invasion paths from axon fiber tracts to perivascular routes.

Teaching an Old Drug New Tricks: Dexamethasone as an In Vivo Inhibitor of Glioblastoma Dispersal.

Identifying drugs that can mitigate dispersal of glioblastoma cells, particularly after patients undergo radiotherapy and concomitant chemotherapy, may increase the length of time to recurrence and improve overall survival. Previous studies have shown that dexamethasone (Dex), a drug currently used to treat brain tumor-related edema, which is tapered immediately after the edema has resolved, induces fibronectin matrix assembly (FNMA) and reduces dispersal of primary human glioblastoma multiforme (GBM) cells in vitro and ex vivo. Here, we utilized an in vivo mouse retina dispersal assay to demonstrate that Dex also inhibits dispersal in vivo.

Coherent Timescales and Mechanical Structure of Multicellular Aggregates.

Multicellular aggregates are an excellent model system to explore the role of tissue biomechanics in specifying multicellular reorganization during embryonic developments and malignant invasion. Tissue-like spheroids, when subjected to a compressive force, are known to exhibit liquid-like behaviors at long timescales (hours), largely because of cell rearrangements that serve to effectively dissipate the applied stress. At short timescales (seconds to minutes), before cell rearrangement, the mechanical behavior is strikingly different.

Dexamethasone-Mediated Upregulation of Calreticulin Inhibits Primary Human Glioblastoma Dispersal Ex Vivo.

Dispersal of Glioblastoma (GBM) renders localized therapy ineffective and is a major cause of recurrence. Previous studies have demonstrated that Dexamethasone (Dex), a drug currently used to treat brain tumor-related edema, can also significantly reduce dispersal of human primary GBM cells from neurospheres. It does so by triggering α5 integrin activity, leading to restoration of fibronectin matrix assembly (FNMA), increased neurosphere cohesion, and reduction of neurosphere dispersal velocity (DV).

Dexamethasone-mediated inhibition of Glioblastoma neurosphere dispersal in an ex vivo organotypic neural assay.

Glioblastoma is highly aggressive. Early dispersal of the primary tumor renders localized therapy ineffective. Recurrence always occurs and leads to patient death.

Inhibition of glioblastoma dispersal by the MEK inhibitor PD0325901.

Background: Dispersal of glioblastoma (GBM) cells leads to recurrence and poor prognosis. Accordingly, molecular pathways involved in dispersal are potential therapeutic targets. The mitogen activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) pathway is commonly dysregulated in GBM, and targeting this pathway with MEK inhibitors has proven effective in controlling tumor growth.

Dexamethasone-Mediated Activation of Fibronectin Matrix Assembly Reduces Dispersal of Primary Human Glioblastoma Cells.

Despite resection and adjuvant therapy, the 5-year survival for patients with Glioblastoma multiforme (GBM) is less than 10%. This poor outcome is largely attributed to rapid tumor growth and early dispersal of cells, factors that contribute to a high recurrence rate and poor prognosis. An understanding of the cellular and molecular machinery that drive growth and dispersal is essential if we are to impact long-term survival.

Measurement of intercellular cohesion by tissue surface tensiometry.

Intercellular adhesion plays a vital role in many biological processes including embryonic development, malignant invasion, and wound healing, and can be manipulated to generate complex structures in tissue engineering applications. Accurate measurement of the strength of intercellular adhesion is not trivial and requires methods rooted in sound physical principles. Tissue surface tensiometry (TST) rigorously quantifies intercellular cohesive energy of 3D tissue-like aggregates under physiological conditions.

Differential adhesion in model systems.

During embryonic development, cells or groups of cells migrate from their locations of origin to assume their correct anatomical positions. Intercellular adhesion plays an active and instructive role in orchestrating this process. Precisely how adhesion provides spatial positioning information is a subject of intense interest.

Tumor cohesion and glioblastoma cell dispersal.

Patients with glioblastoma typically present when tumors are at an advanced stage. Surgical resection, radiotherapy and adjuvant chemotherapy are currently the standard of care for glioblastoma. However, due to the infiltrative and dispersive nature of the tumor, recurrence rate remains high and typically results in very poor prognosis.

Fibronectin matrix-mediated cohesion suppresses invasion of prostate cancer cells.

Background: Invasion is an important early step in the metastatic cascade and is the primary cause of death of prostate cancer patients. In order to invade, cells must detach from the primary tumor. Cell-cell and cell-ECM interactions are important regulators of cohesion--a property previously demonstrated to mediate cell detachment and invasion.

Fibronectin matrix assembly suppresses dispersal of glioblastoma cells.

Glioblastoma (GBM), the most aggressive and most common form of primary brain tumor, has a median survival of 12-15 months. Surgical excision, radiation and chemotherapy are rarely curative since tumor cells broadly disperse within the brain. Preventing dispersal could be of therapeutic benefit.

A simple hanging drop cell culture protocol for generation of 3D spheroids.

Studies of cell-cell cohesion and cell-substratum adhesion have historically been performed on monolayer cultures adherent to rigid substrates. Cells within a tissue, however, are typically encased within a closely packed tissue mass in which cells establish intimate connections with many near-neighbors and with extracellular matrix components. Accordingly, the chemical milieu and physical forces experienced by cells within a 3D tissue are fundamentally different than those experienced by cells grown in monolayer culture.

Measurement of aggregate cohesion by tissue surface tensiometry.

Rigorous measurement of intercellular binding energy can only be made using methods grounded in thermodynamic principles in systems at equilibrium. We have developed tissue surface tensiometry (TST) specifically to measure the surface free energy of interaction between cells. The biophysical concepts underlying TST have been previously described in detail.

Identification of immunoreactive regions of homology between soluble epidermal growth factor receptor and α5-integrin.

Proteins encoded by the epidermal growth factor receptor (EGFR/HER1/ERBB1) gene are being studied as diagnostic, prognostic, and theragnostic biomarkers for numerous human cancers. The clinical application of these tissue/tumor biomarkers has been limited, in part, by discordant results observed for epidermal growth factor receptor (EGFR) expression using different immunological reagents. Previous studies have used EGFR-directed antibodies that cannot distinguish between full-length and soluble EGFR (sEGFR) expression.

Alpha5beta1 integrin-fibronectin interactions specify liquid to solid phase transition of 3D cellular aggregates.

Background: Tissue organization during embryonic development and wound healing depends on the ability of cells on the one hand to exchange adhesive bonds during active rearrangement and on the other to become fixed in place as tissue homeostasis is reached. Cells achieve these contradictory tasks by regulating either cell-cell adhesive bonds, mediated by cadherins, or cell-extracellular matrix (ECM) connections, regulated by integrins. Integrin alpha5beta1 and soluble fibronectin (sFN) are key players in cell-ECM force generation and in ECM polymerization.

Lung self-assembly is modulated by tissue surface tensions.

To identify cell-intrinsic properties that facilitate interaction between epithelial endodermal and mesenchymal mesodermal cells during lung morphogenesis, we developed a model of lung self-assembly that mimics fetal lung formation in structure, polarity, vasculature, and extracellular matrix expression. Three-dimensional pulmonary bodies (PBs) spontaneously self-assemble from single-cell suspensions and exhibit liquid-like properties that allow measurements of compaction rate and cohesion, and that may help to specify cellular self-organization. We hypothesized that changes in one or more of these parameters could potentially explain the lung hypoplasia associated with abnormal lung development.

Coaction of intercellular adhesion and cortical tension specifies tissue surface tension.

In the course of animal morphogenesis, large-scale cell movements occur, which involve the rearrangement, mutual spreading, and compartmentalization of cell populations in specific configurations. Morphogenetic cell rearrangements such as cell sorting and mutual tissue spreading have been compared with the behaviors of immiscible liquids, which they closely resemble. Based on this similarity, it has been proposed that tissues behave as liquids and possess a characteristic surface tension, which arises as a collective, macroscopic property of groups of mobile, cohering cells.

Cellular morphogenesis in silico.

We describe a model that simulates spherical cells of different types that can migrate and interact either attractively or repulsively. We find that both expected morphologies and previously unreported patterns spontaneously self-assemble. Among the newly discovered patterns are a segmented state of alternating discs, and a "shish-kebab" state, in which one cell type forms a ring around a second type.

Quantitative differences in tissue surface tension influence zebrafish germ layer positioning.

This study provides direct functional evidence that differential adhesion, measurable as quantitative differences in tissue surface tension, influences spatial positioning between zebrafish germ layer tissues. We show that embryonic ectodermal and mesendodermal tissues generated by mRNA-overexpression behave on long-time scales like immiscible fluids. When mixed in hanging drop culture, their cells segregate into discrete phases with ectoderm adopting an internal position relative to the mesendoderm.

Tissue surface tensions guide in vitro self-assembly of rodent pancreatic islet cells.

The organization of endocrine cells in pancreatic islets is established through a series of morphogenetic events involving cell sorting, migration, and re-aggregation processes for which intercellular adhesion is thought to play a central role. In animals, these morphogenetic events result in an islet topology in which insulin-secreting cells form the core, while glucagon, somatostatin, and pancreatic polypeptide-secreting cells segregate to the periphery. Isolated pancreatic islet cells self-assemble in vitro into pseudoislets with the same cell type organization as native islets.

Tissue fusion and cell sorting in embryonic development and disease: biomedical implications.

Throughout embryonic development, segregated epithelial and/or mesenchymal cell populations make contact and fuse to shape new tissue units. This process, known as tissue fusion, is a key event in many essential morphogenetic mechanisms and its disruption can lead to congenital malformations. Another mechanism whereby complex tissues can arise involves a cell sorting process in which originally intermixed cells de-mix to generate distinct phases or layers.

Extracellular matrix metalloproteinase inducer (CD147) confers resistance of breast cancer cells to Anoikis through inhibition of Bim.

Overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN or CD147), a member of the immunoglobulin family and a glycoprotein enriched on the surface of tumor cells, promotes invasion, metastasis, and growth and survival of malignant cells and confers resistance to some chemotherapeutic drugs. However, the molecular mechanisms underlying the actions of EMMPRIN are not fully understood. In this study we sought to determine whether EMMPRIN contributes to the malignant phenotype of breast cancer by inhibiting anoikis, a form of apoptosis induced by loss or alteration of cell-cell or cell-matrix anchorage, and to explore the signaling pathways involved.