Search results for "mesenchymal"

Selective targeting of collagen IV in the cancer cell microenvironment reduces tumor burden

2018

Goodpasture antigen-binding protein (GPBP) is an exportable1 Ser/Thr kinase that induces collagen IV expansion and has been associated with chemoresistance following epithelial-to-mesenchymal transition (EMT). Here we demonstrate that cancer EMT phenotypes secrete GPBP (mesenchymal GPBP) which displays a predominant multimeric oligomerization and directs the formation of previously unrecognized mesh collagen IV networks (mesenchymal collagen IV). Yeast two-hybrid (YTH) system was used to identify a 260SHCIE264 motif critical for multimeric GPBP assembly which then facilitated design of a series of potential peptidomimetics. The compound 3-[4''-methoxy-3,2'-dimethyl-(1,1';4',1'')terphenyl-2'…

Intratumoral Heterogeneity in EGFR-Mutant NSCLC Results in Divergent Resistance Mechanisms in Response to EGFR Tyrosine Kinase Inhibition

2015

Abstract Non–small cell lung cancers (NSCLC) that have developed resistance to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI), including gefitinib and erlotinib, are clinically linked to an epithelial-to-mesenchymal transition (EMT) phenotype. Here, we examined whether modulating EMT maintains the responsiveness of EGFR-mutated NSCLCs to EGFR TKI therapy. Using human NSCLC cell lines harboring mutated EGFR and a transgenic mouse model of lung cancer driven by mutant EGFR (EGFR-Del19-T790M), we demonstrate that EGFR inhibition induces TGFβ secretion followed by SMAD pathway activation, an event that promotes EMT. Chronic exposure of EGFR-mutated NSCLC cells to TGFβ was sufficient to ind…

A quest for initiating cells of head and neck cancer and their treatment.

2010

The biology of head and neck squamous cell carcinomas (HNSCC) and other cancers have been related to cancer stem-like cells (CSC). Specific markers, which vary considerably depending on tumor type or tissue of origin, characterize CSC. CSC are cancer initiating, sustaining and mostly quiescent. Compared to bulk tumors, CSC are less sensitive to chemo- and radiotherapy and may have low immunogenicity. Therapeutic targeting of CSC may improve clinical outcome. HNSCC has two main etiologies: human papillomavirus, a virus infecting epithelial stem cells, and tobacco and alcohol abuse. Here, current knowledge of HNSCC-CSC biology is reviewed and parallels to CSC of other origin are drawn where n…

RELEVANCE OF MESENCHYMAL THYMUS CELLS (MC) FOR ACCEPTANCE OF ALLOGENEIC MATURE THYMUS GRAFTS AND INDUCTION OF ALLOTOLERANCE IN NUDE MICE

1984

Allogeneic thymus (aTh) from an adult immunocompetent donor cannot be transplanted successfully in thymusless nude mice even if the graft is irradiated. The graft is destroyed for unknown reasons and no immunocompetence is achieved in the host. Two approaches were established to achieve acceptance of aTh. In experiment 1, mature aTh was transplanted in nude mice, after specific tolerance to the recipient was induced in the donor during the neonatal period. This resulted in acceptance of the aTh, immunological reconstitution and tolerance to the donor's and recipient's MHC-haplotype as proved by skin-grafts and MLC. In experiment 2, neonatal thymus was grafted into allogeneic nude mice and r…

Paracrine in vivo inhibitory effects of adipose tissue–derived mesenchymal stromal cells in the early stages of the acute inflammatory response

2015

Abstract Background aims Excessive or unresolved inflammation leads to tissue lesions. Adipose tissue–derived mesenchymal stromal cells (AMSCs) have shown protective effects that may be dependent on the modulation of inflammation by secreted factors. Methods We used the zymosan-induced mouse air pouch model at two time points (4 h and 18 h) to evaluate the in vivo effects of AMSCs and their conditioned medium (CM) on key steps of the early inflammatory response. We assessed the effects of AMSCs and CM on leukocyte migration and myeloperoxidase activity. The levels of chemokines, cytokines and eicosanoids in exudates were measured by use of enzyme-linked immunoassay or radio-immunoassay. In …

CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC

2019

Abstract Although EGFR mutant–selective tyrosine kinase inhibitors (TKI) are clinically effective, acquired resistance can occur by reactivating ERK. We show using in vitro models of acquired EGFR TKI resistance with a mesenchymal phenotype that CXCR7, an atypical G protein-coupled receptor, activates the MAPK–ERK pathway via β-arrestin. Depletion of CXCR7 inhibited the MAPK pathway, significantly attenuated EGFR TKI resistance, and resulted in mesenchymal-to-epithelial transition. CXCR7 overexpression was essential in reactivation of ERK1/2 for the generation of EGFR TKI–resistant persister cells. Many patients with non–small cell lung cancer (NSCLC) harboring an EGFR kinase domain mutatio…

Isolation and phenotypical characterization of mesenchymal stem cells from the Wharton's jelly of pre-term human umbilical cord.

2014

Innate Sensing by Mesenchymal TLR4/MyD88 Signals Promotes Spontaneous Intestinal Tumorigenesis

2018

MyD88, an adaptor molecule downstream of innate pathways, plays a significant tumor-promoting role in sporadic intestinal carcinogenesis, which is dependent on its function in the stroma. Here, we show that deletion of MyD88 in intestinal mesenchymal cells (IMCs) significantly reduces Apc-mediated intestinal tumorigenesis. This phenotype is associated with decreased epithelial cell proliferation, altered inflammatory and tumorigenic immune cell infiltration, and modified gene expression similar to complete MyD88 knockout mice. Genetic deletion of TLR4, but not IL1R, in IMCs led to altered molecular profiles and reduction of intestinal tumors similar to the MyD88 deficiency. Ex vivo analysis…

Transcriptional profiling of circulating tumor cells in multiple myeloma: a new model to understand disease dissemination

2020

The reason why a few myeloma cells egress from the bone marrow (BM) into peripheral blood (PB) remains unknown. Here, we investigated molecular hallmarks of circulating tumor cells (CTCs) to identify the events leading to myeloma trafficking into the bloodstream. After using next-generation flow to isolate matched CTCs and BM tumor cells from 32 patients, we found high correlation in gene expression at single-cell and bulk levels (r ≥ 0.94, P = 10−16), with only 55 genes differentially expressed between CTCs and BM tumor cells. CTCs overexpressed genes involved in inflammation, hypoxia, or epithelial–mesenchymal transition, whereas genes related with proliferation were downregulated in CTCs…

Biostable Scaffolds of Polyacrylate Polymers Implanted in the Articular Cartilage Induce Hyaline-Like Cartilage Regeneration in Rabbits

2017

[EN] Purpose: To study the influence of scaffold properties on the organization of ¿in vivo¿ cartilage regeneration. Our hypothesis is that stress transmission to the cells seeded inside the scaffold pores or surrounding it, which is highly dependent on the scaffold properties, determine differentiation of both mesenchymal cells and dedifferentiated autologous chondrocytes. Methods: Four series of porous scaffolds made of different polyacrylate polymers, previously seeded with cultured rabbit chondrocytes or without cells preseeded, were implanted in cartilage defects in rabbits. Subchondral bone was always injured during the surgery in order to allow blood to reach the implantation site an…