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Stem cell functionality is microenvironmentally defined during tumour expansion and therapy response in colon cancer.

ABSTRACT: Solid malignancies have been speculated to depend on cancer stem cells (CSCs) for expansion and relapse after therapy. Here we report on quantitative analyses of lineage tracing data from primary colon cancer xenograft tissue to assess CSC functionality in a human solid malignancy. The temporally obtained clone size distribution data support a model in which stem cell function in established cancers is not intrinsically, but is entirely spatiotemporally orchestrated. Functional stem cells that drive tumour expansion predominantly reside at the tumour edge, close to cancer-associated fibroblasts. Hence, stem cell properties change in time depending on the cell location. Furthermore, although chemotherapy enriches for cells with a CSC phenotype, in this context functional stem cell properties are also fully defined by the microenvironment. To conclude, we identified osteopontin as a key cancer-associated fibroblast-produced factor that drives in situ clonogenicity in colon cancer.

SUBMITTER: Lenos KJ

PROVIDER: S-EPMC6163039 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Stem cell functionality is microenvironmentally defined during tumour expansion and therapy response in colon cancer.

Lenos Kristiaan J KJ Miedema Daniël M DM Lodestijn Sophie C SC Nijman Lisanne E LE van den Bosch Tom T Romero Ros Xavier X Lourenço Filipe C FC Lecca Maria C MC van der Heijden Maartje M van Neerven Sanne M SM van Oort Anita A Leveille Nicolas N Adam Ronja S RS de Sousa E Melo Felipe F Otten Joy J Veerman Patrick P Hypolite Guillaume G Koens Lianne L Lyons Scott K SK Stassi Giorgio G Winton Douglas J DJ Medema Jan Paul JP Morrissey Edward E Bijlsma Maarten F MF Vermeulen Louis L

Nature cell biology 20180903 10

Solid malignancies have been speculated to depend on cancer stem cells (CSCs) for expansion and relapse after therapy. Here we report on quantitative analyses of lineage tracing data from primary colon cancer xenograft tissue to assess CSC functionality in a human solid malignancy. The temporally obtained clone size distribution data support a model in which stem cell function in established cancers is not intrinsically, but is entirely spatiotemporally orchestrated. Functional stem cells that d ...[more]

PMID: 30177776

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Project description:Granulocytopenia frequently occurs in alcohol abusers with severe bacterial infection, which strongly correlates with poor clinical outcome. Knowledge of the molecular mechanisms underlying the granulopoietic response to bacterial infection remains limited. This study investigated the involvement of stem cell antigen-1 expression by granulocyte lineage-committed progenitors in the granulopoietic response to septicemia and how alcohol affected this response.: Laboratory investigation.University laboratory.Male Balb/c mice.Thirty mins after intraperitoneal injection of alcohol (20% ethanol in saline at 5 g of ethanol/kg) or saline, mice received an intravenous Escherichia coli challenge.E. coli septicemia activated stem cell antigen-1 expression by marrow immature granulocyte differentiation antigen-1 precursors which correlated with an increase in proliferation, granulocyte macrophage colony-forming unit production, and expansion of this granulopoietic precursor cell pool. Acute alcohol treatment suppressed stem cell antigen-1 activation and inhibited the infection-induced increases in proliferation, granulocyte macrophage colony-forming unit production, and expansion the of immature granulocyte differentiation antigen-1 precursor cell population. Consequently, recovery of the marrow mature granulocyte differentiation antigen-1 cell population after E. coli challenge was impaired. Stem cell antigen-1 was induced in sorted granulocyte differentiation antigen-1, stem cell antigen-1' cells by lipopolysaccharide-stimulated C-Jun kinase activation that was also inhibited by alcohol. Furthermore, stem cell antigen-1 knockout mice failed to expand the marrow immature granulocyte differentiation antigen-1 cell pool and demonstrated fewer newly produced granulocytes in the circulation after the E. coli challenge.Alcohol suppresses the stem cell antigen-1 response in granulocyte lineage-committed precursors and restricts granulocyte production during septicemia, which may serve as a novel mechanism underlying impaired host defense in alcohol abusers.

Project description:Human embryonic stem (hES) cells are pluripotent, capable of differentiating into any cell type of the body, and therefore have the ability to provide insights into mechanisms of human development and disease, as well as to provide a potentially unlimited supply of cells for cell-based therapy and diagnostics. Knowledge of the adhesion receptors that hES cells employ to engage extracellular matrix (ECM) proteins is of basic biological interest and can enhance the design of cell culture and implantation systems to enable these biomedical applications. Although hES cells express a variety of cell surface receptors, little is known about which integrins are involved during subculture and passage. Matrigel is broadly used as a cell adhesive matrix for hES cell culture. Here, we sought to identify which integrins hES cells exploit for adhesion to Matrigel-coated surfaces in defined medium conditions. Using RT-PCR, flow cytometry, and fluorescence immunochemistry, we found that numerous integrins were expressed by H1 hES cells; however, antibody blocking assays indicated that only alpha(v)beta(3), alpha(6), beta(1), and alpha(2)beta(1) played a significant role in the initial adhesion of the hES cells to Matrigel in defined medium conditions. We subsequently identified a cohort of synthetic peptides that, when adsorbed to the culture surface, promoted H1 hES cell attachment and proliferation, as well as maintained a pluripotent phenotype. Peptides designed to engage with alpha(v)beta(3), alpha(6), beta(1), and alpha(2)beta(1) integrins and syndecan-1 were tested both individually and in various combinations. A combination of two integrin-engaging peptides (AG-10, C-16) and one syndecan-engaging peptide (AG-73) was sufficient to promote hES cell adhesion, maintenance, and proliferation. We propose that a specific integrin "fingerprint" is necessary for maintenance of hES cell self-renewal, and synthetic culture systems must capture this engagement profile for hES cells to remain undifferentiated.-Meng, Y., Eshghi, S., Li, Y. J., Schmidt, R., Schaffer, D. V., Healy, K. E. Characterization of integrin engagement during defined human embryonic stem cell culture.

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Stem cell functionality is microenvironmentally defined during tumour expansion and therapy response in colon cancer.

Publications

Stem cell functionality is microenvironmentally defined during tumour expansion and therapy response in colon cancer.

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