Gene expression profiling of the functionally distinct human bone marrow stromal cell lines HS-5 and HS-27a

Graf, Lynn; Iwata, Mineo; Torok‐Storb, Beverly

doi:10.1182/blood-2002-03-0844

Cited by 66 publications

(82 citation statements)

References 5 publications

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“…HS5 cells express approximately 167-fold more IL-6 transcript than HS27a cells, with IL-6 being the third most highly differentially expressed gene in HS5 cells when compared with HS27a cells. 21 Consistent with those results, we found by western blot that HS5 conditioned media contained comparatively high levels of IL-6 protein (approximately four-fold more IL-6 protein than media supplemented with 50 ng/ml recombinant human IL-6 protein) that was not detectable in the conditioned media from HS27a cells, nor in media from C4-2 or C4-2B cells ( Fig. 2A).…”

Section: Resultssupporting

confidence: 77%

Interleukin-6

Delk

Farach-Carson

2012

Autophagy

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Keywords: bone metastatic prostate cancer, interleukin-6, paracrine signaling, neuroendocrine differentiation, autophagy Abbreviations: BMSC, bone marrow stromal cell; CM, conditioned media; CQ, chloroquine; IL-6, interleukin-6; LC3, microtubule-associated protein 1 light chain 3; NE, neuroendocrine; NED, neuroendocrine differentiation; PCa, prostate cancer; PE, phosphatidylethanolamine; STAT3, signal transducer and activator of transcription 3Autophagy reallocates nutrients and clears normal cells of damaged proteins and organelles. In the context of metastatic disease, invading cancer cells hijack autophagic processes to survive and adapt in the host microenvironment. We sought to understand how autophagy is regulated in the metastatic niche for prostate cancer (PCa) cells where bone marrow stromal cell (BMSC) paracrine signaling induces PCa neuroendocrine differentiation (NED). In PCa, this transdifferentiation of metastatic PCa cells to neuronal-like cells correlates with advanced disease. Because autophagy provides a survival advantage for cancer cells and promotes cell differentiation, we hypothesized that autophagy mediates PCa NED in the bone. Thus, we determined the ability of paracrine factors in conditioned media (CM) from two separate BMSC subtypes, HS5 and HS27a, to induce autophagy in C4-2 and C4-2B bone metastatic PCa cells by characterizing the autophagy marker, LC3. Unlike HS27a CM, HS5 CM induced LC3 accumulation in PCa cells, suggesting autophagy was induced and indicating that HS5 and HS27a secrete a different milieu of paracrine factors that influence PCa autophagy. We identified interleukin-6 (IL-6), a cytokine more highly expressed in HS5 cells than in HS27a cells, as a paracrine factor that regulates PCa autophagy. Pharmacological inhibition of STAT3 activity did not attenuate LC3 accumulation, implying that IL-6 regulates NED and autophagy through different pathways. Finally, chloroquine inhibition of autophagic flux blocked PCa NED; hence autophagic flux maintains NED. Our studies imply that autophagy is cytoprotective for PCa cells in the bone, thus targeting autophagy is a potential therapeutic strategy.

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Section: Resultssupporting

confidence: 77%

Interleukin-6

Delk

Farach-Carson

2012

Autophagy

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“…These two clusters are associated primarily by RAB11A/BECN1, CLTC/BECN1, ARPC5/CLN3, and SH3GLB1/ MAP1LC3B relationships, as well as less heavily weighted links through DPM1 and PSMC2. The four primary relationships are driven by a wide variety of microarray correlations, led by data sets investigating retinal pigment epithelium (Tian et al 2004), macrophage infection (Detweiler et al 2001), bone marrow (Graf et al 2002), and DNA damage (Rieger and Chu 2004). The secondary relationships are also predicted based on diverse microarray data and information from the GSEA gene sets (Subramanian et al 2005).…”

Section: Functional Associations: Genetic Disorders and Biological Prmentioning

confidence: 99%

Exploring the human genome with functional maps

Huttenhower¹,

Haley²,

Hibbs³

et al. 2009

Genome Res.

190

249

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Human genomic data of many types are readily available, but the complexity and scale of human molecular biology make it difficult to integrate this body of data, understand it from a systems level, and apply it to the study of specific pathways or genetic disorders. An investigator could best explore a particular protein, pathway, or disease if given a functional map summarizing the data and interactions most relevant to his or her area of interest. Using a regularized Bayesian integration system, we provide maps of functional activity and interaction networks in over 200 areas of human cellular biology, each including information from ∼30,000 genome-scale experiments pertaining to ∼25,000 human genes. Key to these analyses is the ability to efficiently summarize this large data collection from a variety of biologically informative perspectives: prediction of protein function and functional modules, cross-talk among biological processes, and association of novel genes and pathways with known genetic disorders. In addition to providing maps of each of these areas, we also identify biological processes active in each data set. Experimental investigation of five specific genes, AP3B1, ATP6AP1, BLOC1S1, LAMP2, and RAB11A, has confirmed novel roles for these proteins in the proper initiation of macroautophagy in amino acid-starved human fibroblasts. Our functional maps can be explored using HEFalMp (Human Experimental/Functional Mapper), a web interface allowing interactive visualization and investigation of this large body of information.

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“…Human HS27 stromal cells 38 were transduced with lentiviral vector containing hTSLP (+T stroma) or with control vector (-T stroma). Culture supernatant collected from stroma after the initial transduction showed hTSLP levels of approximately 500 pg/mL ( Figure 2B, Transduction 1).…”

Section: Engineering Xenograft Mice To Express Normal Serum Levels Ofmentioning

confidence: 99%

A novel xenograft model to study the role of TSLP-induced CRLF2 signals in normal and malignant human B lymphopoiesis

et al. 2015

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T hymic stromal lymphopoietin (TSLP) stimulates in vitro proliferation of human fetal B-cell precursors. However, its in vivo role during normal human B lymphopoiesis is unknown. Genetic alterations that cause overexpression of its receptor component, cytokine receptor-like factor 2 (CRLF2), lead to high-risk B-cell acute lymphoblastic leukemia implicating this signaling pathway in leukemogenesis. We show that mouse thymic stromal lymphopoietin does not stimulate the downstream pathways (JAK/STAT5 and PI3K/AKT/mTOR) activated by the human cytokine in primary high-risk leukemia with overexpression of the receptor component. Thus, the utility of classic patient-derived xenografts for in vivo studies of this pathway is limited. We engineered xenograft mice to produce human thymic stromal lymphopoietin (+T mice) by injection with stromal cells transduced to express the cytokine. Control (-T) mice were produced using stroma transduced with control vector. Normal levels of human thymic stromal lymphopoietin were achieved in sera of +T mice, but were undetectable in -T mice. Patient-derived xenografts generated from +T as compared to -T mice showed a 3-6-fold increase in normal human B-cell precursors that was maintained through later stages of B-cell development. Gene expression profiles in high-risk B-cell acute lymphoblastic leukemia expanded in +T mice indicate increased mTOR pathway activation and are more similar to the original patient sample than those from -T mice. +T/-T xenografts provide a novel pre-clinical model for understanding this pathway in B lymphopoiesis and identifying treatments for high-risk B-cell acute lymphoblastic leukemia with overexpression of cytokine-like factor receptor 2.

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Gene expression profiling of the functionally distinct human bone marrow stromal cell lines HS-5 and HS-27a

Abstract: this novel approach to allogeneic transplantation. We believe that it is important to promote an evidence-based evolutionary approach, rather than a creationist approach, to transplantation research.

Cited by 66 publications

References 5 publications

Interleukin-6

Interleukin-6

Exploring the human genome with functional maps

A novel xenograft model to study the role of TSLP-induced CRLF2 signals in normal and malignant human B lymphopoiesis

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